Functional Brain Imaging Studies Research Articles

Role of glutamate in neuron-glia metabolic coupling

The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiologic principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography. Approximately 10 y ago we provided experimental evidence that indicated a central role of glutamate signaling on astrocytes in neurometabolic coupling. The basic mechanism in neurometabolic coupling is the glutamate-stimulated aerobic glycolysis in astrocytes, such that the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na+-K+ ATPase triggers glucose uptake and its glycolytic processing, which results in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fueling of the neuronal energy demands associated with synaptic transmission. Analyses of this coupling have been extended in vivo and have defined the methods of coupling for inhibitory neurotransmission as well as its spatial extent in relation to the propagation of metabolic signals within the astrocytic syncytium. On the basis of a large body of experimental evidence, we proposed an operational model, “the astrocyte-neuron lactate shuttle.” A series of results obtained by independent laboratories have provided further support for this model. This body of evidence provides a molecular and cellular basis for interpreting data that are obtained with functional brain imaging studies.

Neuroimaging of Narcolepsy

Neuroimaging techniques have refined the characterization of neural structures involved in the regulation of normal sleep-wake cycle in healthy humans. Yet brain imaging studies in patients with sleep disorders still remain scarce. In narcoleptic patients, structural and functional brain imaging studies have suggested the involvement of the hypothalamus in the pathophysiology of narcolepsy, plausibly consistent with an impairment of the hypocretin-orexin system. Some recent studies have further suggested that cataplexy, a key feature of the narcoleptic syndrome, might result from a dysfunction of the hypothalamus and its interactions with limbic structures. Other neuroimaging studies have focused on the assessment of neurotransmission and the effects of pharmacological treatment in narcoleptic patients. However, the neural correlates of some main symptoms of narcolepsy, such as sleep attacks, hypnagogic/hypnopompic hallucinations and sleep paralysis, are still unknown. In addition, the description of brain activity patterns during sleep in narcoleptic patients needs further investigation. Neuroimaging has proven to be a valuable tool for the study of sleep regulation and sleep disorders; its future developments will undoubtedly improve our understanding of the neural mechanisms underlying narcolepsy with cataplexy.

The Role of Serotonin in the Pathophysiology of Depression: As Important As Ever

Featured Article: Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994;40: 288–95.1 Fifteen years have elapsed since we published this article focusing on the serotonin transporter (SERT)2 . Although developed as a review, this report ultimately included original data from a large study of drug-free depressed patients and controls showing that platelet [3H]imipramine binding, the ligand of choice for labeling serotonin transporters, was significantly decreased in depression. We also showed data indicating that the decreased platelet [3H]imipramine binding was specific for major depression. The high number of citations, including numerous citations even in 2009, reflects the ongoing importance of serotonin in depression. Since this report was published, remarkable advances have occurred in our understanding of the molecular neurobiology of serotonergic neurons, and in functional brain imaging studies, which have provided further evidence for a preeminent role for serotonergic circuits in the pathogenesis of major depression and suicide (1). These advances include (a) the development of specific positron-emission tomography ligands for the SERT and their use in detecting alterations in serotonergic circuits in patients with major depression and suicidality, as well as quantifying the magnitude of SERT occupancy associated with antidepressant treatment; (b) functional polymorphism in the promoter region of …

Visceral pain hypersensitivity in functional gastrointestinal disorders

Functional gastrointestinal disorders (FGIDs) are a highly prevalent group of heterogeneous disorders whose diagnostic criteria are symptom based in the absence of a demonstrable structural or biochemical abnormality. Chronic abdominal pain or discomfort is a defining characteristic of these disorders and a proportion of patients may display heightened pain sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity (VPH). We examined the most recent literature in order to concisely review the evidence for some of the most important recent advances in the putative mechanisms concerned in the pathophysiology of VPH. VPH may occur due to anomalies at any level of the visceral nociceptive neuraxis. Important peripheral and central mechanisms of sensitization that have been postulated include a wide range of ion channels, neurotransmitter receptors and trophic factors. Data from functional brain imaging studies have also provided evidence for aberrant central pain processing in cortical and subcortical regions. In addition, descending modulation of visceral nociceptive pathways by the autonomic nervous system, hypothalamo-pituitary-adrenal axis and psychological factors have all been implicated in the generation of VPH. Particular areas of controversy have included the development of efficacious treatment of VPH. Therapies have been slow to emerge, mainly due to concerns regarding safety. The burgeoning field of genome wide association studies may provide further evidence for the pleiotropic genetic basis of VPH development. Tangible progress will only be made in the treatment of VPH when we begin to individually characterize patients with FGIDs based on their clinical phenotype, genetics and visceral nociceptive physiology.

Brain imaging approaches to the study of functional GI disorders: A Rome Working Team Report

Progresses in the understanding of human brain-gut interactions in health and disease have been limited by the lack of non-invasive techniques to study brain activity. The advent of neuroimaging techniques has made it possible not only to study the structure and function of the brain, but also to characterize signaling system underlying brain function. This article gives a brief overview of relevant functional neuroanatomy, and of the most commonly used brain imaging techniques. It summarizes published functional brain imaging studies using acute visceral stimulation of the oesophagus, stomach and colon in healthy control subjects and patients with functional GI disorders, and briefly discusses pertinent findings from these studies. The article concludes with a critical assessment of published studies, and with recommendations for improved study paradigms and analysis strategies.

The Wisconsin Card Sorting Test and the cognitive assessment of prefrontal executive functions: A critical update

For over four decades the Wisconsin Card Sorting Test (WCST) has been one of the most distinctive tests of prefrontal function. Clinical research and recent brain imaging have brought into question the validity and specificity of this test as a marker of frontal dysfunction. Clinical studies with neurological patients have confirmed that, in its traditional form, the WCST fails to discriminate between frontal and non-frontal lesions. In addition, functional brain imaging studies show rapid and widespread activation across frontal and non-frontal brain regions during WCST performance. These studies suggest that the concept of an anatomically pure test of prefrontal function is not only empirically unattainable, but also theoretically inaccurate. The aim of the present review is to examine the causes of these criticisms and to resolve them by incorporating new methodological and conceptual advances in order to improve the construct validity of WCST scores and their relationship to prefrontal executive functions. We conclude that these objectives can be achieved by drawing on theory-guided experimental design, and on precise spatial and temporal sampling of brain activity, and then exemplify this using an integrative model of prefrontal function [i.e., Miller, E. K. (2000). The prefrontal cortex and cognitive control. Nature Reviews Neuroscience, 1, 59–65.] combined with the formal information theoretical approach to cognitive control [Koechlin, E., & Summerfield, C. (2007). An information theoretical approach to prefrontal executive function. Trends in Cognitive Sciences, 11, 229–235.].

The Neurobiology of Nicotine Addiction: Clinical and Public Policy Implications

Clinicians, social scientists, researchers, and policy makers appreciate the need to understand the neurobiology of nicotine addiction and how this information can lead to new treatments and provide support for public policy debates on parity and preventing adolescent tobacco use. In a “bench-to-bedside” manner, this review covers both clinical and basic science perspectives. Both the reward and sensitization-homeostasis theories of nicotine addiction are supported by new understanding of clinical issues of rapid tolerance, withdrawal, sensitization, and craving when examined by functional brain imaging, genetics, and basic science studies of nicotinic acetylcholine receptors. This review provides information to help shape public policy, fight stigma, and improve clinical treatment and research. The fight for parity in health care requires education about the neurobiological basis of addiction versus the stigmatized bad habit or simple socialization. Parity must support reimbursement for nicotine replacement medications or other FDA approved medications and psychosocial treatments.

Functional brain imaging of swallowing: an activation likelihood estimation meta-analysis

Background: The neuroanatomy and functional significance of swallowing-related networks in humans are not entirely clear. Activation likelihood estimation (ALE), a novel quantitative meta-analysis technique, was employed to pool the results of functional brain imaging studies for the investigation of the neural control of swallowing (Soros et al. 2008). Methods: Studies that were included in the meta-analysis 1) examined water swallowing, saliva swallowing, or both, and 2) reported brain activation as coordinates in standard space. Using these criteria, a systematic literature search identified 7 studies that examined water swallowing, and 5 studies of saliva swallowing. An ALE meta-analysis of these studies was performed with GingerALE (http://brainmap.org). Results: For water swallowing, clusters with high activation likelihood were found in the bilateral sensorimotor cortex (Fig.1; clusters 1, 2), right inferior parietal lobule (cluster 3), and right anterior insula (cluster 6). For saliva swallowing, highest ALE values were found in the bilateral cingulate gyrus (Fig.2; clusters 1b, 1c), the right supplementary motor area (cluster 1a), left pre- and postcentral gyrus (clusters 2a, 2b), and right posterior insula (cluster 3). A between-condition meta-analysis revealed clusters with higher activation likelihood for water than for saliva swallowing in the right inferior parietal lobule (cluster 1), right postcentral gyrus (cluster 2), and right anterior insula (cluster 3). Clusters with higher activation likelihood for saliva than for water swallowing were found in the right supplementary motor area (Fig.3; cluster 6c), bilateral anterior cingulate gyrus (clusters 6a, 6b), and bilateral precentral gyrus (clusters 7, 8). Conclusions: This meta-analysis emphasizes the distributed and partly overlapping cortical networks involved in the control of water and saliva swallowing. Water swallowing is associated with right inferior parietal activation, likely reflecting the sensory processing of intraoral water stimulation. Saliva swallowing more strongly involves premotor areas, which are crucial for the initiation and control of movements. Reference: Soros P, Inamoto Y, Martin R. Functional brain imaging of swallowing: An activation likelihood estimation meta-analysis. Hum Brain Mapp 2008 (in press).

Recognizing brain motor imagery activities by identifying chaos properties of oxy-hemoglobin dynamics time series

In recent years, functional near-infrared spectroscopy (NIRS) has been introduced as a new neuroimaging modality with which to conduct functional brain-imaging studies. With its advanced features, NIRS signal processing has become a very attractive field in computational science. This work explores nonlinear physical aspects of cerebral hemodynamic changes over the time series of NIRS. Detecting the presence of chaos in a dynamical system is an important problem in studying the irregular or chaotic motion that is generated by nonlinear systems whose dynamical laws uniquely determine the time of evolution of a state of the system. The strategy results directly from the definition of the largest Lyapunov exponent. The Lyapunov exponents quantify the exponential divergence of initially close state–space trajectories and estimate the amount of chaos in a system. The method is an application of the Rosenstein algorithm, an efficient method for calculating the largest Lyapunov exponent from an experimental time series. In the present paper, the authors focus mainly on the detection of chaos characteristics of the time series associated to hemoglobin dynamics. Furthermore, the chaos parameters obtained can be used to identify the active state period of the human brain.

There may be more to reaching than meets the eye: Re-thinking optic ataxia

Optic ataxia (OA) is generally thought of as a disorder of visually guided reaching movements that cannot be explained by any simple deficit in visual or motor processing. In this paper we offer a new perspective on optic ataxia; we argue that the popular characterisation of this disorder is misleading and is unrepresentative of the pattern of reaching errors typically observed in OA patients. We begin our paper by reviewing recent neurophysiological, neuropsychological, and functional brain imaging studies that have led to the proposal that the medial parietal cortex in the vicinity of the parietal-occipital junction (POJ) – the key anatomical site associated with OA – represents reaching movements in eye-centred coordinates, and that this ability is impaired in optic ataxia. Our perspective stresses the importance of the POJ and superior parietal regions of the human PPC for representing reaching movements in both extrinsic (eye-centred) and intrinsic (postural) coordinates, and proposes that it is the ability to simultaneously represent multiple spatial locations that must be directly compared with one another that is impaired in non-foveal OA patients. In support of this idea we review recent fMRI and behavioural studies conducted by our group that have investigated the anatomical correlates of posturally guided movements, and the movements guided by postural cues in patients presenting with optic ataxia.

Making Tools and Making Sense: Complex, Intentional Behaviour in Human Evolution

Stone tool-making is an ancient and prototypically human skill characterized by multiple levels of intentional organization. In a formal sense, it displays surprising similarities to the multi-level organization of human language. Recent functional brain imaging studies of stone tool-making similarly demonstrate overlap with neural circuits involved in language processing. These observations are consistent with the hypothesis that language and tool-making share key requirements for the construction of hierarchically structured action sequences and evolved together in a mutually reinforcing way.

Brain glucose metabolism difference between bipolar and unipolar mood disorders in depressed and euthymic states

Background Functional brain imaging studies have consistently demonstrated abnormalities in regional cerebral glucose metabolism in the prefrontal cortex in patients with mood disorders (MD). These studies, however, have not clarified the differential characteristics of glucose metabolism between depressed and euthymic states, or between bipolar mood disorder (BP) and unipolar mood disorder (UP). Methods We used [ 18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) to evaluate the differences in glucose metabolism at resting state. We compared 30 depressed and 17 euthymic female patients with mood disorders with age-, IQ-, and socioeconomically matched 20 healthy controls (HCs). Then, BP and UP patients were separately analyzed. The PET data were objectively analyzed by statistical parametric mapping (SPM). Results Compared with HCs, the depressed MD patients showed significantly lower glucose metabolism in the bilateral frontal gyri, left cingulate gyrus, bilateral temporal gyri, right insula, bilateral inferior parietal lobules, and right occipital gyrus. In contrast, the euthymic MD patients demonstrated fewer areas with significant reduction. When the depressed BP patients were separately compared with HCs, the glucose metabolism was found to be significantly lower in the bilateral frontal gyri, right cingulate gyrus, and bilateral inferior parietal lobules. Meanwhile, the depressed UP patients showed a significantly lower metabolism in the bilateral frontal gyri, left cingulate gyrus, bilateral temporal gyri, bilateral insulae, bilateral inferior parietal lobules, and right occipital gyrus. Conclusions The results of this study provide evidence of persistent hypometabolism in depressed MD patients, particularly in the frontal gyrus. Although the conclusions are limited in the cross-sectional study, these findings suggest that abnormalities in the right frontal gyrus, left temporal gyrus, and left cingulate gyrus tend to normalize as the depression symptoms improve, although those in the left frontal gyrus, right cingulate gyrus, and right temporal gyrus persist. This study also elucidated the cerebral hypofunction specific to each BP and UP. BP patients showed a decrease in glucose metabolism in the right anterior cingulate and UP patients did in the right temporal gyrus, right insula, and left posterior cingulate. This study clarified the differences between subtypes.

Head, Neck, and Eye Movements That Modulate Tinnitus

Recent functional brain imaging studies in humans suggest that the neural generator(s) for tinnitus may reside in the central nervous system and involve both auditory as well as nonauditory centers. The contribution of nonauditory centers in the pathogenesis and regulation of tinnitus is reinforced by studies showing that many patients have somatic tinnitus whereby movements and manipulations of the eyes, head, neck, jaw, and shoulder can modulate the loudness and pitch of their tinnitus. In most cases, the maneuvers lead to increases in tinnitus loudness or pitch rather than decreases. Our results indicate that most tinnitus patients experience only a modest change in loudness or pitch when performing these maneuvers. However, some patients report that these maneuvers significantly modulate the loudness or pitch, sometimes by a factor of 2 to 3. The high prevalence of somatic tinnitus serves to illustrate the complex multimodal interactions that exist between the auditory pathway and other sensory-motor systems innervating the head, neck, shoulders, and eyes.

Neurophysiology and neuroanatomy of smooth pursuit in humans

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.

Actions, Words, and Numbers

Recent findings in neuroscience challenge the view that the motor system is exclusively dedicated to the control of actions, and it has been suggested that it may contribute critically to conceptual processes such as those involved in language and number representation. The aim of this review is to address this issue by illustrating some interactions between the motor system and the processing of words and numbers. First, we detail functional brain imaging studies suggesting that motor circuits may be recruited to represent the meaning of action-related words. Second, we summarize a series of experiments demonstrating some interference between the size of grip used to grasp objects and the magnitude processing of words or numbers. Third, we report data suggestive of a common representation of numbers and finger movements in the adult brain, a possible trace of the finger-counting strategies used in childhood. Altogether, these studies indicate that the motor system interacts with several aspects of word and number representations. Future research should determine whether these findings reflect a causal role of the motor system in the organization of semantic knowledge.

Brain imaging in patients with freezing of gait

Freezing of gait (FOG) is a disabling gait disturbance with unknown cerebral pathophysiology. In this review, we discuss the functional brain imaging studies that address gait physiology and pathophysiology of FOG. Radiotracer metabolic studies show basal ganglia-cortical circuitry involvement in different aspects of gait control. FOG patients showed orbitofrontal and posterior parietal deficits and possibly predominant involvement of right-sided circuitry. We suggest that FOG results from neuronal circuitry dysfunction in right-sided parietal-lateral premotor circuits. These circuits incorporate sensory information into the control of gait. Furthermore, abnormal function of frontostriatal loops, which probably sheer cognitive and attentional activities is also a main factor in FOG. Gait-induced brain circuitry activation can not adequately be achieved when investigated subjects are in a supine rest position, as is the case in most present day imaging studies. Some radiotracer activation studies were performed after walking. Imagination of gait has been used in some radiotracer activation studies with positron emission tomography (PET) and in studies with functional magnetic resonance imaging (fMRI), showing cortical activation patterns involved in several aspects of gait control. For future investigation of FOG, it is suggested to design PET and fMRI studies which concentrate on activation of neuropsychological and sensory integration circuits.

Neural correlates of self-face recognition: An effect-location meta-analysis

Recent evidence from neuropsychological patients with focalized lesions and functional brain imaging studies indicate that processing of self is distinguishable from processing of information about others (e.g., recognizing a familiar face). Here, we conduct an effect-location meta-analysis (Fox et al., 1998) of 9 functional neuroimaging studies of self-face recognition. The evidence provides support for a right-dominated, but largely bilaterally distributed model for self-face processing. Four areas are consistently activated: the left fusiform gyrus, bilateral middle and inferior frontal gyri, and right precuneus. The evidence is interpreted in light of a developing model of self-face recognition as part of a larger social cognitive stream of processing.

Neurocognitive Aging and the Compensation Hypothesis

The most unexpected and intriguing result from functional brain imaging studies of cognitive aging is evidence for age-related overactivation: greater activation in older adults than in younger adults, even when performance is age-equivalent. Here we examine the hypothesis that age-related overactivation is compensatory and discuss the compensation-related utilization of neural circuits hypothesis (CRUNCH). We review evidence that favors a compensatory account, discuss questions about strategy differences, and consider the functions that may be served by overactive brain areas. Future research directed at neurocognitively informed training interventions may augment the potential for plasticity that persists into the later years of the human lifespan.

Normalized Cut Group Clustering of Resting-State fMRI Data

BackgroundFunctional brain imaging studies have indicated that distinct anatomical brain regions can show coherent spontaneous neuronal activity during rest. Regions that show such correlated behavior are said to form resting-state networks (RSNs). RSNs have been investigated using seed-dependent functional connectivity maps and by using a number of model-free methods. However, examining RSNs across a group of subjects is still a complex task and often involves human input in selecting meaningful networks.Methodology/Principal FindingsWe report on a voxel based model-free normalized cut graph clustering approach with whole brain coverage for group analysis of resting-state data, in which the number of RSNs is computed as an optimal clustering fit of the data. Inter-voxel correlations of time-series are grouped at the individual level and the consistency of the resulting networks across subjects is clustered at the group level, defining the group RSNs. We scanned a group of 26 subjects at rest with a fast BOLD sensitive fMRI scanning protocol on a 3 Tesla MR scanner.Conclusions/SignificanceAn optimal group clustering fit revealed 7 RSNs. The 7 RSNs included motor/visual, auditory and attention networks and the frequently reported default mode network. The found RSNs showed large overlap with recently reported resting-state results and support the idea of the formation of spatially distinct RSNs during rest in the human brain.

A regulation role of the prefrontal cortex in the fist-edge-palm task: Evidence from functional connectivity analysis

The Fist-Edge-Palm (FEP) task is a motor sequencing task that is widely used in neurological examination. Deficits in this task are believed to reflect impairment in the frontal lobe regions. However, two recent functional brain imaging studies of the FEP task using conventional subtraction analysis failed to demonstrate FEP-induced activation in the prefrontal cortex (PFC), which contradicts existing neuropsychological literature. In this study, psychophysiological interaction (PPI) analysis was used to reanalyze our previous neuroimaging dataset from 10 healthy subjects in order to evaluate the changes of functional connectivity between the sensorimotor cortex and the prefrontal regions during the performances of the FEP task relative to simple motor control tasks. The PPI analysis revealed significantly increased functional connectivity between bilateral sensorimotor cortex and the right inferior and middle frontal cortex during the performance of the FEP task compared with the control tasks. However, regional signal changes showed no significant activation differences in these prefrontal regions. These results provide evidence supporting the involvement of the frontal lobe in the performance of the FEP task, and suggest a role of regulation, rather than direct participation, of the prefrontal cortex in the execution of complex motor sequence tasks such as the FEP task.