Functional Magnetic Resonance Imaging in Conscious Animals: A New Tool in Behavioural Neuroscience Research

In this study, the extravascular (EV) contribution to blood oxygenation level-dependent (BOLD) signal changes was evaluated, based on a numerical analysis of the nondimensional Bloch-Torrey equation for a vascular network model of randomly oriented paramagnetic vessels. From a statistical point of view, the susceptibility-induced EV BOLD signal changes for both gradient- and spin-echoes are shown to be proportional to cerebral blood volume (CBV). These changes can be expressed by a function of two nondimensional parameters: one represents the characteristic phase change of the signal induced by the deoxyhemoglobin-containing vessels, and the other represents a diffusion effect relative to the vessel radius. The numerical results showed excellent agreement with the analytical solutions obtained previously for the regimes of small and large diffusion effects. Based on the numerical results for gradient- and spin-echoes, it is possible to show the dependence of the EV BOLD contribution on the echo time, the static magnetic field strength, and the stimulation-induced CBV change. This dependence can be demonstrated for vessels of small, intermediate, and large radii, which correspond respectively to the slow, intermediate, and fast diffusion regimes. A more realistic functional MRI (fMRI) simulation which includes an intravascular (IV) contribution is presented, with emphasis on the field strength dependence of the BOLD signal changes.

Background:Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine.Methods:Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03–0.6mg/kg) on the BOLD signal was investigated for 10min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated.Results:A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal.Conclusions:These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function.

Comment on “The physiology of developmental changes in BOLD functional imaging signals” by Harris, Reynell, and Attwell

In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), increased neuronal activity from epileptiform spikes commonly elicits positive blood oxygenation level-dependent (BOLD) responses. Negative responses are also occasionally seen and have not been explained. Recent studies describe BOLD signal changes before focal EEG spikes. We aimed to systematically study if the undershoot of a preceding positive response might explain the negative BOLD seen in the focus. Eighty-two patients with focal epilepsy who underwent EEG-fMRI at 3T were retrospectively studied. Studies with a focal negative BOLD response in the region of the spike field were reanalyzed using models with hemodynamic response functions (HRFs) peaking from -9 to +9 s around the spike. Eight patients met the inclusion criteria, showing negative BOLD responses in the spike field on standard analysis. None had positive BOLD responses immediately adjacent to the areas of deactivation. Regions of deactivation were found to have congruent preceding positive responses in two cases. These early activations were seen at the combined maps of -5 to -9 s. This study indicates that in a small proportion of patients with focal epilepsy in whom the standard analysis reveals focal negative responses, an earlier positive BOLD response is probably the cause. The origin of negative BOLD signal changes in the focus as a result of an epileptic event remains, however, unexplained in most of the patients in whom it occurs.

In patients with nonlesional frontal lobe epilepsy (FLE), the delineation of the epileptogenic zone is difficult. Therefore these patients are often not considered for surgery due to an unclear seizure focus. The aim of this study was to investigate whether EEG-fMRI can add useful information in the preoperative evaluation of these patients. Nine nonlesional FLE patients were studied with EEG-fMRI using a 3 T scanner. Spike-related blood oxygen level dependent (BOLD) signal changes were compared to the topography of the spikes and to PET and SPECT results if available. The structural MRIs were reviewed for subtle abnormalities in areas that showed BOLD responses. For operated patients, postoperative resection and histology were compared to BOLD responses. Concordance between spike localization and positive BOLD response was found in 8 patients. PET and SPECT investigations corresponded with BOLD signal changes in 6 of 7 investigations. In 2 cases, reviewing the structural MRI guided by EEG-fMRI data resulted in considering a suspicious deep sulcus. Two patients were operated. In 1, the resected cortex corresponded with the suspicious sulcus and fMRI results and histology showed cortical dysplasia. In another, histology revealed an extended microdysgenesis not visible on structural MRI. EEG-fMRI had shown activation just adjacent to the resected pathologic area. Our study provides different types of support (topography, concordance with PET and SPECT, structural peculiarities, postoperative histology) that EEG-fMRI may help to delineate the epileptic focus in patients with nonlesional frontal lobe epilepsy, a challenging group in the preoperative evaluation.

Neural circuitry underlying voluntary suppression of sadness

We used EEG-fMRI to study epileptiform activity in a cohort of untreated children with typical absence seizures (AS). Our aim was to identify cortical and subcortical regions involved in spike and wave events and to explore the timing of activity in these regions. Eleven children with AS confirmed on video-EEG underwent EEG-fMRI. An event-related analysis of epileptiform activity was performed. Regions of interest (ROIs), identified in the event-related analysis, were used to study the time course of the blood oxygen level-dependent (BOLD) signal prior to and immediately following events of interest in these ROIs. Group analysis confirmed positive BOLD in the thalamus and negative BOLD in the lateral and mesial parietal lobe, caudate nuclei, and additionally the brainstem reticular formation. The event-related time course differed between the thalamus, the parietal cortex, and the pons and caudate nuclei. In the subcortical structures, BOLD signal change occurred at, or immediately after, electrographic onset. Importantly, in the parietal cortex, but not in other cortical regions, there was a subtle BOLD signal increase for 10 seconds prior to the onset of epileptiform activity. In children with typical AS, we have confirmed a core network of structures involved in generalized epileptiform activity that includes the reticular structures of the brainstem. Furthermore, we have identified changes in parietal BOLD signal which precede the onset of epileptiform activity, suggesting the parietal cortex has a role in the initiation of epileptiform activity.

Essential tremor is a neurological syndrome of heterogeneous pathology and aetiology that is characterized by tremor primarily in the upper extremities. This tremor is commonly hypothesized to be driven by a single or multiple neural oscillator(s) within the cerebello-thalamo-cortical pathway. Several studies have found an association of blood-oxygen level-dependent (BOLD) signal in the cerebello-thalamo-cortical pathway with essential tremor, but there is behavioural evidence that also points to the possibility that the severity of tremor could be influenced by visual feedback. Here, we directly manipulated visual feedback during a functional MRI grip force task in patients with essential tremor and control participants, and hypothesized that an increase in visual feedback would exacerbate tremor in the 4-12 Hz range in essential tremor patients. Further, we hypothesized that this exacerbation of tremor would be associated with dysfunctional changes in BOLD signal and entropy within, and beyond, the cerebello-thalamo-cortical pathway. We found that increases in visual feedback increased tremor in the 4-12 Hz range in essential tremor patients, and this increase in tremor was associated with abnormal changes in BOLD amplitude and entropy in regions within the cerebello-thalamo-motor cortical pathway, and extended to visual and parietal areas. To determine if the tremor severity was associated with single or multiple brain region(s), we conducted a birectional stepwise multiple regression analysis, and found that a widespread functional network extending beyond the cerebello-thalamo-motor cortical pathway was associated with changes in tremor severity measured during the imaging protocol. Further, this same network was associated with clinical tremor severity measured with the Fahn, Tolosa, Marin Tremor Rating Scale, suggesting this network is clinically relevant. Since increased visual feedback also reduced force error, this network was evaluated in relation to force error but the model was not significant, indicating it is associated with force tremor but not force error. This study therefore provides new evidence that a widespread functional network is associated with the severity of tremor in patients with essential tremor measured simultaneously at the hand during functional imaging, and is also associated with the clinical severity of tremor. These findings support the idea that the severity of tremor is exacerbated by increased visual feedback, suggesting that designers of new computing technologies should consider using lower visual feedback levels to reduce tremor in essential tremor.

Activation volume vs BOLD signal change as measures of fMRI activation – Its impact on GABA – fMRI activation correlation

We present a new method for the calculation of a blood oxygen level dependent (BOLD) signal which is meaningful for a quantitative comparison with near infrared spectroscopy (NIRS) data. Since optical tomography of the human brain still poses several difficulties, in this study we propose a way to project the BOLD signal on a two-dimensional (2D) map for comparison with NIRS data. The underlying assumption is that fMRI and NIRS are sensitive to similar aspects of the hemodynamic changes occurring during a functional task, and therefore they should have similar spatial and temporal features. We present a case study of functional activation during a finger-tapping test where we used the new method for the calculation of BOLD signal. For every optical source-detector pair we calculated a weighted BOLD signal by using a photon hitting-density weight function, and by using a simple back-projection algorithm we were able to generate BOLD 2D maps. We found that the weighted BOLD signals calculated from different source-detector pairs scale in a similar way to the corresponding oxy and deoxy-hemeoglobin concentration changes calculated from NIRS data, for most of the time range of the task. Therefore the BOLD 2D maps were quantitatively similar to the optical maps calculated at different times during the protocol.

Background Antidepressants exert their therapeutic effects through ameliorating negative emotional biases that underpin depression. However, therapeutic gains may depend upon restructuring how emotional information is processed. This can be achieved through Cognitive Bias Modification (CBM), a technique for positively shifting recognition of emotional facial expressions. Here, we examined how CBM modifies emotional processing circuits in individuals with depression who were taking Selective Serotonin Reuptake Inhibitors (SSRIs). Methods A double-blind Randomised Controlled Trial was conducted in 84 participants with depression who had recently started SSRI medication. Participants received five sessions of ‘active’ or ‘sham’ CBM over one week before fMRI scanning where they viewed emotional faces (happy, fearful, sad). Results Across all emotional expressions, greater Blood Oxygen Level Dependent (BOLD) signal was observed in the inferior occipital gyrus for the active compared to sham CBM. Emotional-specific effects were observed in the medial Prefrontal Cortex (mPFC), with reduced BOLD signal in the active (compared to sham) group for viewing happy vs. fearful faces. Changes in BOLD signal were also associated with individual differences in response to CBM. Enhanced functional connectivity between mPFC and right Dorsolateral Prefrontal Cortex (rDLPFC) predicted improvement in depressive symptoms four weeks later. Conclusions These results indicate that CBM modifies the neural circuits involved in emotion processing in people with depression currently taking antidepressants. Converting these changes in emotional perception to improved depressive symptoms was related to changing mPFC-rDLPFC connectivity. Future trials are needed to test CBM’s clinical utility as a simple, affordable and accessible adjunct therapy for depression.

Introduction: Fetal brain growth is altered in congenital heart disease (CHD). The role of disturbed placental and fetal blood flow/oxygenation remains poorly understood. We compared the effect of maternal hyperoxia on cerebral and placental oxygenation in CHD vs control fetuses using blood oxygenation level dependent (BOLD) functional MRI (fMRI). Methods: We studied 85 pregnant women (51 healthy /34 CHD fetuses) at 22-39 weeks gestational age (GA), using MRI and Doppler. After 2min baseline recording at normoxia (NO), we made BOLD fMRI measurements in 4 phases, (1) early hyperoxia (HO; 100% O2) for 2min (2) late HO (2min), (3) early return NO (1.75min), (4) late return NO (1.75min). We measured % BOLD signal changes in fetal brain and placenta and correlated these with umbilical artery (UA) pulsatility index (PI) obtained at baseline. Results: Mean GA of CHD vs control fetuses was 32 4/7 and 32 2/7 (p=0.77). 41.2% had 1-ventricle (1V; all HLHS) vs 2-ventricle (2V) physiology. In controls, brain BOLD signal increased in phase 1 HO and remained elevated through phase 4. In CHD fetuses, the BOLD signal increased in phase 1 and continued to rise through phase 4. Differences in brain BOLD elevation in CHD vs controls (3.1% vs 0.9%, p=0.04) was significant in phase 4 (Fig. 1). Brain BOLD differed between 1V (3.4%, p=0.04) and 2V (0.9%, p=0.15) in phases 3 & 4. Placental BOLD signal increased during HO in control (4.4%, p<0.001) and CHD fetuses (6.4%, p<0.001). UA PI in CHD fetuses was higher than controls (1.11 vs 1.03, p=0.03). UA PI correlated with placental BOLD during HO in healthy and CHD fetuses (p<0.05). Conclusions: In this first report of placental and fetal brain responses to maternal HO, we show a significantly increased brain BOLD response in CHD fetuses, specifically 1V. These data suggest that maternal HO improves brain oxygenation in CHD fetuses in the short-term. Studies evaluating the prolonged effects of HO are needed to determine the role of HO management in select CHD fetuses.

Functional magnetic resonance imaging (fMRI) has been a popular approach in brain research over the past 20 years. It offers a noninvasive method to probe the brain and uses blood oxygenation level dependent (BOLD) signal changes to access brain function. However, the BOLD signal only represents a small fraction of the total MR signal. System instability and various noise have a strong impact on the BOLD signal. Additionally, fMRI applies fast imaging technique to record brain cognitive process over time, requiring high temporal stability of MR scanners. Furthermore, data acquisition, image quality, processing, and statistical analysis methods also have a great effect on the results of fMRI studies. Quality assurance (QA) programs for fMRI can test the stability of MR scanners, evaluate the quality of fMRI and help to find errors during fMRI scanning, thereby greatly enhancing the success rate of fMRI. In this review, we focus on previous studies which developed QA programs and methods in SCI/SCIE citation peer-reviewed publications over the last 20 years, including topics on existing fMRI QA programs, QA phantoms, image QA metrics, quality evaluation of existing preprocessing pipelines and fMRI statistical analysis methods. The summarized studies were classified into four categories: QA of fMRI systems, QA of fMRI data, quality evaluation of data processing pipelines and statistical methods and QA of task-related fMRI. Summary tables and figures of QA programs and metrics have been developed based on the comprehensive review of the literature.

The hemodynamic response (HDR) function is the basis for standard functional magnetic resonance imaging (fMRI) analysis. HDR is influenced by white matter inflammation. Traumatic brain injury (TBI) is frequently accompanied by diffuse white matter injury, but the effect of this on the HDR has not been investigated. The aims of the present study were to describe the HDR in visual cortex and examine its relationship with the microstructure of the optic radiation in severe TBI survivors and controls. Ten severe TBI survivors without visual impairments, but with known diffuse axonal injury, and 9 matched controls underwent diffusion tensor imaging (DTI) and fMRI. From the fMRI time series obtained during brief randomized visual stimuli, blood oxygenation level-dependent (BOLD) signal changes for each subject were estimated in V1, and group HDR curves were produced. Standard between-group analysis of BOLD activation in V1 + V2 was performed. For each individual the optic radiations were identified and fractional anisotropy (FA) plus mean apparent diffusion coefficient (ADC(mean)) values for these tracts were calculated. Group HDR curves from the visual cortex were fully transposable between TBI survivors and controls, despite a significant reduction in FA in the optic radiation in TBI survivors. A significant correlation between BOLD signal in the visual cortex and FA values in the optical tract was present in controls, but not in TBI survivors. Between-group comparisons showed that TBI survivors had increased areas of activation in V1 and V2. The HDR appears to be intact in traumatic white matter damage, supporting the validity of using standard fMRI methodology to study neuroplasticity in TBI.

Resting-state brain activity has been widely investigated using blood oxygenation level dependent (BOLD) contrast techniques. However, BOLD signal changes reflect a combination of the effects of cerebral blood flow (CBF), cerebral blood volume (CBV), as well as the cerebral metabolic rate of oxygen (CMRO2). In this study, resting-state brain activation was detected and compared using the following techniques: (a) BOLD, using a gradient-echo echo planar imaging (GE-EPI) sequence; (b) CBV-weighted signal, acquired using gradient and spin echo (GRASE) based vascular space occupancy (VASO); and (c) CBF, using pseudo-continuous arterial spin labeling (pCASL). Reliable brain networks were detected using VASO and ASL, including sensorimotor, auditory, primary visual, higher visual, default mode, salience and left/right executive control networks. Differences between the resting-state activation detected with ASL, VASO and BOLD could potentially be due to the different temporal signal-to-noise ratio (tSNR) and the short post-labeling delay (PLD) in ASL, along with differences in the spin-echo readout of VASO. It is also possible that the dynamics of spontaneous fluctuations in BOLD, CBV and CBF could differ due to biological reasons, according to their location within the brain.