Functional MRI Signal Research Articles

Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study

The main reason for recreational use of cannabis is the 'high', the primary psychotropic effect of Δ9-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates bloodflow-based neuroimaging of psychotropic effects of THC. In this study we investigated the effects of THC on baseline brain perfusion and activity in association with the induction of 'feeling high'. Twenty-three subjects participated in a pharmacological MRI study, where we applied arterial spin labelling (ASL) to measure perfusion, and resting-state functional MRI to assess blood oxygen level-dependent signal fluctuation as a measure of baseline brain activity. Feeling high was assessed with a visual analogue scale and was compared to the imaging measures. THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, and reduced perfusion in the post-central and occipital gyrus. Baseline brain activity was altered, indicated by increased amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula, substantia nigra and cerebellum. Perfusion changes in frontal cortex were negatively correlated with ratings of feeling high, suggesting an interaction between cognitive control and subjective effects of THC. In conclusion, an acute THC challenge altered baseline brain perfusion and activity, especially in frontal brain areas involved in cognitive and emotional processes, and the insula, associated with interoceptive awareness. These changes may represent the THC-induced neurophysiological correlates of feeling high. The alterations in baseline brain perfusion and activity also have relevance for studies on task-related effects of THC on brain function.

Increased Activity Imbalance in Fronto-Subcortical Circuits in Adolescents with Major Depression

BackgroundA functional discrepancy exists in adolescents between frontal and subcortical regions due to differential regional maturational trajectories. It remains unknown how this functional discrepancy alters and whether the influence from the subcortical to the frontal system plays a primacy role in medication naïve adolescent with major depressive disorder (MDD).Methodology/Principal FindingsEighteen MDD and 18 healthy adolescents were enrolled. Depression and anxiety severity was assessed by the Short Mood and Feeling Questionnaire (SMFQ) and Screen for Child Anxiety Related Emotional Disorders (SCARED) respectively. The functional discrepancy was measured by the amplitude of low-frequency fluctuations (ALFF) of resting-state functional MRI signal. Correlation analysis was carried out between ALFF values and SMFQ and SCARED scores. Resting brain activity levels measured by ALFF was higher in the frontal cortex than that in the subcortical system involving mainly (para) limbic-striatal regions in both HC and MDD adolescents. The difference of ALFF values between frontal and subcortical systems was increased in MDD adolescents as compared with the controls.Conclusions/SignificanceThe present study identified an increased imbalance of resting-state brain activity between the frontal cognitive control system and the (para) limbic-striatal emotional processing system in MDD adolescents. The findings may provide insights into the neural correlates of adolescent MDD.

On the numerically predicted spatial BOLD fMRI specificity for spin echo sequences

This work utilises general numerical magnetic resonance imaging MRI simulations to predict the spatial specificity of the blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal. A Monte Carlo simulation approach was utilized on a microvascular structure consisting of randomly oriented cylinders representing blood vessels. This framework was employed to numerically investigate the spatial specificity, defined as ratio of pial vessel to microvascular signal, of the spin echo BOLD fMRI signal as a function of field strength, echo time and tissue types [grey matter (GM) and cerebrospinal fluid (CSF), respectively]. Spatial specificity of spin echo BOLD fMRI signal was determined to increase with field strength up to 16 T and with maximal specificity for echo time shorter than tissue T 2. In addition, it was found that, for large pial vessels, the extravascular signal decay could not be described using the oversimplified but nevertheless commonly employed mono-exponential signal decay approximation (MEA). Consequently, a recently proposed model relying on the MEA deviates substantially from our results on the spatial specificity. A refinement of this model is proposed based on an available, more detailed signal description. Finally, the effect of CSF on the spatial specificity was investigated. While a large spatial specificity of the spin echo BOLD fMRI signal is observed if a pial vessel is surrounded by grey matter, this is greatly reduced for a pial vessel situated on a GM/CSF interface, rendering the suppression of pial vessels on the cortex surface unlikely.

Variability of the Relationship between Electrophysiology and BOLD-fMRI across Cortical Regions in Humans

The relationship between blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal and the underlying neural electrical activity in humans is a topic of intense interest to systems neuroscience. This relationship has generally been assumed to be invariant regardless of the brain region and the cognitive task being studied. We critically evaluated these assumptions by comparing the BOLD-fMRI response with local field potential (LFP) measurements during visually cued common noun and verb generation in 11 humans in whom 1210 subdural electrodes were implanted. As expected, power in the mid-gamma band (60-120 Hz) correlated positively (r(2) = 0.16, p < 10(-16)) and power in the beta band (13-30 Hz) correlated negatively (r(2) = 0.09, p < 10(-16)) with the BOLD signal change. Beta and mid-gamma band activity independently explain different components of the observed BOLD signal. Importantly, we found that the location (i.e., lobe) of the recording site modulates the relationship between the electrocorticographic (ECoG) signal and the observed fMRI response (p < 10(-16), F(21,1830) = 52.7), while the type of language task does not. Across all brain regions, ECoG activity in the gamma and beta bands explains 22% of the fMRI response, but if the lobar location is considered, 28% of the variance can be explained. Further evaluation of this relationship at the level of individual gyri provides additional evidence of differences in the BOLD-LFP relationship by cortical locus. This spatial variability in the relationship between the fMRI signal and neural activity carries implications for modeling of the hemodynamic response function, an essential step for interregional fMRI comparisons.

Resting-state activity in development and maintenance of normal brain function

One of the most intriguing recent discoveries concerning brain function is that intrinsic neuronal activity manifests as spontaneous fluctuations of the blood oxygen level-dependent (BOLD) functional MRI signal. These BOLD fluctuations exhibit temporal synchrony within widely distributed brain regions known as resting-state networks. Resting-state networks are present in the waking state, during sleep, and under general anesthesia, suggesting that spontaneous neuronal activity plays a fundamental role in brain function. Despite its ubiquitous presence, the physiological role of correlated, spontaneous neuronal activity remains poorly understood. One hypothesis is that this activity is critical for the development of synaptic connections and maintenance of synaptic homeostasis. We had a unique opportunity to test this hypothesis in a 5-y-old boy with severe epileptic encephalopathy. The child developed marked neurologic dysfunction in association with a seizure disorder, resulting in a 1-y period of behavioral regression and progressive loss of developmental milestones. His EEG showed a markedly abnormal pattern of high-amplitude, disorganized slow activity with frequent generalized and multifocal epileptiform discharges. Resting-state functional connectivity MRI showed reduced BOLD fluctuations and a pervasive lack of normal connectivity. The child underwent successful corpus callosotomy surgery for treatment of drop seizures. Postoperatively, the patient's behavior returned to baseline, and he resumed development of new skills. The waking EEG revealed a normal background, and functional connectivity MRI demonstrated restoration of functional connectivity architecture. These results provide evidence that intrinsic, coherent neuronal signaling may be essential to the development and maintenance of the brain's functional organization.

Effects of alcohol intoxication and gender on cerebral perfusion: an arterial spin labeling study

An increasing number of studies use functional MRI (fMRI) and blood oxygen level-dependent (BOLD) signal to investigate the neurofunctional basis of acute alcohol effects on the brain. However, the BOLD signal reflects neural activity only indirectly as it depends on regional hemodynamic changes and is therefore sensitive to vasoactive substances, such as alcohol. We used MRI-based pulsed arterial spin labeling (ASL) method to quantify effects of acute intoxication on resting cerebral perfusion. Gender effects have not been previously examined and yet they are of particular interest given the differences in hormonal dynamics, alcohol metabolism, and hemodynamic regulation. Nineteen young, healthy individuals (nine women) with no personal or familial alcohol- or drug-related problems served as their own controls by participating in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo scanning sessions in a counterbalanced manner. Regionally specific effects of the moderate alcohol dose on gray matter perfusion were examined with voxel-wise and region-of-interest analyses suggesting an interaction between gender and alcohol beverage. Acute intoxication increased perfusion in bilateral frontal regions in men but not in women. Under placebo, stronger cortical perfusion was observed in women compared with men primarily in the left hemisphere in frontal, parietal, and temporal areas. These results emphasize gender differences and regional specificity of alcohol’s effects of cerebral perfusion possibly because of interactive influences on hormonal, metabolic, and hemodynamic autoregulatory systems. Alcohol-induced perfusion increase correlated positively with impulsivity/antisocial tendencies, consistent with dopaminergic mediation of reward, and its effects on cortical perfusion. Additional ASL studies are needed to investigate dose- and time-dependent effects of alcohol intoxication and gender on the hemodynamic factors that conjointly influence BOLD signal to disambiguate the vascular/metabolic mechanisms from the neurally based changes.

Structural and functional bases for individual differences in motor learning.

People vary in their ability to learn new motor skills. We hypothesize that between-subject variability in brain structure and function can explain differences in learning. We use brain functional and structural MRI methods to characterize such neural correlates of individual variations in motor learning. Healthy subjects applied isometric grip force of varying magnitudes with their right hands cued visually to generate smoothly-varying pressures following a regular pattern. We tested whether individual variations in motor learning were associated with anatomically colocalized variations in magnitude of functional MRI (fMRI) signal or in MRI differences related to white and grey matter microstructure. We found that individual motor learning was correlated with greater functional activation in the prefrontal, premotor, and parietal cortices, as well as in the basal ganglia and cerebellum. Structural MRI correlates were found in the premotor cortex [for fractional anisotropy (FA)] and in the cerebellum [for both grey matter density and FA]. The cerebellar microstructural differences were anatomically colocalized with fMRI correlates of learning. This study thus suggests that variations across the population in the function and structure of specific brain regions for motor control explain some of the individual differences in skill learning. This strengthens the notion that brain structure determines some limits to cognitive function even in a healthy population. Along with evidence from pathology suggesting a role for these regions in spontaneous motor recovery, our results also highlight potential targets for therapeutic interventions designed to maximize plasticity for recovery of similar visuomotor skills after brain injury.

Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal

Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with "upstream" propagation of vasodilation toward the cortical surface along the diving arterioles and "downstream" propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the "initial dip" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.

Real-time fMRI-based brain–computer interfacing for neurofeedback therapy and compensation of lost motor functions

Real-time functional MRI (rt-fMRI) allows for brain–computer interfaces based on hemodynamic brain signals and opens up various novel clinical applications. For example, rt-fMRI-based neurofeedback has been suggested as a novel tool for the treatment of neurological and psychopathological disorders. In contrast to conventional offline applications, neurofeedback requires the ana lysis of functional MRI signals online in order to provide participants with information about their brain activation during an ongoing MRI scan. Recent research supports the idea that an improvement of symptoms of diseases can be achieved if patients are trained with rt-fMRI-based neurofeedback to change their brain activation patterns. rt-fMRI also enables online ‘brain-reading‘ applications that can be exploited to develop alternative communication and control devices for patients with severe motor impairments (e.g., ‘locked-in’ patients). Although other methods, especially electroencephalography-based brain–computer interfacing, have been successfully used in this context, rt-fMRI-based methods may enable robust communication and control in cases where traditional approaches do not provide satisfactory results.

Evaluation of group homogeneity during acupuncture stimulation in fMRI studies

To evaluate the extent of individual differences of functional MRI (fMRI) signal changes induced by acupuncture stimulation. Acupuncture at ST36 and checkerboard stimulation was applied to 16 subjects. We calculated the mean distance using beta values in a generalized linear model (GLM) analysis and employed it to study the group homogeneity by detecting the outliers. A more significant individual difference was presented in acupuncture stimulation compared with visual stimulation through evaluation of the mean distance. From the group results, we found that the activations were more significant in the homogeneous group results. Combining the behavior and fMRI results, there was no direct correlation between deqi index and mean distance in acupuncture stimulation. The deqi index of the outlier was in the normal range and did not differ significantly from others. Traditional group results without removing outliers were not sensitive enough to detect the real acupuncture effect. We suggest that individual difference should be taken into consideration for future acupuncture studies. Also, group analysis paralleled with individual analysis is critical for a full understanding of acupuncture effects.

Central mechanism of electric-acupuncture at Zusanli (ST36) for gastric mucous membrane protection with FMRI

To explore the central mechanism of acupuncture in protecting gastric mucous membrane by a composite analysis of gastric mucous membrane related indices in peripheral blood and functional MRI (fMRI) signal changes after electric-acupuncturing Zusanli (ST36) acupoint. Sixteen healthy adult volunteers were divided into true acupoint group (A) and sham acupoint group (B). Zusanli acupoint was used for Group A. Peripheral blood was drawn 5 min before and 5, 15, 25, 30 min after needle-removal for the detection of gastric mucous membrane related indices. fMRI was performed during acupuncture and the acquired fMRI data were analyzed by SPM2 (P < 0.001). The levels of calcitonin gene related peptide (CGRP) and prostaglandin E2 (PGE2) increased while those of endothelin (ET) and gastrin (GAS) decreased significantly after acupuncture in Group A (P < 0.01). And there was no significant change in Group B (P > 0.05). Acupuncturing Zusanli activated the bilateral middle frontal gyrus, caudate, left precentral and postcentral gyri, hypothalamus, anterior cingulate cortex, right hippocampus, insula and cerebellar hemisphere. But acupuncturing the sham acupoint only activated the paracentral lobule and cerebellar hemisphere. Acupuncturing Zusanli acupoint activates certain cortex areas and multiple systems to stimulate the release of neurotransmitters and regulate the peripheral humoral factors to achieve the protection of gastric mucous membrane.

Depression severity evaluation for female patients based on a functional MRI model

To develop a functional MRI (fMRI) signal based model that can evaluate depression severity in a numeric form; therefore, depressed patients can be identified during the course of illness, independent from symptoms. Data from 20 medication-free depressed patients and 16 healthy subjects were analyzed. The event-related fMRI scanning features under sad facial emotional stimuli were extracted as model inputs. Fuzzy logic and a genetic algorithm were used to provide suitable model outputs for numeric estimations of depression. The correlation value r between the model estimations and the professional Hamilton Depression Rating Scales (HAMD) was 0.7886 with P < 0.00016. A typical tracking history for a particular subject has also promised the possibility for early disease warning, when the clinal symptoms are ambiguous or recessive. A numeric and objective estimation for the course of illness can be provided. The model can be used by psychiatrists to track the recovery process. As a simple extended application, the proposed model can be applied to classify subjects into different patterns: major depression, moderate depression, or healthy.

Functional MRI Signal Changes in Primary Visual Cortex Corresponding to the Central Normal Visual Field of Patients with Primary Open-Angle Glaucoma

To investigate, by functional magnetic resonance imaging (fMRI), the impact of glaucomatous neuropathy of primary open-angle glaucoma (POAG) on neuronal activity in the primary visual cortex, which corresponds to the central normal visual field. Six POAG patients with asymmetric visual field damage and spared central vision were enrolled in the study. All patients underwent detailed ophthalmic examinations, including visual acuity, intraocular pressure, refraction, gonioscopy, and fundus examination. Scanning laser polarimetry with variable corneal compensation, confocal scanning laser ophthalmoscopy, posterior segment optical coherence tomography (OCT), and SITA-standard 30-2 and 10-2 visual field perimetry were also performed on each patient. Block-design fMRI was then performed. The stimulus was a hemifield checkerboard contrast, reversing at 8 Hz and viewed by the examined eye monocularly during fMRI scanning, with the fellow eye occluded. The blood oxygen level-dependent (BOLD) fMRI signal change in the primary visual cortex corresponding to central visual input from the more severely affected eye was less than that of the fellow eye. Such a difference in fMRI response did not correlate with interocular differences in measurements of scanning laser polarimetry, OCT, and scanning laser ophthalmoscopy, but showed a negative correlation with interocular pattern SD (PSD) difference of visual field analysis. Glaucomatous neuropathy from POAG may lead to decreased cortical activity in the primary visual cortex, which corresponds to the central normal visual field. The resultant cortical depression is not related to interocular differences in results of polarimetry, OCT, and ophthalmoscopy, but is negatively correlated with PSD of visual field analysis.

Comparison of contrast-response functions from multifocal visual evoked potentials (mfVEPs) and functional MRI signals

Comparison of contrast-response functions from multifocal visual evoked potentials (mfVEPs) and functional MRI signals

Differences in Early Face Processing between Shy and Nonshy Undergraduates: Electrophysiological Evidence from an ERP Study

Shyness refers to individual's behavioral inhibition in social situations and a fear for negative evaluation in social situations which is closely associated with social cognition.Face recognition is an important type of social cognitive abilities in social life.In recent years,the majority of the neurophysiologic studies on shyness have focused on the effect of expressional valence and facial new-old effects upon face processing of shy individuals.It has been found that shyness predicted significantly smaller N400 amplitudes in response to anger and to a neutral expression (Marco,et al.,2005).In addition,it has also been reported that there existed greater functional MRI signal response within the amygdala to novel than to familiar faces among healthy young adults who were originally categorized as behaviorally inhibited and temperamentally shy in early childhood (Schwartz,Wright,Shin,Kagan, Rauch,2003).Shy adults exhibited greater bilateral amygdala activation during the presentation of strange faces and greater left amygdala activation during personally familiar faces than their bold counterparts (Beaton,et al.,2008).Although these results revealed that shy individuals and nonshy individuals had cognitive and neural differences in facial expression recognition and old-new face recognition,whether there exist cognitive and neural differences in the basic face recognition ability (e.g.,face and object recognition) between shy and nonshy individuals remains an issue to be examined.This study investigated into N170 component via the face-object recognition tasks in order to explore the neurophysiologic differences in the early face processing between shy and nonshy undergraduates.The subjects were 17 shy undergraduates and 17 nonshy undergraduates.The major findings of the present study were:(1) the level of shyness interacted significantly with the types of stimuli,with the N170 amplitude of shy undergraduates being greater than that of nonshy undergraduates in face recognition,but this difference did not exist in object recognition.(2) There existed a significant effect of types of stimuli,such that the N170 amplitude elicited by face images was higher than that elicited by object images,and the N170 latency elicited by face images was shorter than by object images.(3) There was significant interaction between the hemispheres of the brain and the types of stimuli.Compared with left hemisphere,the N170 amplitude of right hemisphere was greater in face recognition,but the difference wasn't significant between left and right hemisphere in object recognition.The findings of this study suggest that nonshy undergraduates have processing dominance in facial configuration,and the N170 amplitude of the nonshy undergraduates is greater than that of the shy undergraduates in face recognition.N170 is the special component in face recognition.The right hemisphere manifests processing dominance in N170 in face processing.

To dip or not to dip: Reconciling optical imaging and fMRI data

Several optical studies have reported a brief initial increase of deoxyhemoglobin (1), which is consistent with an initial dip observed in the functional MRI (fMRI) signal, evoked by local neuronal activity. This effect is small and not always present (2), but it has stirred great interest because it may reflect a rapid increase of oxidative metabolism before increases in blood flow and, thus, may have a narrower spatial spread than the main positive hemodynamic response.

Emotion and attention effects: is it all a matter of timing? Not yet.

Controversy surrounds the relationship between emotion and attention in brain and behavior. Two recent studies acquired millisecond-level data to investigate the timing of emotion and attention effects in the amygdala (Luo et al., 2010; Pourtois et al., 2010). Both studies argued that the effects of emotional content temporally precede those of attention and that prior discrepancies in the literature may stem from the temporal characteristics of the functional MRI (fMRI) signal. Although both studies provide important insights about the temporal unfolding of affective responses in the brain, several issues are discussed here that qualify their results. Accordingly, it may not be yet time to accept the conclusion that “automaticity is a matter of timing”. Indeed, emotion and attention may be more closely linked than suggested in the two studies discussed here.

Disease and the brain's dark energy

Brain function has traditionally been studied in terms of physiological responses to environmental demands. This approach, however, ignores the fact that much of the brain's energy is devoted to intrinsic neuronal signaling. Recent studies indicate that intrinsic neuronal activity manifests as spontaneous fluctuations in the blood oxygen level-dependent (BOLD) functional MRI (fMRI) signal. The study of such fluctuations could potentially provide insight into the brain's functional organization. In this article, we begin by presenting an overview of the strategies used to explore intrinsic neuronal activity. Considering the possibility that intrinsic signaling accounts for a large proportion of brain activity, we then examine whether the functional architecture of intrinsic activity is altered in neurological and psychiatric diseases. We also review a clinical application of brain mapping, in which intrinsic activity is employed for the preoperative localization of functional brain networks in patients undergoing neurosurgery. To end the article, we explore some of the basic science pursuits that have been undertaken to further understand the physiology behind intrinsic activity as imaged with BOLD fMRI.

A MATLAB toolbox for Granger causal connectivity analysis

Assessing directed functional connectivity from time series data is a key challenge in neuroscience. One approach to this problem leverages a combination of Granger causality analysis and network theory. This article describes a freely available MATLAB toolbox – ‘Granger causal connectivity analysis’ (GCCA) – which provides a core set of methods for performing this analysis on a variety of neuroscience data types including neuroelectric, neuromagnetic, functional MRI, and other neural signals. The toolbox includes core functions for Granger causality analysis of multivariate steady-state and event-related data, functions to preprocess data, assess statistical significance and validate results, and to compute and display network-level indices of causal connectivity including ‘causal density’ and ‘causal flow’. The toolbox is deliberately small, enabling its easy assimilation into the repertoire of researchers. It is however readily extensible given proficiency with the MATLAB language.

Impact of Alzheimers Disease on the Functional Connectivity of Spontaneous Brain Activity

Alzheimer's disease (AD) prominently affects the structure and function of cerebral networks. Reflecting the complex network structure of the brain, spontaneous brain activity is organized by synchronized activity across distinct temporal and spatial scales. Temporal correlations of the functional MRI (fMRI) signal during rest have been used to characterize the impact of AD on the functional connectivity of spontaneous brain activity. Here we review studies using resting-state fMRI (rs-fMRI) to explore AD-induced changes of synchronized intrinsic activity at three levels of brain organization: the regional, inter-regional and large-scale level. Changes in posterior areas of the default network (DN) and the medial temporal lobes seem to be central to AD. These areas show remarkable disturbances in neuronal communication at all spatial levels and in very early stages of the disease. Finally, rs-fMRI seems to have the potential to produce connectivity-related biomarkers that distinguish AD and healthy aging.