Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. METHODS: We performed 18 F-FDG positron emission tomography (PET) imaging in 4-, 6-, and 12-month-old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis. RESULTS: The 5XFAD model mice showed age-related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. DISCUSSION: The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.

Edge time series components of functional connectivity and cognitive function in Alzheimer's disease.

Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

White matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer's disease continuum.

BACKGROUND: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. METHODS: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. RESULTS: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment. CONCLUSION: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.

Edge Time Series Components of Functional Connectivity and Cognitive Function in Alzheimer's Disease.

Understanding the interrelationships of brain function as measured by resting-state magnetic resonance imaging and neuropsychological/behavioral measures in Alzheimer's disease is key for advancement of neuroimaging analysis methods in clinical research. The edge time-series framework recently developed in the field of network neuroscience, in combination with other network science methods, allows for investigations of brain-behavior relationships that are not possible with conventional functional connectivity methods. Data from the Indiana Alzheimer's Disease Research Center sample (53 cognitively normal control, 47 subjective cognitive decline, 32 mild cognitive impairment, and 20 Alzheimer's disease participants) were used to investigate relationships between functional connectivity components, each derived from a subset of time points based on co-fluctuation of regional signals, and measures of domain-specific neuropsychological functions. Multiple relationships were identified with the component approach that were not found with conventional functional connectivity. These involved attentional, limbic, frontoparietal, and default mode systems and their interactions, which were shown to couple with cognitive, executive, language, and attention neuropsychological domains. Additionally, overlapping results were obtained with two different statistical strategies (network contingency correlation analysis and network-based statistics correlation). Results demonstrate that connectivity components derived from edge time-series based on co-fluctuation reveal disease-relevant relationships not observed with conventional static functional connectivity.

Levetiracetam Modulates Brain Metabolic Networks and Transcriptomic Signatures in the 5XFAD Mouse Model of Alzheimer's disease.

INTRODUCTION: Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. METHODS: Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. RESULTS: Pharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e. positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. DISCUSSION: This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration- dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value towards informing clinical study design.

Amyloid and tau pathology are associated with cerebral blood flow in a mixed sample of nondemented older adults with and without vascular risk factors for Alzheimer's disease.

Identification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOEε4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.

Effects of acute alcohol exposure and chronic alcohol use on neurite orientation dispersion and density imaging (NODDI) parameters.

RATIONALE: Little is known about how acute and chronic alcohol exposure may alter the in vivo membrane properties of neurons. OBJECTIVES: We employed neurite orientation dispersion and density imaging (NODDI) to examine acute and chronic effects of alcohol exposure on neurite density. METHODS: Twenty-one healthy social drinkers (CON) and thirteen nontreatment-seeking individuals with alcohol use disorder (AUD) underwent a baseline multi-shell diffusion magnetic resonance imaging (dMRI) scan. A subset (10 CON, 5 AUD) received dMRI during intravenous infusions of saline and alcohol during dMRI. NODDI parametric images included orientation dispersion (OD), isotropic volume fraction (ISOVF), and corrected intracellular volume fraction (cICVF). Diffusion tensor imaging metrics of fractional anisotropy and mean, axial, and radial diffusivity (FA, MD, AD, RD) were also computed. Average parameter values were extracted from white matter (WM) tracts defined by the Johns Hopkins University atlas. RESULTS: There were group differences in FA, RD, MD, OD, and cICVF, primarily in the corpus callosum. Both saline and alcohol had effects on AD and cICVF in WM tracts proximal to the striatum, cingulate, and thalamus. This is the first work to indicate that acute fluid infusions may alter WM properties, which are conventionally believed to be insensitive to acute pharmacological challenges. It also suggests that the NODDI approach may be sensitive to transient changes in WM. The next steps should include determining if the effect on neurite density differs with solute or osmolality, or both, and translational studies to assess how alcohol and osmolality affect the efficiency of neurotransmission.

White matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer's disease continuum.

BACKGROUND: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. METHODS: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥55 years, including 276 cognitively normal older adults (CN), 142 mild cognitive impairment (MCI), and 87 AD, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. RESULTS: Compared to CN, AD and MCI subjects showed decreased WM integrity in the bilateral CBH. Cognition, mood, and higher amyloid burden were also associated with poorer WM integrity in the CBH. CONCLUSION: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.

Levetiracetam modulates brain metabolic networks and transcriptomic signatures in the 5XFAD mouse model of Alzheimer's disease.

Introduction: Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. Methods: Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. Results: Pharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. Discussion: This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design.

Cortico-subcortical interactions in overlapping communities of edge functional connectivity.

Both cortical and subcortical regions can be functionally organized into networks. Regions of the basal ganglia are extensively interconnected with the cortex via reciprocal connections that relay and modulate cortical function. Here we employ an edge-centric approach, which computes co-fluctuations among region pairs in a network to investigate the role and interaction of subcortical regions with cortical systems. By clustering edges into communities, we show that cortical systems and subcortical regions couple via multiple edge communities, with hippocampus and amygdala having a distinct pattern from striatum and thalamus. We show that the edge community structure of cortical networks is highly similar to one obtained from cortical nodes when the subcortex is present in the network. Additionally, we show that the edge community profile of both cortical and subcortical nodes can be estimates solely from cortico-subcortical interactions. Finally, we used a motif analysis focusing on edge community triads where a subcortical region coupled to two cortical regions and found that two community triads where one community couples the subcortex to the cortex were overrepresented. In summary, our results show organized coupling of the subcortex to the cortex that may play a role in cortical organization of primary sensorimotor/attention and heteromodal systems and puts forth the motif analysis of edge community triads as a promising method for investigation of communication patterns in networks.

Cerebral Blood Flow in the Salience Network of Individuals with Alcohol Use Disorder.

AIMS: Magnetic resonance imaging (MRI) studies have identified structural and functional differences in salience network nodes of individuals with alcohol use disorders (AUDs) after chronic exposure to alcohol. However, no studies have investigated cerebral blood flow (CBF) in nontreatment-seeking (NTS) individuals with AUD. METHODS: In this work, we sought to quantify putative CBF deficits in NTS individuals relative to social drinking (SD) controls and determine if CBF in the salience network is associated with AUD severity. Fifteen NTS (36.5 ± 11.2 years old, 30.0 ± 22.7 drinks/week) and 22 SD (35.6 ± 11.9 years old, 9.1 ± 5.7 drinks/week) underwent pseudocontinuous arterial spin labeling MRI. RESULTS: Compared with social drinkers, NTS individuals had significantly lower CBF in the right and left dorsal anterior insula, and the left ventral anterior and posterior insula. The Alcohol Use Disorder Identification Test (AUDIT) score showed a significant negative relationship with CBF in the bilateral caudal anterior cingulate cortex. In addition, a significant negative correlation was present between number of standard drinks consumed per week and the left frontal opercular CBF. CONCLUSION: These results provide evidence that insular CBF is negatively associated with heavy drinking, and that severity of alcohol use is related to CBF deficits in key nodes of the salience network. Longitudinal data are needed to understand if disruptions of CBF in the insula and the salience network are a predisposition for or a consequence of chronic AUD.

The diversity and multiplexity of edge communities within and between brain systems.

The human brain is composed of functionally specialized systems that support cognition. Recently, we proposed an edge-centric model for detecting overlapping communities. It remains unclear how these communities and brain systems are related. Here, we address this question using data from the Midnight Scan Club and show that all brain systems are linked via at least two edge communities. We then examine the diversity of edge communities within each system, finding that heteromodal systems are more diverse than sensory systems. Next, we cluster the entire cortex to reveal it according to the regions' edge-community profiles. We find that regions in heteromodal systems are more likely to form their own clusters. Finally, we show that edge communities are personalized. Our work reveals the pervasive overlap of edge communities across the cortex and their relationship with brain systems. Our work provides pathways for future research using edge-centric brain networks.

Temporal stability of the ventral attention network and general cognition along the Alzheimer's disease spectrum.

Understanding the interrelationships of clinical manifestations of Alzheimer's disease (AD) and functional connectivity (FC) as the disease progresses is necessary for use of FC as a potential neuroimaging biomarker. Degradation of resting-state networks in AD has been observed when FC is estimated over the entire scan, however, the temporal dynamics of these networks are less studied. We implemented a novel approach to investigate the modular structure of static (sFC) and time-varying (tvFC) connectivity along the AD spectrum in a two-sample Discovery/Validation design (n = 80 and 81, respectively). Cortical FC networks were estimated across 4 diagnostic groups (cognitively normal, subjective cognitive decline, mild cognitive impairment, and AD) for whole scan (sFC) and with sliding window correlation (tvFC). Modularity quality (across a range of spatial scales) did not differ in either sFC or tvFC. For tvFC, group differences in temporal stability within and between multiple resting state networks were observed; however, these differences were not consistent between samples. Correlation analyses identified a relationship between global cognition and temporal stability of the ventral attention network, which was reproduced in both samples. While the ventral attention system has been predominantly studied in task-evoked designs, the relationship between its intrinsic dynamics at-rest and general cognition along the AD spectrum highlights its relevance regarding clinical manifestation of the disease.

Anterior cingulate cortex metabolites and white matter microstructure: a multimodal study of emergent alcohol use disorder.

Multimodal imaging is increasingly used to address neuropathology associated with alcohol use disorder (AUD). Few studies have investigated relationships between metabolite concentrations and white matter (WM) integrity; currently, there are no such data in AUD. In this preliminary study, we used complementary neuroimaging techniques, magnetic resonance spectroscopy (MRS), and diffusion weighted imaging (DWI), to study AUD neurophysiology. We tested for relationships between metabolites in the dorsal anterior cingulate cortex (dACC) and adjacent WM microstructure in young adult AUD and control (CON) subjects. Sixteen AUD and fourteen CON underwent whole-brain DWI and MRS of the dACC. Outcomes were dACC metabolites, and diffusion tensor metrics of dACC-adjacent WM. Multiple linear regression terms included WM region, group, and region × group for prediction of dACC metabolites. dACC myo-inositol was positively correlated with axial diffusivity in the left anterior corona radiata (p < 0.0001) in CON but not AUD (group effect: p < 0.001; region × group: p < 0.001; Bonferroni-corrected). In the bilateral anterior corona radiata and right genu of the corpus callosum, glutamate was negatively related to mean diffusivity in AUD, but not CON subjects (all model terms: p < 0.05, uncorrected). In AUD subjects, dACC glutamate was negatively correlated with AUD symptom severity. This is likely the first integrative study of cortical metabolites and WM integrity in young individuals with AUD. Differential relationships between dACC metabolites and adjacent WM tract integrity in AUD could represent early consequences of hazardous drinking, and/or novel biomarkers of early-stage AUD. Additional studies are required to replicate these findings, and to determine the behavioral relevance of these results.

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder.

BACKGROUND: Magnetic resonance imaging (MRI) studies have shown differences in volume and structure in the brains of individuals with alcohol use disorder (AUD). Most research has focused on neuropathological effects of alcohol that appear after years of chronic alcohol misuse. However, few studies have investigated white matter (WM) microstructure and diffusion MRI-based (DWI) connectivity during early stages of AUD. Therefore, the goal of this work was to investigate WM integrity and structural connectivity in emerging adulthood AUD subjects using both conventional DWI metrics and a novel connectomics approach. METHODS: Twenty-two AUD and 18 controls (CON) underwent anatomic and diffusion MRI. Outcome measures were scalar diffusion metrics and structural network connectomes. Tract-Based Spatial Statistics was used to investigate group differences in diffusion measures. Structural connectomes were used as input into a community structure procedure to obtain a coclassification index matrix (an indicator of community association strength) for each subject. Differences in coclassification and structural connectivity (indexed by streamline density) were assessed via the Network Based Statistics Toolbox. RESULTS: AUD had higher fractional anisotropy (FA) values throughout the major WM tracts, but also had lower FA values in WM tracts in the cerebellum and right insula (pTFCE  < 0.05). Mean diffusivity was generally lower in the AUD group (pTFCE  < 0.05). AUD had lower coclassification of nodes between ventral attention and default mode networks and higher coclassification between nodes of visual, default mode, and somatomotor networks. Additionally, AUD had higher fiber density between an adjacent pair of nodes within the default mode network. CONCLUSIONS: Our results indicate that emerging adulthood AUD subjects may have differential patterns of FA and distinct differences in structural connectomes compared with CON. These data suggest that such alterations in microstructure and structural connectivity may uniquely characterize early stages of AUD and/or a predisposition for development of AUD.

Aberrations of anterior insular cortex functional connectivity in nontreatment-seeking alcoholics.

An emergent literature suggests that resting state functional magnetic resonance imaging (rsfMRI) functional connectivity (FC) patterns are aberrant in alcohol use disorder (AUD) populations. The salience network (SAL) is an established set of brain regions prominent in salience attribution and valuation, and includes the anterior insular cortex (AIC). The SAL is thought to play a role in AUD through directing increased attention to interoceptive cues of intoxication. There is very little information on the salience network (SAL) in AUD, and, in particular, there are no data on SAL FC in currently drinking, nontreatment seeking individuals with AUD (NTS). rsfMRI data from 16 NTS and 21 social drinkers (SD) were compared using FC correlation maps from ten seed regions of interest in the bilateral AIC. As anticipated, SD subjects demonstrated greater insular FC with frontal and parietal regions. We also found that, compared to SD, NTS had higher insular FC with hippocampal and medial orbitofrontal regions. The apparent overactivity in brain networks involved in salience, learning, and behavioral control in NTS suggests possible mechanisms in the development and maintenance of AUD.

Differences in White Matter Microstructure and Connectivity in Nontreatment-Seeking Individuals with Alcohol Use Disorder.

BACKGROUND: Diffusion-weighted imaging (DWI) has been widely used to investigate the integrity of white matter (WM; indexed by fractional anisotropy [FA]) in alcohol dependence and cigarette smoking. These disorders are highly comorbid, yet cigarette use has often not been adequately controlled in neuroimaging studies of alcohol-dependent populations. In addition, information on WM deficits in currently drinking, nontreatment-seeking (NTS) individuals with alcohol dependence is limited. Therefore, the aim of this work was to investigate WM microstructural integrity in alcohol use disorder by comparing matched samples of cigarette smoking NTS and social drinkers (SD). METHODS: Thirty-eight smoking NTS and 19 smoking SD subjects underwent DWI as well as structural magnetic resonance imaging. After an in-house preprocessing of the DWI data, FA images were analyzed with tract-based spatial statistics (TBSS). FA obtained from the TBSS skeleton was tested for correlation with recent alcohol consumption. RESULTS: Smoking NTS had lower FA relative to smoking SD, predominantly in the left hemisphere (p < 0.05, family-wise error rate corrected across FA skeleton). Across the full sample, FA and number of drinks per week were negatively related (ρ = -0.348, p = 0.008). Qualitative analyses of the structural connections through compromised WM as identified by TBSS showed differential connectivity of gray matter in NTS compared to SD subjects of left frontal, temporal, and parietal regions. CONCLUSIONS: NTS subjects had lower WM FA than SD, indicating compromised WM integrity in the NTS population. The inverse relationship of entire WM skeleton FA with self-reported alcohol consumption supports previous evidence of a continuum of detrimental effects of alcohol consumption on WM. These results provide additional evidence that alcohol dependence is associated with reduced WM integrity in currently drinking NTS alcohol-dependent individuals, after controlling for the key variable of cigarette smoking.

Differential dopamine function in fibromyalgia.

Approximately 30 % of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [(18)F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and 11 female controls completed study procedures. Subjects received one FAL PET scan while performing a "2-back" task, and one while performing a "0-back" (attentional control, "baseline") task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.