Negative BOLD Response Research Articles

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.

Dissociations between glucose metabolism and blood oxygenation in the human default mode network revealed by simultaneous PET-fMRI

The finding of reduced functional MRI (fMRI) activity in the default mode network (DMN) during externally focused cognitive control has been highly influential to our understanding of human brain function. However, these negative fMRI responses, measured as relative decreases in the blood-oxygenation-level-dependent (BOLD) response between rest and task, have also prompted major questions of interpretation. Using hybrid functional positron emission tomography (PET)-MRI, this study shows that task-positive and -negative BOLD responses do not reflect antagonistic patterns of synaptic metabolism. Task-positive BOLD responses in attention and control networks were accompanied by concomitant increases in glucose metabolism during cognitive control, but metabolism in widespread DMN remained high during rest and task despite negative BOLD responses. Dissociations between glucose metabolism and the BOLD response specific to the DMN reveal functional heterogeneity in this network and demonstrate that negative BOLD responses during cognitive control should not be interpreted to reflect relative increases in metabolic activity during rest. Rather, neurovascular coupling underlying BOLD response patterns during rest and task in DMN appears fundamentally different from BOLD responses in other association networks during cognitive control.

Contribution of Excitatory and Inhibitory Neuronal Activity to BOLD fMRI.

The BOLD fMRI response in the cortex is often assumed to reflect changes in excitatory neural activity. However, the contribution of inhibitory neurons to BOLD fMRI is unclear. Here, the role of inhibitory and excitatory activity was examined using multimodal approaches: electrophysiological recording, 15.2 T fMRI, optical intrinsic signal imaging, and modeling. Inhibitory and excitatory neuronal activity in the somatosensory cortex were selectively modulated by 20-s optogenetic stimulation of VGAT-ChR2 and CaMKII-ChR2 mice, respectively. Somatosensory stimulation and optogenetic stimulation of excitatory neurons induced positive BOLD responses in the somatosensory network, whereas stimulation of inhibitory neurons produced biphasic responses at the stimulation site, initial positive and later negative BOLD signals, and negative BOLD responses at downstream sites. When the stimulation duration was reduced to 5 s, the hemodynamic response of VGAT-ChR2 mice to optogenetic stimulation was only positive. Lastly, modeling performed from neuronal and hemodynamic data shows that the hemodynamic response function (HRF) of excitatory neurons is similar across different conditions, whereas the HRF of inhibitory neurons is highly sensitive to stimulation frequency and peaks earlier than that of excitatory neurons. Our study provides insights into the neurovascular coupling of excitatory and inhibitory neurons and the interpretation of BOLD fMRI signals.

Cerebrovascular Reactivity After Sport Concussion: From Acute Injury to 1 Year After Medical Clearance.

Neuroimaging has identified significant disturbances in cerebrovascular reactivity (CVR) in the early symptomatic phase of sport-related concussion. However, less is known about how whole-brain alterations in CVR evolve after concussion and whether they remain present beyond medical clearance to return to play (RTP). In the present study, CVR was evaluated using blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) during a respiratory challenge. Imaging data were collected for 110 university-level athletes, including 39 concussed athletes and 71 athletic controls. The concussed athletes were imaged at the acute phase of injury (1–7 days post-injury), the subacute phase (8-14 days post-injury), medical clearance to RTP, 1 month post-RTP, and 1 year post-RTP. Enhanced negative BOLD response to controlled breathing was seen at acute injury, with attenuation of the effect mainly occurring by 1 year post-RTP. Secondary analyses showed that greater symptom severity and prolonged recovery were associated with enhanced BOLD response in the acute phase of injury, but a more attenuated BOLD response in the subacute phase. This study provides novel information characterizing the CVR response after concussion and shows CVR to be a sensitive technique for evaluating long-term brain recovery.

Reversal of neurovascular coupling in the default mode network: Evidence from hypoxia

Local changes in cerebral blood flow are thought to match changes in neuronal activity, a phenomenon termed neurovascular coupling. Hypoxia increases global resting cerebral blood flow, but regional cerebral blood flow (rCBF) changes are non-uniform. Hypoxia decreases baseline rCBF to the default mode network (DMN), which could reflect either decreased neuronal activity or altered neurovascular coupling. To distinguish between these hypotheses, we characterized the effects of hypoxia on baseline rCBF, task performance, and the hemodynamic (BOLD) response to task activity. During hypoxia, baseline CBF increased across most of the brain, but decreased in DMN regions. Performance on memory recall and motion detection tasks was not diminished, suggesting task-relevant neuronal activity was unaffected. Hypoxia reversed both positive and negative task-evoked BOLD responses in the DMN, suggesting hypoxia reverses neurovascular coupling in the DMN of healthy adults. The reversal of the BOLD response was specific to the DMN. Hypoxia produced modest increases in activations in the visual attention network (VAN) during the motion detection task, and had no effect on activations in the visual cortex during visual stimulation. This regional specificity may be particularly pertinent to clinical populations characterized by hypoxemia and may enhance understanding of regional specificity in neurodegenerative disease pathology.

Evidence for asymmetric inhibitory activity during motor planning phases of sensorimotor synchronization

Sensorimotor synchronization (SMS) is frequently dependent on coordination of excitatory and inhibitory activity across hemispheres, as well as the cognitive control over environmental distractors. However, the timing (motor planning versus execution) and cortical regions involved in these processes remain actively debated. Functional magnetic resonance imaging data were therefore analyzed from 34 strongly right-handed healthy adults performing a cued (to initiate motor planning) SMS task with either their right or left hand (motor execution phase) based on spatially congruent or incongruent visual stimuli. Behavioral effects of incongruent stimuli were limited to the first stimulus. Functionally, greater activation was observed in left sensorimotor cortex (SMC) and right cerebellar Lobule V for congruent versus incongruent stimuli. A negative blood-oxygen level dependent response, a putative marker of neural inhibition, was present in bilateral SMC, right supplemental motor area (SMA) and bilateral cerebellar Lobule V during the motor planning, but not execution phase. The magnitude of the inhibitory response was greater in right cortical regions and cerebellar Lobule V. Homologue connectivity was associated with inhibitory activity in the right SMA, suggesting that individual differences in intrinsic connectivity may mediate transcallosal inhibition. In summary, results suggest increased inhibition (i.e., greater negative BOLD response) within the right relative to left hemisphere, which was released once motor programs were executed. Both task and intrinsic functional connectivity results highlight a critical role of the left SMA in interhemispheric inhibition and motor planning.

Spatially congruent negative BOLD responses to different stimuli do not summate in visual cortex

The negative BOLD response (NBR) is a prevalent feature of brain activity during sensory and cognitive tasks. It is thought to reflect suppression or deactivation of cortical areas unrequired for task performance, but much remains to be understood regarding its response properties and generative pathways. Here we study a unique property of sensory cortex NBR that most distinguishes it from positive BOLD responses (PBR), its appearance in a single location due to different stimuli. We investigate whether such NBR are additive, as a means of studying whether stimulus driven NBR arise via a single or multiple pathways.During fMRI, subject’s passively viewed separate checkerboard stimulation of the foveal and middle-eccentricity areas of the left visual field and a third condition that stimulated both areas concurrently. PBR was observed in the contralateral primary visual cortex and NBR was seen throughout the ipsilateral cortex as well as in contralateral regions superior and anterior to the PBR. Strong spatial overlap of NBRs to all three conditions was observed.We found that neither PBR nor NBR were additive. NBR amplitudes to combined stimuli were equal to those of the strongest (foveal) stimulus alone, despite the mid-eccentricity stimulus inducing substantial NBR on its own. The lack of summation of NBRs, both in the same and opposite hemispheres to the PBR, suggests that they arise from a single pathway. Our findings suggest that although individual stimuli each exert a separate inhibitory effect on non-stimulated regions, once in combination these effects operate as a binary system. Deactivation of a given visual area is driven by a single signal, representing only the largest of the contributing sources.

Task-evoked Negative BOLD Response and Functional Connectivity in the Default Mode Network are Representative of Two Overlapping but Separate Neurophysiological Processes

The topography of the default mode network (DMN) can be obtained with one of two different functional magnetic resonance imaging (fMRI) methods: either from the spontaneous but organized synchrony of the low-frequency fluctuations in resting-state fMRI (rs-fMRI), known as “functional connectivity”, or from the consistent and robust deactivations in task-based fMRI (tb-fMRI), here referred to as the “negative BOLD response” (NBR). These two methods are fundamentally different, but their results are often used interchangeably to describe the brain’s resting-state, baseline, or intrinsic activity. While the DMN was initially defined by consistent task-based decreases in blood flow in a set of specific brain regions using PET imaging, recently nearly all studies on the DMN employ functional connectivity in rs-fMRI. In this study, we first show the high level of spatial overlap between NBR and functional connectivity of the DMN extracted from the same tb-fMRI scan; then, we demonstrate that the NBR in putative DMN regions can be significantly altered without causing any change in their overlapping functional connectivity. Furthermore, we present evidence that in the DMN, the NBR is more closely related to task performance than the functional connectivity. We conclude that the NBR and functional connectivity of the DMN reflect two separate but overlapping neurophysiological processes, and thus should be differentiated in studies investigating brain-behavior relationships in both healthy and diseased populations. Our findings further raise the possibility that the macro-scale networks of the human brain might internally exhibit a hierarchical functional architecture.

The relationship between negative BOLD responses and ERS and ERD of alpha/beta oscillations in visual and motor cortex

Previous work has investigated the electrophysiological origins of the intra-modal (within the stimulated sensory cortex) negative BOLD fMRI response (NBR, decrease from baseline) but little attention has been paid to the origin of cross-modal NBRs, those in a different sensory cortex. In the current study we use simultaneous EEG-fMRI recordings to assess the neural correlates of both intra- and cross-modal responses to left-hemifield visual stimuli and right-hand motor tasks, and evaluate the balance of activation and deactivation between the visual and motor systems. Within- and between-subject covariations of EEG and fMRI responses to both tasks are assessed to determine how patterns of event-related desynchronization/synchronisation (ERD/ERS) of alpha/beta frequency oscillations relate to the NBR in the two sensory cortices.We show that both visual and motor tasks induce intra-modal NBR and cross-modal NBR (e.g. visual stimuli evoked NBRs in both visual and motor cortices). In the EEG data, bilateral intra-modal alpha/beta ERD were consistently observed to both tasks, whilst the cross-modal EEG response varied across subjects between alpha/beta ERD and ERS. Both the mean cross-modal EEG and fMRI response amplitudes showed a small increase in magnitude with increasing task intensity.In response to the visual stimuli, subjects displaying cross-modal ERS of motor beta power displayed a significantly larger magnitude of cross-modal NBR in motor cortex. However, in contrast to the motor stimuli, larger cross-modal ERD of visual alpha power was associated with larger cross-modal visual NBR. Single-trial correlation analysis provided further evidence of relationship between EEG signals and the NBR, motor cortex beta responses to motor tasks were significantly negatively correlated with cross-modal visual cortex NBR amplitude, and positively correlated with intra-modal motor cortex PBR.This study provides a new body of evidence that the coupling between BOLD and low-frequency (alpha/beta) sensory cortex EEG responses extends to cross-modal NBR.

Bottom-up sensory processing can induce negative BOLD responses and reduce functional connectivity in nodes of the default mode-like network in rats

The default mode network is a large-scale brain network that is active during rest and internally focused states and deactivates as well as desynchronizes during externally oriented (top-down) attention demanding cognitive tasks. However, it is not sufficiently understood if salient stimuli, able to trigger bottom-up attentional processes, could also result in similar reduction of activity and functional connectivity in the DMN. In this study, we investigated whether bottom-up sensory processing could influence the default mode-like network (DMLN) in rats. DMLN activity was examined using block-design visual functional magnetic resonance imaging (fMRI) while its synchronization was investigated by comparing functional connectivity during a resting versus a continuously stimulated brain state by unpredicted light flashes. We demonstrated that the BOLD response in DMLN regions was decreased during visual stimulus blocks and increased during blanks. Furthermore, decreased inter-network functional connectivity between the DMLN and visual networks as well as decreased intra-network functional connectivity within the DMLN was observed during the continuous visual stimulation. These results suggest that triggering of bottom-up attention mechanisms in sedated rats can lead to a cascade similar to top-down orienting of attention in humans and is able to deactivate and desynchronize the DMLN.

Negative BOLD responses during hand and foot movements: An fMRI study.

The present study employed functional magnetic resonance imaging (fMRI) to examine the characteristics of negative blood oxygen level-dependent (Negative BOLD) signals during motor execution. Subjects repeated extension and flexion of one of the following: the right hand, left hand, right ankle, or left ankle. Negative BOLD responses during hand movements were observed in the ipsilateral hemisphere of the hand primary sensorimotor area (SMI), medial frontal gyrus (MeFG), middle frontal gyrus (MFG), and superior frontal gyrus (SFG). Negative BOLD responses during foot movements were also noted in the bilateral hand SMI, MeFG, MFG, SFG, inferior frontal gyrus, middle temporal gyrus, parahippocampal gyrus, anterior cingulate cortex, cingulate gyrus (CG), fusiform gyrus, and precuneus. A conjunction analysis showed that portions of the MeFG and CG involving similar regions to those of the default mode network were commonly deactivated during voluntary movements of the right/left hand or foot. The present results suggest that three mechanisms are involved in the Negative BOLD responses observed during voluntary movements: (1) transcallosal inhibition from the contralateral to ipsilateral hemisphere in the SMI, (2) the deactivated neural network with several brain regions, and (3) the default mode network in the MeFG and CG.

The impact of elevated body mass on brain responses during appetitive prediction error in postpartum women

Repeated exposure to highly palatable foods and elevated weight promote: 1) insensitivity to punishment in striatal regions and, 2) increased willingness to work for food. We hypothesized that BMI would be positively associated with negative prediction error BOLD response in the occipital cortex. Additionally, we postulated that food reinforcement value would be negatively associated with negative prediction error BOLD response in the orbital frontal cortex and amygdala. Postpartum women (n = 47; BMI = 25.5 ± 5.1) were ‘trained’ to associate specific cues paired to either a highly palatable milkshake or a sub-palatable milkshake. We then violated these cue-taste pairings in 40% of the trials by showing a palatable cue followed by the sub-palatable taste (negative prediction error). Contrary to our hypotheses, during negative prediction error (mismatched cue-taste) versus matched palatable cue-taste, women showed increased BOLD response in the central operculum (pFWE = 0.002; k = 1680; MNI: -57, −7,14) and postcentral gyrus (pFWE = 0.006, k = 1219; MNI: 62, −8,18). When comparing the matched sub-palatable cue-taste to the negative prediction error trials, BOLD response increased in the postcentral gyrus (r = −0.60, pFWE = 0.008), putamen (r = −0.55, pFWE = 0.02), and insula (r = −0.50, pFWE = 0.01). Similarly, viewing the palatable cue vs sub-palatable cue was related to BOLD response in the putamen (pFWE = 0.025, k = 53; MNI: -20, 6, −8) and the insula (pFWE = 0.04, k = 19, MNI:38, −12, −6). Neither BMI at 6-month postpartum nor food reinforcement value was related to BOLD response. The insula and putamen appear to encode for visual food cue processing, and the gustatory and somatosensory cortices appear to encode negative prediction errors. Differential response in the somatosensory cortex to the matched cue-taste pairs to negative prediction error may indicate that a palatable cue may dull aversive qualities in the stimulus.

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.

Task-Evoked Negative BOLD Response in the Default Mode Network Does Not Alter Its Functional Connectivity.

While functional connectivity networks are often extracted from resting-state fMRI scans, they have been shown to be active during task performance as well. However, the effect of an in-scanner task on functional connectivity networks is not completely understood. While there is evidence that task-evoked positive BOLD response can alter functional connectivity networks, particularly in the primary sensorimotor cortices, the effect of task-evoked negative BOLD response on the functional connectivity of the Default mode network (DMN) is somewhat ambiguous. In this study, we aim to investigate whether task performance, which is associated with negative BOLD response in the DMN regions, alters the time-course of functional connectivity in the same regions obtained by independent component analysis (ICA). ICA has been used to effectively extract functional connectivity networks during task performance and resting-state. We first demonstrate that performing a simple visual-motor task alters the temporal time-course of the network extracted from the primary visual cortex. Then we show that despite detecting a robust task-evoked negative BOLD response in the DMN regions, a simple visual-motor task does not alter the functional connectivity of the DMN regions. Our findings suggest that different mechanisms may underlie the relationship between task-related activation/deactivation networks and the overlapping functional connectivity networks in the human large-scale brain networks.

Dynamic metabolic changes in human visual cortex in regions with positive and negative blood oxygenation level-dependent response

Dynamic metabolic changes were investigated by functional magnetic resonance spectroscopy (fMRS) during sustained stimulation of human primary visual cortex. Two established paradigms, consisting of either a full-field or a small-circle flickering checkerboard, were employed to generate wide-spread areas of positive or negative blood oxygenation level-dependent (BOLD) responses, respectively. Compared to baseline, the glutamate concentration increased by 5.3% (p = 0.007) during activation and decreased by −3.8% (p = 0.017) during deactivation. These changes were positively correlated with the amplitude of the BOLD response (R = 0.60, p = 0.002) and probably reflect changes of tricarboxylic acid cycle activity. During deactivation, the glucose concentration decreased by −7.9% (p = 0.025) presumably suggesting increased consumption or reduced glucose supply. Other findings included an increased concentration of glutathione (4.2%, p = 0.023) during deactivation and a negative correlation of glutathione and BOLD signal changes (R = −0.49, p = 0.012) as well as positive correlations of aspartate (R = 0.44, p = 0.035) and N-acetylaspartylglutamate (R = 0.42, p = 0.035) baseline concentrations with the BOLD response. It remains to be shown in future work if the observed effects on glutamate and glucose levels deviate from the assumption of a direct link between glucose utilization and regulation of blood flow or support previous suggestions that the hemodynamic response is mainly driven by feedforward release of vasoactive messengers.

Disconnected and Hyperactive: A Replication of Sensorimotor Cortex Abnormalities in Patients With Schizophrenia During Proactive Response Inhibition.

Inhibitory failure represents a core dysfunction in patients with schizophrenia (SP), which has predominantly been tested in the literature using reactive (ie, altering behavior after a stimulus) rather than proactive (ie, purposefully changing behavior before a stimulus) response inhibition tasks. The current study replicates/extends our previous findings of SP exhibiting sensorimotor cortex (SMC) hyperactivity and connectivity abnormalities in independent samples of patients and controls. Specifically, 49 clinically well-characterized SP and 54 matched healthy controls (HC) performed a proactive response inhibition task while undergoing functional magnetic resonance imaging and resting-state data collection. Results indicated that the majority of SP (84%) and HC (88%) successfully inhibited all overt motor responses following a cue, eliminating behavioral confounds frequently present in this population. Observations of left SMC hyperactivity during proactive response inhibition, reduced cortical connectivity with left SMC, and increased connectivity between left SMC and ventrolateral thalamus were replicated for SP relative to HC in the current study. Similarly, negative symptoms (eg, motor retardation) were again associated with SMC functional and connectivity abnormalities. In contrast, findings of a negative blood oxygenation level-dependent response in the SMC of HC did not replicate. Collectively, current and previous findings suggest that SMC connectivity abnormalities may be more robust relative to evoked hemodynamic signals during proactive response inhibition. In addition, there is strong support that these SMC abnormalities are a key component of SP pathology, along with dysfunction within other sensory cortices, and may be associated with certain clinical deficits such as negative symptoms.

Negative BOLD Response and Functional Connectivity in the Default Mode Network are Representative of Two Overlapping but Separate Neurophysiological Processes (P4.191)

Negative BOLD Response and Functional Connectivity in the Default Mode Network are Representative of Two Overlapping but Separate Neurophysiological Processes (P4.191)

Mapping and characterization of positive and negative BOLD responses to visual stimulation in multiple brain regions at 7T.

External stimuli and tasks often elicit negative BOLD responses in various brain regions, and growing experimental evidence supports that these phenomena are functionally meaningful. In this work, the high sensitivity available at 7T was explored to map and characterize both positive (PBRs) and negative BOLD responses (NBRs) to visual checkerboard stimulation, occurring in various brain regions within and beyond the visual cortex. Recently-proposed accelerated fMRI techniques were employed for data acquisition, and procedures for exclusion of large draining vein contributions, together with ICA-assisted denoising, were included in the analysis to improve response estimation. Besides the visual cortex, significant PBRs were found in the lateral geniculate nucleus and superior colliculus, as well as the pre-central sulcus; in these regions, response durations increased monotonically with stimulus duration, in tight covariation with the visual PBR duration. Significant NBRs were found in the visual cortex, auditory cortex, default-mode network (DMN) and superior parietal lobule; NBR durations also tended to increase with stimulus duration, but were significantly less sustained than the visual PBR, especially for the DMN and superior parietal lobule. Responses in visual and auditory cortex were further studied for checkerboard contrast dependence, and their amplitudes were found to increase monotonically with contrast, linearly correlated with the visual PBR amplitude. Overall, these findings suggest the presence of dynamic neuronal interactions across multiple brain regions, sensitive to stimulus intensity and duration, and demonstrate the richness of information obtainable when jointly mapping positive and negative BOLD responses at a whole-brain scale, with ultra-high field fMRI.

Contralateral Negative Bold Responses in the Motor Network during Subthreshold High-Frequency Interleaved Tms-Fmri over the Human Primary Motor Cortex

Objective: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that stimulates a localized brain region underneath a coil. Recently, the application of repetitive Transcranial Magnetic Stimulation (rTMS) to the primary motor cortex (M1) has been used to promote functional recovery in stroke patients with hemiparesis. High-frequency rTMS (5 Hz or greater) was applied over the affected hemisphere to reactivate hypoactive regions. Because of recent advances in MRI technology and, in particular, the gradient coils, high-frequency whole brain rTMS-fMRI is possible. The use of interleaved rTMS-fMRI during stimulation at a frequency of 5 Hz aids in understanding how the brain is modulated during stimulation. Method: We measured BOLD signal changes in whole brain during interleaved rTMS-fMRI (5Hz) using 3T MRI. Image processing and statistical analyses were carried out using the Statistical Parametric Mapping (SPM8) software. Results: Distinct BOLD signal changes extending to the remote motor network during 5 Hz-rTMS over the M1 were successfully demonstrated using interleaved rTMS-fMRI. Negative BOLD responses were observed in the contralateral M1, the dorsal premotor cortex (PMd), and the bilateral supplementary motor cortex (SMA), even though no significant BOLD signal changes were observed in the stimulated M1. The negative BOLD responses gradually became marked during (3 mins 57 sec). Therefore, long-lasting plastic changes may occur within 4 mins. Negative BOLD responses in remote regions away from the directly stimulated M1 suggest that subthreshold high frequency rTMS over the motor cortex induced neuromodulation via neuronal networks. Conclusion: The remarkable negative BOLD responses in the contralateral M1 induced by high-frequency rTMS may be useful for identifying a treatment strategy involving M1 stimulation.

Determining Excitatory and Inhibitory Neuronal Activity from Multimodal fMRI Data Using a Generative Hemodynamic Model.

Hemodynamic responses, in general, and the blood oxygenation level-dependent (BOLD) fMRI signal, in particular, provide an indirect measure of neuronal activity. There is strong evidence that the BOLD response correlates well with post-synaptic changes, induced by changes in the excitatory and inhibitory (E-I) balance between active neuronal populations. Typical BOLD responses exhibit transients, such as the early-overshoot and post-stimulus undershoot, that can be linked to transients in neuronal activity, but they can also result from vascular uncoupling between cerebral blood flow (CBF) and venous cerebral blood volume (venous CBV). Recently, we have proposed a novel generative hemodynamic model of the BOLD signal within the dynamic causal modeling framework, inspired by physiological observations, called P-DCM (Havlicek et al., 2015). We demonstrated the generative model's ability to more accurately model commonly observed neuronal and vascular transients in single regions but also effective connectivity between multiple brain areas (Havlicek et al., 2017b). In this paper, we additionally demonstrate the versatility of the generative model to jointly explain dynamic relationships between neuronal and hemodynamic physiological variables underlying the BOLD signal using multi-modal data. For this purpose, we utilized three distinct data-sets of experimentally induced responses in the primary visual areas measured in human, cat, and monkey brain, respectively: (1) CBF and BOLD responses; (2) CBF, total CBV, and BOLD responses (Jin and Kim, 2008); and (3) positive and negative neuronal and BOLD responses (Shmuel et al., 2006). By fitting the generative model to the three multi-modal experimental data-sets, we showed that the presence or absence of dynamic features in the BOLD signal is not an unambiguous indication of presence or absence of those features on the neuronal level. Nevertheless, the generative model that takes into account the dynamics of the physiological mechanisms underlying the BOLD response allowed dissociating neuronal from vascular transients and deducing excitatory and inhibitory neuronal activity time-courses from BOLD data alone and from multi-modal data.