Negative Blood Oxygenation Level-dependent Research Articles

Laminar CBV and BOLD response-characteristics over time and space in the human primary somatosensory cortex at 7T.

Uncovering the cortical representation of the body has been at the core of human brain mapping for decades, with special attention given to the digits. In the last decade, advances in functional magnetic resonance imaging (fMRI) technologies have opened the possibility of noninvasively unraveling the 3rd dimension of digit representations in humans along cortical layers. In laminar fMRI it is common to combine the use of the highly sensitive blood oxygen level dependent (BOLD) contrast with cerebral blood volume sensitive measurements, like vascular space occupancy (VASO), that are more specific to the underlying neuronal populations. However, the spatial and temporal VASO response characteristics across cortical depth to passive stimulation of the digits are still unknown. Therefore, we characterized haemodynamic responses to vibrotactile stimulation of individual digit-tips across cortical depth at 0.75 mm in-plane spatial resolution using BOLD and VASO fMRI at 7T. We could identify digit-specific regions of interest (ROIs) in putative Brodmann area 3b, following the known anatomical organization. In the ROIs, the BOLD response increased towards the cortical surface due to the draining vein effect, while the VASO response was more shifted towards middle cortical layers, likely reflecting bottom-up input from the thalamus, as expected. Interestingly, we also found slightly negative BOLD and VASO responses for non-preferred digits in the ROIs, potentially indicating neuronal surround inhibition. Finally, we explored the temporal signal dynamics for BOLD and VASO as a function of distance from activation peaks resulting from stimulation of contralateral digits. With this analysis, we showed a triphasic response consisting of an initial peak and a subsequent negative deflection during stimulation, followed by a positive post-stimulus response in BOLD and to some extent in VASO. While similar responses were reported with invasive methods in animal models, here we demonstrate a potential neuronal excitation-inhibition mechanism in a center-surround architecture across layers in the human somatosensory cortex. Given that, unlike in animals, human experiments do not rely on anesthesia and can readily implement extensive behavioral testing, obtaining this effect in humans is an important step towards further uncovering the functional significance of the different aspects of the triphasic response.

When the brain turns on with sexual desire: fMRI findings, issues, and future directions.

More than 2 decades of neuroimaging research has sought to uncover the neurologic basis of sexual desire. However, the lack of a clear conceptual distinction between sexual desire and sexual arousal or even a broadly accepted definition of sexual desire has led to confusion in the literature regarding brain areas uniquely associated with sexual desire. (1) To critically review the neuroimaging literature that seeks to identify brain areas and networks involved in sexual desire; (2) to identify and discuss those brain areas and potential networks that are most promising for providing insights to sexual desire; and (3) to offer recommendations for future studies. Existing meta-analyses were used as a starting point to identify relevant neuroimaging studies on sexual desire, arousal, and love. This base was then expanded via Google Scholar and forward citation tracking of already identified studies. Brain areas that are commonly associated with sexual desire and arousal include the amygdala, hypothalamus, dorsal and ventral striatum, anterior cingulate, insula, and prefrontal and orbitofrontal cortex. However, because the same basic paradigm has been used to study sexual desire and arousal, unambiguous conclusions regarding areas uniquely involved in sexual desire cannot be drawn. Moreover, the lack of connectivity analyses and a failure to acknowledge negative BOLD (blood-oxygen level dependent) significantly limit conclusions on the neural basis of sexual desire. Five recommendations are made. First, stimulus types (ie, erotic vs sexually explicit) should be selected by the meaningful theoretical conceptualization of the constructs of interest. Second, participants should be provided with definitions of sexual desire, mental sexual arousal, and perceived genital sexual arousal, so they can choose which terms best describe their experience. Third, event-related designs should be used with caution when investigating sexual desire. Fourth, time series analyses should be used to identify both positive and negative BOLD. Fifth, connectivity analyses should be performed to identify brain networks.

Dorsal striatal response to taste is modified by obesity and insulin resistance.

In preclinical models, insulin resistance in the dorsal striatum (DS) contributes to overeating. Although human studies support the concept of central insulin resistance, they have not investigated its effect on consummatory reward-induced brain activity. Taste-induced activation was assessed in the caudate and putamen of the DS with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. Three phenotypically distinct groups were studied: metabolically healthy lean, metabolically healthy obesity, and metabolically unhealthy obesity (MUO; presumed to have central insulin resistance). Participants with MUO also completed a weight loss intervention followed by a second functional magnetic resonance imaging session. The three groups were significantly different at baseline consistent with the design. The metabolically healthy lean group had a primarily positive BOLD response, the MUO group had a primarily negative BOLD response, and the metabolically healthy obesity group had a response in between the two other groups. Food craving was predicted by taste-induced activation. After weight loss in the MUO group, taste-induced activation increased in the DS. These data support the hypothesis that insulin resistance and obesity contribute to aberrant responses to taste in the DS, which is only partially attenuated by weight loss. Aberrant responses to food exposure may be a barrier to weight loss.

Multi-echo investigations of positive and negative CBF and concomitant BOLD changes

Unlike the positive blood oxygenation level-dependent (BOLD) response (PBR), commonly taken as an indication of an ‘activated’ brain region, the physiological origin of negative BOLD signal changes (i.e. a negative BOLD response, NBR), also referred to as ‘deactivation’ is still being debated. In this work, an attempt was made to gain a better understanding of the underlying mechanism by obtaining a comprehensive measure of the contributing cerebral blood flow (CBF) and its relationship to the NBR in the human visual cortex, in comparison to a simultaneously induced PBR in surrounding visual regions. To overcome the low signal-to-noise ratio (SNR) of CBF measurements, a newly developed multi-echo version of a center-out echo planar-imaging (EPI) readout was employed with pseudo-continuous arterial spin labeling (pCASL). It achieved very short echo and inter-echo times and facilitated a simultaneous detection of functional CBF and BOLD changes at 3 T with improved sensitivity. Evaluations of the absolute and relative changes of CBF and the effective transverse relaxation rate, R2*, the coupling ratios, and their dependence on CBF at rest, CBFrest, indicated differences between activated and deactivated regions. Analysis of the shape of the respective functional responses also revealed faster negative responses with more pronounced post-stimulus transients. Resulting differences in the flow-metabolism coupling ratios were further examined for potential distinctions in the underlying neuronal contributions.

MDD patients with early life stress deactivate the frontostriatal network during facial emotion recognition paradigm: A functional MRI study

IntroductionEarly life stress (ELS) is a significant risk factor for major depressive disorder (MDD) in adults. Functional magnetic resonance imaging (fMRI) studies using face emotion processing paradigms have found altered blood-oxygen-level-dependent (BOLD) responses in the cortico-limbic network both in individuals exposed to ELS and in patients with MDD. Thus, early life stress may have a long-lasting impact on brain areas responsible for the processing of socio-affective cues.ObjectivesBy applying a facial emotion recognition (FER) fMRI paradigm, we examined the long-term effect of childhood adversity on brain activity in MDD patients with and without ELS.MethodsMDD patients without ELS (MDD, N=19), those with ELS (MDD+ELS, N=21), and healthy controls (HC, N=21) matched for age, sex, and intelligence quotient underwent fMRI scanning while performing a block design FER task with faces expressing negative emotions. The severity of ELS was assessed with the 28-item Childhood Trauma Questionnaire.Results Both MDD and MDD+ELS patients were slightly impaired in recognizing sad faces. Statistical analysis of brain activity found that MDD+ELS patients had significantly reduced negative BOLD responses in the right anterior paracingulate gyrus, subcallosal cortex accumbens compared to HCs. Moreover, the MDD+ELS group had a significantly increased negative BOLD signal in the right postcentral and precentral gyri relative to the HC group. MDD+ELS patients had reduced negative BOLD response in their anterior paracingulate gyrus compared to the MDD group.Conclusions Our results support that adult MDD patients with significant ELS are impaired in facial emotion recognition and they display functional alterations in the frontostriatal circuits.DisclosureThis work was financially supported by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002)

Brain-wide ongoing activity is responsible for significant cross-trial BOLD variability.

A notorious issue of task-based functional magnetic resonance imaging (fMRI) is its large cross-trial variability. To quantitatively characterize this variability, the blood oxygenation level-dependent (BOLD) signal can be modeled as a linear summation of a stimulation-relevant and an ongoing (i.e. stimulation-irrelevant) component. However, systematic investigation on the spatiotemporal features of the ongoing BOLD component and how these features affect the BOLD response is still lacking. Here we measured fMRI responses to light onsets and light offsets in awake rats. The neuronal response was simultaneously recorded with calcium-based fiber photometry. We established that between-region BOLD signals were highly correlated brain-wide at zero time lag, including regions that did not respond to visual stimulation, suggesting that the ongoing activity co-fluctuates across the brain. Removing this ongoing activity reduced cross-trial variability of the BOLD response by ~30% and increased its coherence with the Ca2+ signal. Additionally, the negative ongoing BOLD activity sometimes dominated over the stimulation-driven response and contributed to the post-stimulation BOLD undershoot. These results suggest that brain-wide ongoing activity is responsible for significant cross-trial BOLD variability, and this component can be reliably quantified and removed to improve the reliability of fMRI response. Importantly, this method can be generalized to virtually all fMRI experiments without changing stimulation paradigms.

Unimanual sensorimotor learning-A simultaneous EEG-fMRI aging study.

Sensorimotor coordination requires orchestrated network activity in the brain, mediated by inter‐ and intra‐hemispheric interactions that may be affected by aging‐related changes. We adopted a theoretical model, according to which intra‐hemispheric inhibition from premotor to primary motor cortex is mandatory to compensate for inter‐hemispheric excitation through the corpus callosum. To test this as a function of age we acquired electroencephalography (EEG) simultaneously with functional magnetic resonance imaging (fMRI) in two groups of healthy adults (younger N = 13: 20–25 year and older N = 14: 59–70 year) while learning a unimanual motor task. On average, quality of performance of older participants stayed significantly below that of the younger ones. Accompanying decreases in motor‐event‐related EEG β‐activity were lateralized toward contralateral motor regions, albeit more so in younger participants. In this younger group, the mean β‐power during motor task execution was significantly higher in bilateral premotor areas compared to the older adults. In both groups, fMRI blood oxygen level dependent (BOLD) signals were positively correlated with source‐reconstructed β‐amplitudes: positive in primary motor and negative in premotor cortex. This suggests that β‐amplitude modulation is associated with primary motor cortex “activation” (positive BOLD response) and premotor “deactivation” (negative BOLD response). Although the latter results did not discriminate between age groups, they underscore that enhanced modulation in primary motor cortex may be explained by a β‐associated excitatory crosstalk between hemispheres.

Laminar-specific functional connectivity mapping with multi-slice line-scanning fMRI.

Despite extensive studies detecting laminar functional magnetic resonance imaging (fMRI) signals to illustrate the canonical microcircuit, the spatiotemporal characteristics of laminar-specific information flow across cortical regions remain to be fully investigated in both evoked and resting conditions at different brain states. Here, we developed a multislice line-scanning fMRI (MS-LS) method to detect laminar fMRI signals in adjacent cortical regions with high spatial (50 μm) and temporal resolution (100 ms) in anesthetized rats. Across different trials, we detected either laminar-specific positive or negative blood-oxygen-level-dependent (BOLD) responses in the surrounding cortical region adjacent to the most activated cortex under the evoked condition. Specifically, in contrast to typical Layer (L) 4 correlation across different regions due to the thalamocortical projections for trials with positive BOLD, a strong correlation pattern specific in L2/3 was detected for trials with negative BOLD in adjacent regions, which indicated brain state-dependent laminar-fMRI responses based on corticocortical interaction. Also, in resting-state (rs-) fMRI study, robust lag time differences in L2/3, 4, and 5 across multiple cortices represented the low-frequency rs-fMRI signal propagation from caudal to rostral slices. In summary, our study provided a unique laminar fMRI mapping scheme to better characterize trial-specific intra- and inter-laminar functional connectivity in evoked and resting-state MS-LS.

Identification of Negative BOLD Responses in Epilepsy Using Windkessel Models.

Alongside positive blood oxygenation level–dependent (BOLD) responses associated with interictal epileptic discharges, a variety of negative BOLD responses (NBRs) are typically found in epileptic patients. Previous studies suggest that, in general, up to four mechanisms might underlie the genesis of NBRs in the brain: (i) neuronal disruption of network activity, (ii) altered balance of neurometabolic/vascular couplings, (iii) arterial blood stealing, and (iv) enhanced cortical inhibition. Detecting and classifying these mechanisms from BOLD signals are pivotal for the improvement of the specificity of the electroencephalography–functional magnetic resonance imaging (EEG-fMRI) image modality to identify the seizure-onset zones in refractory local epilepsy. This requires models with physiological interpretation that furnish the understanding of how these mechanisms are fingerprinted by their BOLD responses. Here, we used a Windkessel model with viscoelastic compliance/inductance in combination with dynamic models of both neuronal population activity and tissue/blood O2 to classify the hemodynamic response functions (HRFs) linked to the above mechanisms in the irritative zones of epileptic patients. First, we evaluated the most relevant imprints on the BOLD response caused by variations of key model parameters. Second, we demonstrated that a general linear model is enough to accurately represent the four different types of NBRs. Third, we tested the ability of a machine learning classifier, built from a simulated ensemble of HRFs, to predict the mechanism underlying the BOLD signal from irritative zones. Cross-validation indicates that these four mechanisms can be classified from realistic fMRI BOLD signals. To demonstrate proof of concept, we applied our methodology to EEG-fMRI data from five epileptic patients undergoing neurosurgery, suggesting the presence of some of these mechanisms. We concluded that a proper identification and interpretation of NBR mechanisms in epilepsy can be performed by combining general linear models and biophysically inspired models.

Childhood maltreatment results in altered deactivation of reward processing circuits in depressed patients: A functional magnetic resonance imaging study of a facial emotion recognition task

Importance and objectivesChildhood adversity is a strong risk factor for the development of various psychopathologies including major depressive disorder (MDD). However, not all depressed patients experience early life trauma. Functional magnetic resonance imaging (fMRI) studies using facial emotion processing tasks have documented altered blood-oxygen-level-dependent (BOLD) responses in specific cortico-limbic networks both in MDD patients and in individuals with a history of childhood maltreatment (CM). Therefore, a history of maltreatment may represent a key modulating factor responsible for the altered processing of socio-affective stimuli. To test this hypothesis, we recruited MDD patients with and without of maltreatment history to study the long-term consequences of childhood trauma and examined the impact of CM on brain activity using a facial emotion recognition fMRI task. MethodsMDD patients with childhood maltreatment (MDD + CM, n = 21), MDD patients without maltreatment (MDD, n = 19), and healthy controls (n = 21) matched for age, sex and intelligence quotient underwent fMRI while performing a block design facial emotion matching task with images portraying negative emotions (fear, anger and sadness). The history of maltreatment was assessed with the 28-item Childhood Trauma Questionnaire. ResultsBoth MDD and MDD + CM patients displayed impaired accuracy to recognize sad faces. Analysis of brain activity revealed that MDD + CM patients had significantly reduced negative BOLD signals in their right accumbens, subcallosal cortex, and anterior paracingulate gyrus compared to controls. Furthermore, MDD + CM patients had a significantly increased negative BOLD response in their right precentral and postcentral gyri compared to controls. We found little difference between MDD and MDD + CM patients, except that MDD + CM patients had reduced negative BOLD response in their anterior paracingulate gyrus relative to the MDD group. ConclusionsOur present data provide evidence that depressed patients with a history of maltreatment are impaired in facial emotion recognition and that they display altered functioning of key reward-related fronto-striatal circuits during a facial emotion matching task.

FMRI and intra-cranial electrocorticography recordings in the same human subjects reveals negative BOLD signal coupled with silenced neuronal activity

Positive blood oxygenation level-dependent (BOLD) responses (PBR), as measured by functional Magnetic Resonance Imaging (fMRI), are the most utilized measurements to non-invasively map activity in the brain. Recent studies have consistently shown that BOLD responses are not exclusively positive. Negative BOLD responses (NBR) have been reported in response to specific sensory stimulations and tasks. However, the exact relationship between NBR and the underlying metabolic and neuronal demand is still under debate. In this study, we investigated the neurophysiological basis of negative BOLD using fMRI and intra-cranial electrophysiology (electrocorticography, ECoG) measurements from the same human participants. We show that, for those electrodes that responded to visual stimulation, PBR are correlated with high-frequency band (HFB) responses. Crucially, NBR were associated with an absence of HFB power responses and an unpredicted decrease in the alpha power responses.

Modulation of cortical and subcortical brain areas at low and high exercise intensities

IntroductionThe brain plays a key role in the perceptual regulation of exercise, yet neuroimaging techniques have only demonstrated superficial brain areas responses during exercise, and little is known about the...

Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla

Negative blood oxygenation–level dependent (BOLD) signal observed during task execution in functional magnetic resonance imaging (fMRI) can be caused by different mechanisms, such as a blood-stealing effect or neuronal deactivation. Electrophysiological recordings showed that neuronal deactivation underlies the negative BOLD observed in the occipital lobe during visual stimulation. In this study, the metabolic demand of such a response was studied by measuring local metabolite concentration changes during a visual checkerboard stimulation using functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. The results showed increases of glutamate and lactate concentrations during the positive BOLD response, consistent with previous fMRS studies. In contrast, during the negative BOLD response, decreasing concentrations of glutamate, lactate and gamma-aminobutyric acid (GABA) were found, suggesting a reduction of glycolytic and oxidative metabolic demand below the baseline. Additionally, the respective changes of the BOLD signal, glutamate and lactate concentrations of both groups suggest that a local increase of inhibitory activity might occur during the negative BOLD response.

PD04-02 SUPRASPINAL CONTROL VARIAITONS IN MULTIPLE SCLEROSIS PATIENTS WHO VOID SPONTANOUSLY VERUS PATIENTS WITH VOIDING DYSFUNCTION

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction I1 Apr 2018PD04-02 SUPRASPINAL CONTROL VARIAITONS IN MULTIPLE SCLEROSIS PATIENTS WHO VOID SPONTANOUSLY VERUS PATIENTS WITH VOIDING DYSFUNCTION Rose Khavari, Christof Karmonik, and Timothy Boone Rose KhavariRose Khavari More articles by this author , Christof KarmonikChristof Karmonik More articles by this author , and Timothy BooneTimothy Boone More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.280AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In this study, we seek to compare brain activity processes at the time of initiation of voiding in Multiple Sclerosis (MS) patients who are voiders versus patients with voiding dysfunction. We hypothesize that female MS patients with voiding dysfunction have a distinct Blood Oxygen Level Dependent (BOLD) pattern activation in specific a priori regions of interest (ROIs) at the time of initiation of voiding when compared to patients who void spontaneously. METHODS Twenty seven ambulatory female MS patients with lower urinary tract dysfunction were recruited for this IRB approved study: Group 1; voiders (n=15) and group 2; voiding dysfunction (n=12) which was defined as patients with postvoid residual urine of = 40% of their maximum cystometric capacity or patients who performed self-catheterization. We recorded brain activity via fMRI with simultaneous urodynamic testing (UDS). From the transformed datasets, average fMRI activation maps (student t-test) for both groups were created, and areas of significant activation were identified (p<0.05). A priori ROIs identified by a prior meta-analysis to be involved in voiding were selected. RESULTS Group-averaged BOLD activation maps indicated distinct differences in activation patterns between groups (figure 1a). A reversed (negative) BOLD effect was noted in the PMC, PAG, left cingulate, left thalamus and the reticular formation. Interpretation of results Earlier positron emission topography studies have identified right dorsomedial pontine tegmentum and the right inferior frontal gyrus to be associated with significantly increased blood flow in healthy women at the time of voiding. Our results are consistent with these preliminary data in the literature where PMC, PAG, left cingulate, left thalamus and the reticular formation seem to have different pattern of activation between female MS voiders and the ones with voiding dysfunction. CONCLUSIONS Our preliminary group and network analyses demonstrate that distinct supraspinal patterns of activation and deactivation exists between MS patients who are voiders and who have voiding dysfunction. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e77-e78 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Rose Khavari More articles by this author Christof Karmonik More articles by this author Timothy Boone More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Neural inhibition can explain negative BOLD responses: A mechanistic modelling and fMRI study

Functional magnetic resonance imaging (fMRI) of hemodynamic changes captured in the blood oxygen level-dependent (BOLD) response contains information of brain activity. The BOLD response is the result of a complex neurovascular coupling and comes in at least two fundamentally different forms: a positive and a negative deflection. Because of the complexity of the signaling, mathematical modelling can provide vital help in the data analysis. For the positive BOLD response, there are plenty of mathematical models, both physiological and phenomenological. However, for the negative BOLD response, no physiologically based model exists. Here, we expand our previously developed physiological model with the most prominent mechanistic hypothesis for the negative BOLD response: the neural inhibition hypothesis. The model was trained and tested on experimental data containing both negative and positive BOLD responses from two studies: 1) a visual-motor task and 2) a working-memory task in conjunction with administration of the tranquilizer diazepam. Our model was able to predict independent validation data not used for training and provides a mechanistic underpinning for previously observed effects of diazepam. The new model moves our understanding of the negative BOLD response from qualitative reasoning to a quantitative systems-biology level, which can be useful both in basic research and in clinical use.

Positive and Negative Somatotopic BOLD Responses in Contralateral Versus Ipsilateral Penfield Homunculus.

One of the basic properties of sensory cortices is their topographical organization. Most imaging studies explored this organization using the positive blood oxygenation level-dependent (BOLD) signal. Here, we studied the topographical organization of both positive and negative BOLD in contralateral and ipsilateral primary somatosensory cortex (S1). Using phase-locking mapping methods, we verified the topographical organization of contralateral S1, and further showed that different body segments elicit pronounced negative BOLD responses in both hemispheres. In the contralateral hemisphere, we found a sharpening mechanism in which stimulation of a given body segment triggered a gradient of activation with a significant deactivation in more remote areas. In the ipsilateral cortex, deactivation was not only located in the homolog area of the stimulated parts but rather was widespread across many parts of S1. Additionally, analysis of resting-state functional magnetic resonance imaging signal showed a gradient of connectivity to the neighboring contralateral body parts as well as to the ipsilateral homologous area for each body part. Taken together, our results indicate a complex pattern of baseline and activity-dependent responses in the contralateral and ipsilateral sides. Both primary sensory areas were characterized by unique negative BOLD responses, suggesting that they are an important component in topographic organization of sensory cortices.

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone.

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (μ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high μ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the μ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the μ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other μ opioid agonists.

FMRI at High Spatial Resolution: Implications for BOLD-Models.

As high-resolution functional magnetic resonance imaging (fMRI) and fMRI of cortical layers become more widely used, the question how well high-resolution fMRI signals reflect the underlying neural processing, and how to interpret laminar fMRI data becomes more and more relevant. High-resolution fMRI has shown laminar differences in cerebral blood flow (CBF), volume (CBV), and neurovascular coupling. Features and processes that were previously lumped into a single voxel become spatially distinct at high resolution. These features can be vascular compartments such as veins, arteries, and capillaries, or cortical layers and columns, which can have differences in metabolism. Mesoscopic models of the blood oxygenation level dependent (BOLD) response therefore need to be expanded, for instance, to incorporate laminar differences in the coupling between neural activity, metabolism and the hemodynamic response. Here we discuss biological and methodological factors that affect the modeling and interpretation of high-resolution fMRI data. We also illustrate with examples from neuropharmacology and the negative BOLD response how combining BOLD with CBF- and CBV-based fMRI methods can provide additional information about neurovascular coupling, and can aid modeling and interpretation of high-resolution fMRI.

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.

Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.

Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were ‘odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.