Blood Oxygen Level-dependent Signal Response Research Articles

Perceptual Pattern of Cleft-Related Speech: A Task-fMRI Study on Typical Mandarin-Speaking Adults.

Congenital cleft lip and palate is one of the common deformities in the craniomaxillofacial region. The current study aimed to explore the perceptual pattern of cleft-related speech produced by Mandarin-speaking patients with repaired cleft palate using the task-based functional magnetic resonance imaging (task-fMRI) technique. Three blocks of speech stimuli, including hypernasal speech, the glottal stop, and typical speech, were played to 30 typical adult listeners with no history of cleft palate speech exploration. Using a randomized block design paradigm, the participants were instructed to assess the intelligibility of the stimuli. Simultaneously, fMRI data were collected. Brain activation was compared among the three types of speech stimuli. Results revealed that greater blood-oxygen-level-dependent (BOLD) responses to the cleft-related glottal stop than to typical speech were localized in the right fusiform gyrus and the left inferior occipital gyrus. The regions responding to the contrast between the glottal stop and cleft-related hypernasal speech were located in the right fusiform gyrus. More significant BOLD responses to hypernasal speech than to the glottal stop were localized in the left orbital part of the inferior frontal gyrus and middle temporal gyrus. More significant BOLD responses to typical speech than to the glottal stop were localized in the left inferior temporal gyrus, left superior temporal gyrus, left medial superior frontal gyrus, and right angular gyrus. Furthermore, there was no significant difference between hypernasal speech and typical speech. In conclusion, the typical listener would initiate different neural processes to perceive cleft-related speech. Our findings lay a foundation for exploring the perceptual pattern of patients with repaired cleft palate.

A mechanistic computational framework to investigate the hemodynamic fingerprint of the blood oxygenation level-dependent signal.

Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is one of the most used imaging techniques to map brain activity or to obtain clinical information about human cortical vasculature, in both healthy and disease conditions. Nevertheless, BOLD fMRI is an indirect measurement of brain functioning triggered by neurovascular coupling. The origin of the BOLD signal is quite complex, and the signal formation thus depends, among other factors, on the topology of the cortical vasculature and the associated hemodynamic changes. To understand the hemodynamic evolution of the BOLD signal response in humans, it is beneficial to have a computational framework available that virtually resembles the human cortical vasculature, and simulates hemodynamic changes and corresponding MRI signal changes via interactions of intrinsic biophysical and magnetic properties of the tissues. To this end, we have developed a mechanistic computational framework that simulates the hemodynamic fingerprint of the BOLD signal based on a statistically defined, three-dimensional, vascular model that approaches the human cortical vascular architecture. The microvasculature is approximated through a Voronoi tessellation method and the macrovasculature is adapted from two-photon microscopy mice data. Using this computational framework, we simulated hemodynamic changes-cerebral blood flow, cerebral blood volume, and blood oxygen saturation-induced by virtual arterial dilation. Then we computed local magnetic field disturbances generated by the vascular topology and the corresponding blood oxygen saturation changes. This mechanistic computational framework also considers the intrinsic biophysical and magnetic properties of nearby tissue, such as water diffusion and relaxation properties, resulting in a dynamic BOLD signal response. The proposed mechanistic computational framework provides an integrated biophysical model that can offer better insights regarding the spatial and temporal properties of the BOLD signal changes.

Involvement of the Thalamus, Hippocampus, and Brainstem in Hypsarrhythmia of West Syndrome: Simultaneous Recordings of Electroencephalography and fMRI Study.

West syndrome is a developmental and epileptic encephalopathy characterized by epileptic spasms, neurodevelopmental regression, and a specific EEG pattern called hypsarrhythmia. Our aim was to investigate the brain activities related to hypsarrhythmia at onset and focal epileptiform discharges in the remote period in children with West syndrome using simultaneous electroencephalography and fMRI recordings. Fourteen children with West syndrome underwent simultaneous electroencephalography and fMRI at the onset of West syndrome. Statistically significant blood oxygen level-dependent responses related to hypsarrhythmia were analyzed using an event-related design of 4 hemodynamic response functions with peaks at 3, 5, 7, and 9 seconds after the onset of each event. Six of 14 children had focal epileptiform discharges after treatment and underwent simultaneous electroencephalography and fMRI from 12 to 25 months of age. At onset, positive blood oxygen level-dependent responses were seen in the brainstem (14/14 patients), thalami (13/14), basal ganglia (13/14), and hippocampi (13/14), in addition to multiple cerebral cortices. Group analysis using hemodynamic response functions with peaks at 3, 5, and 7 seconds showed positive blood oxygen level-dependent responses in the brainstem, thalamus, and hippocampus, while positive blood oxygen level-dependent responses in multiple cerebral cortices were seen using hemodynamic response functions with peaks at 5 and 7 seconds. In the remote period, 3 of 6 children had focal epileptiform discharge-related positive blood oxygen level-dependent responses in the thalamus, hippocampus, and brainstem. Positive blood oxygen level-dependent responses with hypsarrhythmia appeared in the brainstem, thalamus, and hippocampus on earlier hemodynamic response functions than the cerebral cortices, suggesting the propagation of epileptogenic activities from the deep brain structures to the neocortices. Activation of the hippocampus, thalamus, and brainstem was still seen in half of the patients with focal epileptiform discharges after adrenocorticotropic hormone therapy.

Dopaminergic neuromodulation has no detectable effect on visual-cue induced haemodynamic response function in the visual cortex: A double-blind, placebo-controlled functional magnetic resonance imaging study.

The aim of this study was to investigate the effect of acute dopamine agonistic and antagonistic manipulation on the visual-cue induced blood oxygen level-dependent signal response in healthy volunteers. Seventeen healthy volunteers in a double-blind placebo-controlled cross-over design received either a dopamine antagonist, agonist or placebo and underwent functional magnetic resonance imaging. Using classical inference and Bayesian statistics, we found no effect of dopaminergic modulation on properties of visual-cue induced blood oxygen level-dependent signals in the visual cortex, particularly on distinct properties of the haemodynamic response function (amplitude, time-to-peak and width). Dopamine-related effects modulating the neurovascular coupling in the visual cortex might be negligible when measured via functional magnetic resonance imaging.

Sickle Cell Cerebrovascular Reactivity to a CO2 Stimulus Is Both Too Little and Too Slow

Background: By age 30, over 50% of sickle cell disease (SCD) patients have suffered a cerebral infarct. In response to anemia and the reduction in oxygen-carrying capacity, cerebral blood flow (CBF) increases to match metabolic demand. Increased velocity of CBF in major cerebral arteries is a strong risk factor for stroke in SCD children and adolescents. Despite generally increased CBF, silent cerebral infarcts (SCI) can still occur in patients receiving optimal transfusions. This suggests that the increased CBF does not meet metabolic demand and that vasodilatory response is compromised. Hypothesis: In adult patients with SCD, cerebrovascular reactivity (slope of the vasodilatory response to CO2 (CVR) and the steady-state CVR (amplitude) and speed of the vasodilatory response (tau) to a standardized vasodilatory stimulus CO2), are reduced compared to normal subjects. We also explored for possible associations with clinical characteristics. Methods: Functional brain imaging performed as part of routine care in adult (≥18) SCD patients (any phenotype) at the University Health Network Comprehensive Sickle Cell Center (Toronto, Canada) between 2017 and 2018 were reviewed. Patients with known cerebral vasculopathy were excluded. CVR was calculated as the change in CBF measured as the blood oxygenation level dependent (BOLD)-MRI signal, in response to a standard vasoactive stimulus of CO2 (delivered by RespirActTM). To calculate the dynamic (tau) and steady-state CVR (amplitude) components of the BOLD signal response, the PET CO2 waveform was convolved with an exponential decay function. The tau corresponding to the best fit between the convolved CO2 and BOLD signal was defined as the speed of vascular response. The slope of the regression between the convolved CO2 and BOLD signal was defined as amplitude. CVR, amplitude and tau were normalized voxel-wise relative to the mean and standard deviation of the same metric in the corresponding voxels of a previously generated atlas of 42 healthy controls (Z scores). These Z scores were averaged over the vascular territories of the brain for both grey (GM) and white matter (WM). Fisher exact and Pearson correlations were performed to identify possible associations between CVR metrics and SCD comorbid conditions, laboratory parameters, and use of disease-modifying therapy. Associations with univariate P <0.20 were included in the multiple linear regression model. Multi-collinearity was assessed. Results: Fifteen patients were included in the study. The median age was 27 [IQR22-35]. 5/15 (33.3%) were male. 9/15 (60%) were SS or S/b0 and 5/15 (33.3%) were SC. 4/15 (26.7%) were on transfusion. MRI/MRA uncovered Moya moya in 1 patient. SCI were present in 3/15 (21.4%). Compared to the reference atlas of normal subjects, CVR and amplitude were reduced both in GM and WM (mean Z-score for CVR -0.52 [-1.8 - 0.28] and -0.63 [-2.31 - 0.66]; amplitude -0.26 [-2.61 - 0.66] and -0.28 [-2.70 - 0.60] respectively). Tau was lengthened in GM and WM (mean tau Z-score +0.90 [-0.49 - 3.32] and +0.76 [-0.66 - 2.78] respectively). These abnormal metrics were observed with varying severities in all 3 main vascular territories (Figure). CVR decreased linearly with decreasing hematocrit (Hct) (r=0.59, p=0.03). There was also a trend towards lower CVR in SS or S/b0 patients (t=-1.41, p=0.18, d=0.76) and was highly collinear with Hct. Hematocrit was the only significant independent predictor of CVR metrics on multivariable regression. Conclusions: All three measures of cerebrovascular health (CVR, amplitude and tau) in SCD patients were abnormal compared to normal controls. Hematocrit appears to be the strongest independent predictor of these measures. The protocol we applied for measuring CVR provides a standardized reproducible vasodilatory stimulus, enabling comparison against a population of healthy individuals for more accurate assessment of CVR in individual subjects. Furthermore, the stimulus protocol produces rapid changes in arterial CO2 levels within one breath that can be used to measure the speed of response of the vasculature representing a novel metric of vascular performance postulated to represent vessel compliance and functional endothelial integrity. These findings show that CVR methodology represents a promising tool to assess disease state, stroke risk, and therapeutic efficacy in sickle cell patients and merits further investigation. Figure 1 Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer - Global Medical Grants: Research Funding. Sobczyk:Thornhill Research Inc.: Current Employment. Duffin:Thornhill Research Inc.: Current Employment. Fisher:Thornhill Research Inc.: Current equity holder in private company. Mikulis:Thornhill Research Inc.: Current equity holder in private company. Kuo:Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Bluebird Bio: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Apellis: Consultancy; Celgene: Consultancy.

Training-Induced Changes in Radial-Tangential Anisotropy of Visual Crowding.

PurposeOne of the diagnostic features of visual crowding, radial–tangential anisotropy, has been observed both in behavioral experiments as well as in responses of the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal. As has been shown previously, crowding is stronger for radially arranged flankers, and this tendency is reflected in BOLD signal suppression. In the current study, we examined the effect of practice on the neural correlates of crowding. We expected that training on a crowding task would cause shrinkage of the crowding zone that would be mirrored in corresponding BOLD signal responses.MethodsPre- and post-training fMRI images were acquired in 17 healthy volunteers using a 3-tesla MRI scanner. Participants were trained over 4 consecutive days on a crowding task.ResultsComparison of the pre- and post-training behavioral data indicates a significant shrinkage of the crowding zone as a result of training. Moreover, we observed a pronounced radial–tangential anisotropy in the BOLD signal prior to training; that is, radial flankers induced a larger reduction in the BOLD signal compared to equally spaced tangential flankers. After training, this radial–tangential anisotropy in the BOLD signal was significantly reduced. Specifically, we found significant changes in BOLD responses for the radial flanker configuration.ConclusionsOur results demonstrate that training-induced changes in the anisotropic shape of the crowding zone are reflected in the BOLD signal in the early visual cortex.Translational RelevancePerceptual learning tasks may have the potential to improve visual performance by promoting neural plasticity. Our results could motivate the development of suitable rehabilitation protocols for patients with central vision loss.

BOLD responses to inhibition in cannabis-using adolescents and emerging adults after 2weeks of monitored cannabis abstinence.

Previous studies have suggested that chronic cannabis use has been associated with increased blood oxygen level-dependent (BOLD) response during a response inhibition task; however, these studies primarily included males. We investigated whether gender moderated the effects of cannabis use on BOLD response and behavioral performance during a Go-NoGo task in adolescents and young adults following 2weeks of monitored abstinence. Participants included 77 16-26-year olds (MJ = 36, controls = 41). An emotion-based Go-NoGo task required participants to inhibit their response during a calm face. A whole-brain analysis looked at differences between cannabis group, gender, and their interaction. Significant greater BOLD responses were observed in cannabis users compared with that in controls in the left frontal cortex, left cingulate cortex, and the left thalamus during correct response inhibitions; gender did not moderate these effects. Supporting previous research, cannabis users showed greater BOLD responses in core areas associated with response inhibition during a Go-NoGo task, even after a minimum of 2weeks of abstinence.

Aberrant Salience? Brain Hyperactivation in Response to Pain Onset and Offset in Fibromyalgia.

While much brain research on fibromyalgia (FM) focuses on the study of hyperresponsiveness to painful stimuli, some studies suggest that the increased pain-related brain activity often reported in FM studies may be partially explained by stronger responses to salient aspects of the stimulation rather than, or in addition to, the stimulation's painfulness. Therefore, this study was undertaken to test our hypothesis that FM patients would demonstrate elevated brain responses to both pain onset and offset-2 salient sensory events of opposing valences. Thirty-eight FM patients (mean ± SD age 46.1 ± 13.4 years; 33 women) and 15 healthy controls (mean ± SD age 45.5 ± 12.4; 10 women) received a moderately painful pressure stimulus to the leg during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Stimulus onset and offset transients were analyzed using a general linear model as stick functions. During pain onset, higher BOLD signal response was observed in FM patients compared to healthy controls in dorsolateral and ventrolateral prefrontal cortices (DLPFC and VLPFC, respectively), orbitofrontal cortex (OFC), frontal pole, and precentral gyrus (PrCG). During pain offset, higher and more widespread BOLD signal response was demonstrated in FM patients compared to controls in frontal regions significantly hyperactivated in response to onset. In FM patients, some of these responses were positively correlated with pain unpleasantness ratings (VLPFC, onset; r = 0.35, P = 0.03), pain catastrophizing scores (DLPFC, offset; r = 0.33, P = 0.04), or negatively correlated with stimulus intensity (OFC, offset; r = -0.35, P = 0.03) (PrCG, offset; r = -0.39, P = 0.02). Our results suggest that the increased sensitivity exhibited by FM patients in response to the onset and offset of painful stimuli may reflect a more generalized hypersensitivity to salient sensory events, and that brain hyperactivation may be a mechanism potentially involved in the generalized hypervigilance to salient stimuli in FM.

A Comprasion of the Activation of Mirror Neurons Induced by Action Observation between Simple and Complex Hand Movement

Purpose: We compared the activation pattern of the mirror neurons (MN) between two types of hand movement according to action observation using functional MRI. Methods: Twelve right-handed healthy subjects (5 male and 7 female, mean age 21.92±2.02 years) participated in the experiment. Dur ing fMRI scanning, subjects underwent two different stimuli on the screen: 1) video clips showing repeated grasping and releasing of the ball via simple hand movement (SHM), and (2) video clips showing an actor performing a Purdue Pegboard test via complex hand move ment (CHM). paired t-test in statistical parametric mapping (SPM) was used to compare the activation differences between the two types of hand movement. Results: CHM as compared with the SHM produced a higher blood oxygen level dependent (BOLD) signal response in the right superior frontal gyrus, left inferior and superior parietal lobules, and lingual gyrus. However, no greater BOLD signal response was found by SHM compared with CHM (FWE corrected, p<0.05). Conclusion: Our findings provided that the activation patterns for observation of SHM and CHM are different. CHM also elicited boarder or stronger activations in the brain, including inferior parietal lobule called the MN region

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

Optogenetic astrocyte activation evokes BOLD fMRI response with oxygen consumption without neuronal activity modulation.

Functional magnetic resonance imaging (fMRI) based on the blood oxygenation level-dependent (BOLD) signal has been used to infer sites of neuronal activation in the brain. A recent study demonstrated, however, unexpected BOLD signal generation without neuronal excitation, which led us to hypothesize the presence of another cellular source for BOLD signal generation. Collective assessment of optogenetic activation of astrocytes or neurons, fMRI in awake mice, electrophysiological measurements, and histochemical detection of neuronal activation, coherently suggested astrocytes as another cellular source. Unexpectedly, astrocyte-evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Imaging mass spectrometry of brain sections identified synthesis of acetyl-carnitine via oxidative glucose metabolism at the site of astrocyte-, but not neuron-evoked BOLD signal. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.

High spatio‐temporal resolution in functional MRI with 3D echo planar imaging using cylindrical excitation and a CAIPIRINHA undersampling pattern

The combination of 3D echo planar imaging (3D-EPI) with a 2D-CAIPIRINHA undersampling scheme provides high flexibility in the optimization for spatial or temporal resolution. This flexibility can be increased further with the addition of a cylindrical excitation pulse, which exclusively excites the brain regions of interest. Here, 3D-EPI was combined with a 2D radiofrequency pulse to reduce the brain area from which signal is generated, and hence, allowing either reduction of the field of view or reduction of parallel imaging noise amplification. 3D-EPI with cylindrical excitation and 4 × 3-fold undersampling in a 2D-CAIPIRINHA sampling scheme was used to generate functional MRI (fMRI) data with either 2-mm or 0.9-mm in-plane resolution and 1.1-s temporal resolution over a 5-cm diameter cylinder placed over both temporal lobes for an auditory fMRI experiment. Significant increases in image signal-to-noise ratio (SNR) and temporal SNR (tSNR) were found for both 2-mm isotropic data and the high-resolution protocol when using the cylindrical excitation pulse. Both protocols yielded highly significant blood oxygenation level-dependent responses for the presentation of natural sounds. The higher tSNR of the cylindrical excitation 3D-EPI data makes this sequence an ideal choice for high spatiotemporal resolution fMRI acquisitions. Magn Reson Med 79:2589-2596, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Tumor physiological changes during hypofractionated stereotactic body radiation therapy assessed using multi-parametric magnetic resonance imaging.

Radiation therapy is a primary treatment for non-resectable lung cancer and hypoxia is thought to influence tumor response. Hypoxia is expected to be particularly relevant to the evolving new radiation treatment scheme of hypofractionated stereotactic body radiation therapy (SBRT). As such, we sought to develop non-invasive tools to assess tumor pathophysiology and response to irradiation. We applied blood oxygen level dependent (BOLD) and tissue oxygen level dependent (TOLD) MRI, together with dynamic contrast enhanced (DCE) MRI to explore the longitudinal effects of SBRT on tumor oxygenation and vascular perfusion using A549 human lung cancer xenografts in a subcutaneous rat model. Intra-tumor heterogeneity was seen on multi-parametric maps, especially in BOLD, T2* and DCE. At baseline, most tumors showed a positive BOLD signal response (%ΔSI) and increased T2* in response to oxygen breathing challenge, indicating increased vascular oxygenation. Control tumors showed similar response 24 hours and 1 week later. Twenty-four hours after a single dose of 12 Gy, the irradiated tumors showed a significantly decreased T2* (-2.9±4.2 ms) and further decrease was observed (-4.0±6.0 ms) after 1 week, suggesting impaired vascular oxygenation. DCE revealed tumor heterogeneity, but showed minimal changes following irradiation. Rats were cured of the primary tumors by 3×12 Gy, providing long term survival, though with ultimate metastatic recurrence.

Functional Laterality of Task-Evoked Activation in Sensorimotor Cortex of Preterm Infants: An Optimized 3 T fMRI Study Employing a Customized Neonatal Head Coil.

BackgroundFunctional magnetic resonance imaging (fMRI) in neonates has been introduced as a non-invasive method for studying sensorimotor processing in the developing brain. However, previous neonatal studies have delivered conflicting results regarding localization, lateralization, and directionality of blood oxygenation level dependent (BOLD) responses in sensorimotor cortex (SMC). Amongst the confounding factors in interpreting neonatal fMRI studies include the use of standard adult MR-coils providing insufficient signal to noise, and liberal statistical thresholds, compromising clinical interpretation at the single subject level.Patients / methodsHere, we employed a custom-designed neonatal MR-coil adapted and optimized to the head size of a newborn in order to improve robustness, reliability and validity of neonatal sensorimotor fMRI.Thirteen preterm infants with a median gestational age of 26 weeks were scanned at term-corrected age using a prototype 8-channel neonatal head coil at 3T (Achieva, Philips, Best, NL). Sensorimotor stimulation was elicited by passive extension/flexion of the elbow at 1 Hz in a block design. Analysis of temporal signal to noise ratio (tSNR) was performed on the whole brain and the SMC, and was compared to data acquired with an ‘adult’ 8 channel head coil published previously. Task-evoked activation was determined by single-subject SPM8 analyses, thresholded at p < 0.05, whole-brain FWE-corrected.ResultsUsing a custom-designed neonatal MR-coil, we found significant positive BOLD responses in contralateral SMC after unilateral passive sensorimotor stimulation in all neonates (analyses restricted to artifact-free data sets = 8/13). Improved imaging characteristics of the neonatal MR-coil were evidenced by additional phantom and in vivo tSNR measurements: phantom studies revealed a 240% global increase in tSNR; in vivo studies revealed a 73% global and a 55% local (SMC) increase in tSNR, as compared to the ‘adult’ MR-coil.ConclusionsOur findings strengthen the importance of using optimized coil settings for neonatal fMRI, yielding robust and reproducible SMC activation at the single subject level. We conclude that functional lateralization of SMC activation, as found in children and adults, is already present in the newborn period.

Dorsal root ganglion stimulation attenuates the BOLD signal response to noxious sensory input in specific brain regions: Insights into a possible mechanism for analgesia

Targeted dorsal root ganglion (DRG) electrical stimulation (i.e. ganglionic field stimulation – GFS) is an emerging therapeutic approach to alleviate chronic pain. Here we describe blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to noxious hind-limb stimulation in a rat model that replicates clinical GFS using an electrode implanted adjacent to the DRG. Acute noxious sensory stimulation in the absence of GFS caused robust BOLD fMRI response in brain regions previously associated with sensory and pain-related response, such as primary/secondary somatosensory cortex, retrosplenial granular cortex, thalamus, caudate putamen, nucleus accumbens, globus pallidus, and amygdala. These regions differentially demonstrated either positive or negative correlation to the acute noxious stimulation paradigm, in agreement with previous rat fMRI studies. Therapeutic-level GFS significantly attenuated the global BOLD response to noxious stimulation in these regions. This BOLD signal attenuation persisted for 20minutes after the GFS was discontinued. Control experiments in sham-operated animals showed that the attenuation was not due to the effect of repetitive noxious stimulation. Additional control experiments also revealed minimal BOLD fMRI response to GFS at therapeutic intensity when presented in a standard block-design paradigm. High intensity GFS produced a BOLD signal map similar to acute noxious stimulation when presented in a block-design. These findings are the first to identify the specific brain region responses to neuromodulation at the DRG level and suggest possible mechanisms for GFS-induced treatment of chronic pain.

The BOLD cerebrovascular reactivity response to progressive hypercapnia in young and elderly

Blood Oxygenation Level Dependent (BOLD) imaging in combination with vasoactive stimuli can be used to probe cerebrovascular reactivity (CVR). Characterizing the healthy, age-related changes in the BOLD-CVR response can provide a reference point from which to distinguish abnormal CVR from the otherwise normal effects of ageing. Using a computer controlled gas delivery system, we examine differences in BOLD-CVR response to progressive hypercapnia between 16 young (28±3years, 9 female) and 30 elderly subjects (66±4years, 13 female). Furthermore, we incorporate baseline T2* information to broaden our interpretation of the BOLD-CVR response. Significant age-related differences were observed. Grey matter CVR at 7mmHg above resting PetCO2 was lower amongst elderly (0.19±0.06%ΔBOLD/mmHg) as compared to young subjects (0.26±0.07%ΔBOLD/mmHg). White matter CVR at 7mmHg above baseline PetCO2 showed no significant difference between young (0.04±0.02%ΔBOLD/mmHg) and elderly subjects (0.05±0.03%ΔBOLD/mmHg). We saw no significant differences in the BOLD signal response to progressive hypercapnia between male and female subjects in either grey or white matter. The observed differences in the healthy BOLD-CVR response could be explained by age-related changes in vascular mechanical properties.

The Effect of Depo Medroxyprogesterone Acetate (DMPA) on Cerebral Food Motivation Centers: A Pilot Study using Functional Magnetic Resonance Imaging

ObjectiveThe primary objective is to examine activation of food motivation centers in the brain before and 8 weeks after depo medroxyprogesterone acetate (DMPA) administration. Study designThis prospective experimental pilot study examined the effects of DMPA on food motivation centers utilizing functional magnetic resonance imaging (fMRI) in eight nonobese, ovulatory subjects. fMRI blood oxygen level dependent (BOLD) signal was measured using a 3-Tesla Scanner while participants viewed images of high-calorie foods, low-calorie foods and nonfood objects. fMRI scans were performed at baseline and 8 weeks after participants received one intramuscular dose of DMPA 150 mg. fMRI data were analyzed using the FMRIB Software Library. Changes in adiposity and circulating leptin and ghrelin levels were also measured. ResultsThere was a greater BOLD signal response to food cues in brain regions associated with food motivation (anterior cingulate gyrus, orbitofrontal cortex) 8 weeks after DMPA administration compared to baseline (z>2.3, p<.05 whole-brain analysis clustered corrected). No statistically significant change was detected in circulating leptin or ghrelin levels or fat mass 8 weeks after DMPA administration. ConclusionAnalysis of differences in food motivation may guide the development of interventions to prevent weight gain in DMPA users. ImplicationsThese data support a neural origin as one of the mechanisms underlying weight gain in DMPA users and may guide future research examining weight gain and contraception.

Cocaine and methamphetamine induce opposing changes in BOLD signal response in rats

BackgroundNeuroimaging studies in psychostimulant addicts have reported functional neural activity changes in brain regions involved in relapse. However, the difference between the effects of the psychostimulants methamphetamine and cocaine on neuronal activity in a similar setting not been clarified. Since studies in humans are limited by the inability to study the initial impact of psychostimulant drugs, we addressed this issue in a rat model. ObjectiveHere, we report methamphetamine and cocaine-induced blood-oxygen-level dependent (BOLD) signal change using functional magnetic resonance imaging (fMRI) in rats receiving drug for the first time during the imaging session. MethodsTwenty-three male Long Evans rats underwent fMRI imaging and received an intravenous infusion of methamphetamine, cocaine, or saline. Anatomical and pharmacological fMRI (pfMRI) were performed on a 7T BioSpec dedicated research MR scanner under isoflurane gas (1.5–2%). After collecting baseline data for 10min, rats received drug over the next 10min for a total 40min scan time. Data were then preprocessed and statistically analyzed in anatomically defined regions of interest (ROIs) that have been implicated in persistent drug seeking and relapse. ResultsMethamphetamine during the imaging session resulted in a sustained negative BOLD signal change in key regions of the relapse circuit, except for the prefrontal cortex. In contrast, cocaine evoked a positive or unchanged BOLD signal in these same regions. In all of the investigated ROIs, there were no changes in BOLD signal following saline. ConclusionAcute methamphetamine and cocaine have distinct patterns of functional activity as measured by pfMRI.

Biological Motion Perception, Brain Responses, and Schizotypal Personality Disorder.

Exploration of the ability to process socially relevant events portrayed by biological motion and to identify underlying neuronal processes can provide clues for understanding the pathophysiology of psychosis. Individuals with schizotypal personality disorder (SPD) have pervasive interpersonal deficits and odd behaviors. An understanding of the neural mechanisms involved in the perception of biological motion and the relation of activity to clinical symptoms in those mechanisms is needed. To investigate the specificity of brain regions responsive to biological motion perception in individuals with SPD compared with healthy control individuals. Twenty-one patients diagnosed as having SPD and 38 age-, sex-, and IQ-matched controls underwent event-related functional magnetic resonance imaging. The SPD group completed the Scale for the Assessment of Positive Symptoms, the Scale for the Assessment of Negative Symptoms, and the Schizotypal Personality Questionnaire for assessment of symptom severity. During scanning, all participants were required to discriminate biological from scrambled sequences of point-light animations. Data were collected from September 21. 2011, to July 13, 2013, and analyzed from March to May 2015. Blood oxygenation level-dependent signals during event-related scanning and symptom severity in the SPD group. The 21 individuals with SPD (16 men and 5 women) and 38 controls (29 men and 9 women) had a mean (SD) age, 22.8 (3.8) vs 22.2 (2.5) years and a mean (SD) IQ, 115.00 (12.55) vs 120.24 )7.68). Brain imaging revealed the presence of neuronal activation specific to biological motion within the posterior superior temporal sulcus. However, the individuals with SPD exhibited regions of neural responsiveness within brain regions forming the reward network, which consisted of the dorsal striatum and bilateral superior medial frontal cortex (all t ≥ 2.99, P of clusters <.002). The individuals with SPD also exhibited reduced activation in the anterior and middle cingulate cortices and the lingual and superior occipital gyri, which are brain areas responsive to biological motion perception and executive control of perception (all t ≥ 3.29, P of clusters <.001). In addition, significant correlations between the hyperdopaminergic clinical symptoms and enhanced neuronal activation in the caudate nucleus and frontal cortex were observed in the SPD group (all r ≥ 0.52, P < .02). Individuals with SPD display heightened activation in the neural circuitry involved in reward and decision making when viewing biological motion stimuli in addition to a positive correlation between increased blood oxygenation level-dependent signal responses related to biological motions and clinical symptoms. These findings suggest that enhanced responses arise within the reward network in individuals with SPD and are possibly related to the peculiar ways that individuals with SPD behave in social contexts.

Fourier modeling of the BOLD response to a breath-hold task: Optimization and reproducibility

Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to adjust their caliber in order to maintain a steady supply of brain perfusion, and it may provide a sensitive disease biomarker. Measurement of the blood oxygen level dependent (BOLD) response to a hypercapnia-inducing breath-hold (BH) task has been frequently used to map CVR noninvasively using functional magnetic resonance imaging (fMRI). However, the best modeling approach for the accurate quantification of CVR maps remains an open issue. Here, we compare and optimize Fourier models of the BOLD response to a BH task with a preparatory inspiration, and assess the test–retest reproducibility of the associated CVR measurements, in a group of 10 healthy volunteers studied over two fMRI sessions. Linear combinations of sine–cosine pairs at the BH task frequency and its successive harmonics were added sequentially in a nested models approach, and were compared in terms of the adjusted coefficient of determination and corresponding variance explained (VE) of the BOLD signal, as well as the number of voxels exhibiting significant BOLD responses, the estimated CVR values, and their test–retest reproducibility. The brain average VE increased significantly with the Fourier model order, up to the 3rd order. However, the number of responsive voxels increased significantly only up to the 2nd order, and started to decrease from the 3rd order onwards. Moreover, no significant relative underestimation of CVR values was observed beyond the 2nd order. Hence, the 2nd order model was concluded to be the optimal choice for the studied paradigm. This model also yielded the best test–retest reproducibility results, with intra-subject coefficients of variation of 12 and 16% and an intra-class correlation coefficient of 0.74. In conclusion, our results indicate that a Fourier series set consisting of a sine–cosine pair at the BH task frequency and its two harmonics is a suitable model for BOLD-fMRI CVR measurements based on a BH task with preparatory inspiration, yielding robust estimates of this important physiological parameter.