Randy Lyanne Gollub

• MD, PhD
• Researcher at Massachusetts General Hospital

Migraine is a highly prevalent chronic pain disorder that is characterized by sensitization and dysregulation of the central autonomic nervous system. Interoception is the sensing of signals originating from within the body, and is altered in chronic pain conditions including episodic migraine. The relationship between brain mechanisms of interocep...

Background Previous studies have found widespread pain processing alterations in the brain in chronic low back pain (cLBP) patients. We aimed to (1) identify brain regions showing altered amplitude of low-frequency fluctuations (ALFF) using MRI and use these regions to discriminate cLBP patients from healthy controls (HCs) and (2) identify brain re...

Animal studies suggest that caffeine may interfere with acupuncture analgesia. This study investigated the modulation effect of daily caffeine intake on acupuncture analgesia in 27 healthy subjects using a crossover design. We found that real acupuncture increased pain thresholds compared to sham acupuncture. Further, there was no association betwe...

Acupuncture can provide therapeutic analgesic benefits but is limited by its cost and scheduling difficulties. Guided imagery is a commonly used method for treating many disorders, such as chronic pain. The present study examined a novel intervention for pain relief that integrates acupuncture with imagery called video-guided acupuncture imagery tr...

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizop...

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,...

In this study, we mapped graph theory based large-scale characteristics of developing resting state brain networks using magnetoencephalography (MEG), which has a millisecond time resolution, in 131 subjects, ages 7-29. Using this approach, we discovered previously un-mapped frequency-dependent properties of the maturation trajectories of resting s...

Objective: The ARX (Aristaless Related homeoboX) gene encodes a transcription factor which mutations have been associated with syndromes ranging from severe neuronal migration defects such as lissencephaly, to mild or moderate forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent ARX mutation (c.429_...

Objective: The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons (OMIM#300215), and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in this gen...

Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry...

Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of con...

Historically, medical images collected in the course of clinical care have been difficult to access for secondary research studies. While there is a tremendous potential value in the large volume of studies contained in clinical image archives, Picture Archiving and Communication Systems (PACS) are designed to optimize clinical operations and workf...

The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associ...

Neural substrates underlying the human-pet relationship are largely unknown. We examined fMRI brain activation patterns as mothers viewed images of their own child and dog and an unfamiliar child and dog. There was a common network of brain regions involved in emotion, reward, affiliation, visual processing and social cognition when mothers viewed...

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly...

Our expectations about an event can strongly shape our subjective evaluation and actual experience of events. This ability, applied to the modulation of pain, has the potential to affect therapeutic analgesia substantially and constitutes a foundation for non-pharmacological pain relief. A typical example of such modulation is the placebo effect. S...

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 contro...

Expectancy and conditioning are often tested as opposing explanations of placebo analgesia, most commonly by pitting the effects of a conditioning procedure against those of a verbally induced expectation for pain reduction. However, conditioning procedures can also alter expectations, such that the effect of conditioning on pain might be mediated...

Background / Purpose: We aimed to develop age-specific atlases for diffusion images, to enhance our understanding of the normal myelination process in children 0-6 years, using clinical images pulled by the medical imaging informatics bench to bedside (mi2b2) platform. Main conclusion: The mi2b2 can query and access valuable large numbers of...

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of C...

We present a new MRI-based attenuation correction (AC) approach for integrated PET/MRI systems that combines both segmentation- and atlas-based methods by incorporating dual-echo ultra-short echo-time (DUTE) and T1-weighted (T1w) MRI data and a probabilistic atlas. Segmented atlases were constructed from CT training data using a leave-one-out frame...

Placebo analgesia is an indicator of how efficiently the brain translates psychological signals conveyed by a treatment procedure into pain relief. It has been demonstrated that functional connectivity between distributed brain regions predicts placebo analgesia in chronic back pain patients. Greater network efficiency in baseline brain networks ma...

The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Dis...

While patients suffering from fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. In this study we investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain such as anticipati...

This article reviews work published by the ENIGMA Consortium and its Working Groups (http://enigma.ini.usc.edu). It was written collaboratively; P.T. wrote the first draft and all listed authors revised and edited the document for important intellectual content, using Google Docs for parallel editing, and approved it. Some ENIGMA investigators cont...

Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophren...

Aims/objectives/background: Studies have associated chronic low back pain (cLBP) with grey matter thinning. But these studies have not controlled for important clinical variables (such as a comorbid affective disorder, pain medication, age, or pain phenotype), which may reduce or eliminate these associations. Methods: We conducted cortical thick...

Kawasaki disease is an acute and time-limited systemic vasculitis primarily affecting young children. We describe an 18-month-old girl with Kawasaki disease who developed cerebral infarction following complete occlusion of her right internal carotid artery. The occlusion occurred 10 days after the onset of fever, while she was on high-dose aspirin,...

The neural mechanisms underlying genetic risk for schizophrenia, a highly heritable psychiatric condition, are still under investigation. New schizophrenia risk genes discovered through genome-wide association studies (GWAS), such as neurogranin (NRGN), can be used to identify these mechanisms. In this study we examined the association of two commo...

A fundamental characteristic of neural circuits is the capacity for plasticity in response to experience. Neural plasticity is associated with the development of chronic pain disorders. In this study, we investigated 1) brain resting state functional connectivity (FC) differences between patients with chronic low back pain (cLBP) and matched health...

Placebo treatments and healing rituals have been used to treat pain throughout history. The present within-subject crossover study examines the variability in individual responses to placebo treatment with verbal suggestion and visual cue conditioning by investigating whether responses to different types of placebo treatment, as well as conditionin...

Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify s...

First two principal components (PC) plotted against each other for MCIC data and the four HapMap populations. Definition of European subsample as described above (zoomed in on the right picture). Blue cross marks the center of all HapMap CEU individuals (International HapMap Project http://www.hapmap.org/). Blue circles are the single (inner circle...

SI 1 Material and Methods, SI 2 Results. (DOCX)

Expression of NR2F6 in human hippocampus. Hippocampal formation spatially shown in green. Red diamonds represent loci of higher expression compared to other tissues. Figure prepared with Allen Human Brain Atlas – Brain Explorer 2 (Version 2.2 Build 2312) of the Allen Institute for Brain Science (Lau et al., 2008). (TIF)

Forest plot of regression coefficients and corresponding 95% confidence intervals for main hits in the patient group and in healthy controls, respectively (MCIC sample). SZ = patients with schizophrenia; HC = healthy controls. (TIF)

Path model predicting indirect effects of SNP on memory. Standardized path coefficients are given exemplarily for SNP rs35686037. Indirect effect of marker rs35686037 on “Memory” = −0.047 in the MCIC sample. For all other values see Table S4 in File S1. E1 to e5 are error terms. (TIF)

Expertly collected, well-curated data sets consisting of comprehensive clinical characterization and raw structural, functional and diffusion-weighted DICOM images in schizophrenia patients and sex and age-matched controls are now accessible to the scientific community through an on-line data repository (coins.mrn.org). The Mental Illness and Neuro...

Typical brain development includes coordinated changes in both white matter (WM) integrity and cortical thickness (CT). These processes have been shown to be disrupted in schizophrenia, which is characterized by abnormalities in WM microstructure and by reduced CT. The aim of this study was to identify patterns of association between WM markers and...

Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure c...

While high levels of negative affect and cognitions have been associated in chronic pain conditions with greater pain sensitivity, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this study, we hypothesized that 1) catastrophizing modulates brain responses to p...

Patient–physician interactions significantly contribute to placebo effects and clinical outcomes. While the neural correlates of placebo responses have been studied in patients, the neurobiology of the clinician during treatment is unknown. This study investigated physicians’ brain activations during patient–physician interaction while the patient...

The experience of pain can be significantly influenced by expectancy (predictive cues). This ability to modulate pain has the potential to affect therapeutic analgesia substantially and constitutes a foundation for nonpharmacological pain relief. In this study, we investigated (1) brain regions involved in visual cue modulation of pain during antic...

Deqi is one of the core concepts in acupuncture theory and encompasses a range of sensations. In this study, we used the MGH Acupuncture Sensation Scale (MASS) to measure and assess the reliability of the sensations evoked by acupuncture needle stimulation in a longitudinal clinical trial on knee osteoarthritis (OA) patients. The Knee injury and O...

Neuroimaging studies have suggested the presence of alterations in the anatomo-functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroi...

The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we per...

There is considerable evidence implicating brain white matter (WM) abnormalities in the pathophysiology of schizophrenia; however, the spatial localization of WM abnormalities reported in the existing studies is heterogeneous. Thus, the goal of this study was to quantify the spatial characteristics of WM abnormalities in schizophrenia. One hundred...

Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional magnetic resonance imaging, we evaluated brain responses to a wide range of stimulus intensity levels (1 inno...

Structural brain measures are employed as endophenotypes in the search for schizophrenia susceptibility genes. We analyzed two independent structural imaging datasets with voxel-based morphometry and with source-based morphometry, a multivariate, independent components analysis, to determine the stability and heritability of regional gray matter co...

Background: There is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the desc...

A large number of studies have provided evidence for the efficacy of psychological and other non-pharmacological interventions in the treatment of chronic pain. While these methods are increasingly used to treat pain, remarkably few studies focused on the exploration of their neural correlates. The aim of this article was to review the findings fro...

The majority of patients with schizophrenia smoke cigarettes. Both nicotine use and schizophrenia have been associated with alterations in brain white matter microstructure as measured by diffusion tensor imaging (DTI). The purpose of this study was to examine fractional anisotropy (FA) in smoking and non-smoking patients with schizophrenia and in...

The lack of consistency of genetic associations in highly heritable mental illnesses, such as schizophrenia, remains a challenge in molecular psychiatry. Because clinical phenotypes for psychiatric disorders are often ill defined, considerable effort has been made to relate genetic polymorphisms to underlying physiological aspects of schizophrenia...

This study investigated sex similarities and differences in pain-related functional connectivity in 60 healthy subjects. We used functional magnetic resonance imaging and psychophysiological interaction analysis to investigate how exposure to low vs high experimental pain modulates the functional connectivity of the periaqueductal gray (PAG). We fo...

Making an accurate diagnosis of schizophrenia and related psychoses early in the course of the disease is important for initiating treatment and counseling patients and families. In this study, we developed classification models for early disease diagnosis using structural MRI (sMRI) and neuropsychological (NP) testing. We used sMRI measurements an...

LEARNING OBJECTIVES 1) Enhance interpretation of DICOM images through the use of 3D visualization. 2) Gain experience with interactive, quantitative assessment of complex anatomical structures. 3) Present current directions of quantitative imaging as a biomarker in clinical trials. ABSTRACT Technological breakthroughs in medical imaging hardware a...

Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified ''pain genes''. Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been...

We have developed a method for automated probabilistic reconstruction of a set of major white-matter pathways from diffusion-weighted MR images. Our method is called TRACULA (TRActs Constrained by UnderLying Anatomy) and utilizes prior information on the anatomy of the pathways from a set of training subjects. By incorporating this prior knowledge...

Background: Previous studies have suggested that motivational aspects of executive functioning, which may be disrupted in schizophrenia patients with negative symptoms, are mediated in part by the striatum. Negative symptoms have been linked to impaired recruitment of both the striatum and the dorsolateral prefrontal cortex (DLPFC). Here we tested...

The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative, funded by an R13 from the National Institute of Mental Health, seeks to enhance translational research in treatment development for impaired cognition in schizophrenia by developing tools from cognitive neuroscience into useful measures of trea...

The varying nature of chronic pain (CP) is difficult to correlate to neural activity using typical functional magnetic resonance imaging methods. Arterial spin labeling is a perfusion-based imaging technique allowing the absolute quantification of regional cerebral blood flow, which is a surrogate measure of neuronal activity. Subjects with chronic...

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 cortic...

Previous studies have found varying relationships between cognitive functioning and brain volumes in patients with schizophrenia. However, cortical thickness may more closely reflect cytoarchitectural characteristics than gray matter density or volume estimates. Here, we aimed to compare associations between regional variation in cortical thickness...

The gold standard for determining the efficacy of biomedical therapies is the detection of a significant difference between the therapeutic effects of an active pharmacological agent or procedure and a matched inert placebo in a randomized controlled trial. Detecting this difference has become a challenge for medicine, especially for outcomes that...

The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. Seventy-nine medic...

Background Electroacupuncture (EA) is currently one of the most popular acupuncture modalities. However, the continuous stimulation characteristic of EA treatment presents challenges to the use of conventional functional Magnetic Resonance Imaging (fMRI) approaches for the investigation of neural mechanisms mediating treatment response because of...

Unlabelled: Comorbid psychopathology is a variable not explored in the acupuncture RCTs that could explain whether subgroups of patients with chronic low back pain have differential responses to acupuncture or placebo treatments. This was a controlled, blinded, crossover trial of verum acupuncture and validated sham acupuncture in 40 CLBP patients...

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 he...

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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 me...

LEARNING OBJECTIVES 1) Describe the methods used for basic analysis of quantitative imaging biomarkers. 2) Describe the principles of image registration, segmentation, and volume measurement. 3) Select and use appropriate software for 3D reconstruction, visualization and interpretation of complex anatomical structures. 4) Identify key analysis and...

The majority of neuroimaging studies on pain focuses on the study of BOLD activations, and more rarely on deactivations. In this study, in a relatively large cohort of subjects (N=61), we assess (a) the extent of brain activation and deactivation during the application of two different heat pain levels (HIGH and LOW) and (b) the relations between t...

LEARNING OBJECTIVES 1) Enhance interpretation of DICOM images through the use of 3D visualization, 2) Gain experience with interactive assessment of complex anatomical structures, 3) Present the current directions of open-source computer graphics applications in Radiology. ABSTRACT Technological breakthroughs in medical imaging hardware and the em...

Deficits in working memory (WM) are a consistent neurocognitive marker for schizophrenia. Previous studies have suggested that WM is the product of coordinated activity in distributed functionally connected brain regions. Independent component analysis (ICA) is a data-driven approach that can identify temporally coherent networks that underlie fMRI...

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...

Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in c...

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...

Recent advances in placebo research have demonstrated the mind's power to alter physiology. In this study, we combined an expectancy manipulation model with both verum and sham acupuncture treatments to address: 1) how and to what extent treatment and expectancy effects - including both subjective pain intensity levels (pain sensory ratings) and ob...

Automated MRI-derived measurements of in-vivo human brain volumes provide novel insights into normal and abnormal neuroanatomy, but little is known about measurement reliability. Here we assess the impact of image acquisition variables (scan session, MRI sequence, scanner upgrade, vendor and field strengths), FreeSurfer segmentation pre-processing...