Temporal stability of the hemodynamic response function across the majority of human cerebral cortex.

The hemodynamic response function (HRF) measured with functional magnetic resonance imaging is generated by vascular and metabolic responses evoked by brief (<4 s) stimuli. It is known that the human HRF varies across cortex, between subjects, with stimulus paradigms, and even between different measurements in the same cortical location. However, our results demonstrate that strong HRFs are remarkably repeatable across sessions separated by time intervals up to 3 months. In this study, a multisensory stimulus was used to activate and measure the HRF across the majority of cortex (>70%, with lesser reliability observed in some areas of prefrontal cortex). HRFs were measured with high spatial resolution (2-mm voxels) in central gray matter to minimize variations caused by partial-volume effects. HRF amplitudes and temporal dynamics were highly repeatable across four sessions in 20 subjects. Positive and negative HRFs were consistently observed across sessions and subjects. Negative HRFs were generally weaker and, thus, more variable than positive HRFs. Statistical measurements showed that across-session variability is highly correlated to the variability across events within a session; these measurements also indicated a normal distribution of variability across cortex. The overall repeatability of the HRFs over long time scales generally supports the long-term use of event-related functional magnetic resonance imaging protocols.

Retinotopic variations of the negative blood-oxygen-level dependent hemodynamic response function in human primary visual cortex.

Functional magnetic resonance imaging (fMRI) measures blood-oxygen-level-dependent (BOLD) contrast that is generally assumed to be linearly related to excitatory neural activity. The positive hemodynamic response function (pHRF) is the positive BOLD response (PBR) evoked by a brief neural stimulation; the pHRF is often used as the impulse response for linear analysis of neural excitation. Many fMRI studies have observed a negative BOLD response (NBR) that is often associated with neural suppression. However, the temporal dynamics of the NBR evoked by a brief stimulus, the negative HRF (nHRF), remains unclear. Here, a unilateral visual stimulus was presented in a slow event-related design to elicit both pHRFs in the stimulus representation (SR), and nHRFs elsewhere. The observed nHRFs were not inverted versions of the pHRF previously reported. They were characterized by a stronger initial negative response followed by a significantly later positive peak. In contralateral primary visual cortex (V1), these differences varied with eccentricity from the SR. Similar nHRFs were observed in ipsilateral V1 with less eccentricity variation. Experiments with the blocked version of the same stimulus confirmed that brain regions presenting the unexpected nHRF dynamics correspond to those presenting a strong NBR. These data demonstrated that shift-invariant temporal linearity did not hold for the NBR while confirming that the PBR maintained rough linearity. Modeling indicated that the observed nHRFs can be created by suppression of both blood flow and oxygen metabolism. Critically, the nHRF can be misinterpreted as a pHRF due to their similarity, which could confound linear analysis for event-related fMRI experiments.NEW & NOTEWORTHY We investigate dynamics of the negative hemodynamic response function (nHRF), the negative blood-oxygen-level-dependent (BOLD) response (NBR) evoked by a brief stimulus, in human early visual cortex. Here, we show that the nHRFs are not inverted versions of the corresponding pHRFs. The nHRF has complex dynamics that varied significantly with eccentricity. The results also show shift-invariant temporal linearity does not hold for the NBR.

Depth relationships and measures of tissue thickness in dorsal midbrain.

Dorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distances from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for delineating depth for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.

More than BOLD: Dual-spin populations create functional contrast.

PURPOSE: Functional MRI contrast has generally been associated with changes in transverse relaxivity caused by blood oxygen concentration, the so-called blood oxygen level dependent contrast. However, this interpretation of fMRI contrast has been called into question by several recent experiments at high spatial resolution. Experiments were conducted to examine contrast dependencies that cannot be explained only by differences in relaxivity in a single-spin population. METHODS: Measurements of functional signal and contrast were obtained in human early visual cortex during a high-contrast visual stimulation over a large range of TEs and for several flip angles. Small voxels (1.5 mm) were used to restrict the measurements to cortical gray matter in early visual areas identified using retinotopic mapping procedures. RESULTS: Measurements were consistent with models that include 2 spin populations. The dominant population has a relatively short transverse lifetime that is strongly modulated by activation. However, functional contrast is also affected by volume changes between this short-lived population and the longer-lived population. CONCLUSION: Some of the previously observed "nonclassical" behaviors of functional contrast can be explained by these interacting dual-spin populations.

Characterization of the hemodynamic response function across the majority of human cerebral cortex.

A brief (<4 s) period of neural activation evokes a stereotypical sequence of vascular and metabolic events to create the hemodynamic response function (HRF) measured using functional magnetic resonance imaging (fMRI). Linear analysis of fMRI data requires that the HRF be treated as an impulse response, so the character and temporal stability of the HRF are critical issues. Here, a simple audiovisual stimulus combined with a fast-paced task was used to evoke a strong HRF across a majority, ∼77%, of cortex during a single scanning session. High spatiotemporal resolution (2-mm voxels, 1.25-s acquisition time) was used to focus HRF measurements specifically on the gray matter for whole brain. The majority of activated cortex responds with positive HRFs, while ∼27% responds with negative (inverted) HRFs. Spatial patterns of the HRF response amplitudes were found to be similar across subjects. Timing of the initial positive lobe of the HRF was relatively stable across the cortical surface with a mean of 6.1 ±â€¯0.6 s across subjects, yet small but significant timing variations were also evident in specific regions of cortex. The results provide guidance for linear analysis of fMRI data. More importantly, this method provides a means to quantify neurovascular function across most of the brain, with potential clinical utility for the diagnosis of brain pathologies such as traumatic brain injury.

Polar-angle representation of saccadic eye movements in human superior colliculus.

The superior colliculus (SC) is a layered midbrain structure involved in directing both head and eye movements and coordinating visual attention. Although a retinotopic organization for the mediation of saccadic eye-movements has been shown in monkey SC, in human SC the topography of saccades has not been confirmed. Here, a novel experimental paradigm was performed by five participants (one female) while high-resolution (1.2-mm) functional magnetic resonance imaging was used to measure activity evoked by saccadic eye movements within human SC. Results provide three critical observations about the topography of the SC: (1) saccades along the superior-inferior visual axis are mapped across the medial-lateral anatomy of the SC; (2) the saccadic eye-movement representation is in register with the retinotopic organization of visual stimulation; and (3) activity evoked by saccades occurs deeper within SC than that evoked by visual stimulation. These approaches lay the foundation for studying the organization of human subcortical - and enhanced cortical mapping - of eye-movement mechanisms.

Evaluation of spiral acquisition variants for functional imaging of human superior colliculus at 3T field strength.

PURPOSE: High-resolution functional magnetic resonance imaging of human subcortical brain structures is challenging because of their deep location in the cranium, and their comparatively weak blood oxygen level dependent responses to strong stimuli. Magnetic resonance imaging data for subcortical brain regions exhibit both low signal-to-noise ratio and low functional contrast-to-noise ratio. To overcome these challenges, this work evaluates the use of dual-echo spiral variants that combine outward and inward trajectories. Specifically, in-in, in-out, and out-out combinations are evaluated. For completeness, single-echo spiral-in and parallel-receive-accelerated echo-planar-imaging sequences are also evaluated. METHODS: Sequence evaluation was based on comparison of functional contrast-to-noise ratio within retinotopically predefined regions of interest. Superior colliculus was chosen as sample subcortical brain region because it exhibits a strong visual response. All sequences were compared relative to a single-echo spiral-out trajectory to establish a within-session reference. RESULTS: In superior colliculus, the dual-echo out-out outperformed the reference trajectory by 55% in contrast-to-noise ratio, while all other trajectories had performance similar to the reference. The sequences were also compared in early visual cortex. Here, both dual-echo spiral out-out and in-out outperformed the reference by ∼25%. CONCLUSION: Dual-echo spiral variants offer improved contrast-to-noise ratio performance for high-resolution imaging for both superior colliculus and cortex. Magn Reson Med 79:1931-1940, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Arterial impulse model for the BOLD response to brief neural activation.

The blood oxygen level dependent (BOLD) signal evoked by brief neural stimulation, the hemodynamic response function (HRF), is a critical feature of neurovascular coupling. The HRF is directly related to local transient changes in oxygen supplied by cerebral blood flow (CBF) and oxygen demand, the cerebral metabolic rate of oxygen (CMRO2). Previous efforts to explain the HRF have relied upon the hypothesis that CBF produces a non-linear venous dilation within the cortical parenchyma. Instead, the observed dynamics correspond to prompt arterial dilation without venous volume change. This work develops an alternative biomechanical model for the BOLD response based on the hypothesis that prompt upstream dilation creates an arterial flow impulse amenable to linear description. This flow model is coupled to a continuum description of oxygen transport. Measurements using high-resolution fMRI demonstrate the efficacy of the model. The model predicts substantial spatial variations of the oxygen saturation along the length of capillaries and veins, and fits the varied gamut of measured HRFs by the combined effects of corresponding CBF and CMRO2 responses. Three interesting relationships among the hemodynamic parameters are predicted. First, there is an offset linear correlation with approximately unity slope between CBF and CMRO2 responses. Second, the HRF undershoot is strongly correlated to the corresponding CBF undershoot. Third, late-time-CMRO2 response can contribute to a slow recovery to baseline, lengthening the HRF undershoot. The model provides a powerful mathematical framework to understand the dynamics of neurovascular and neurometabolic responses that form the BOLD HRF.

Endogenous attention signals evoked by threshold contrast detection in human superior colliculus.

Human superior colliculus (SC) responds in a retinotopically selective manner when attention is deployed on a high-contrast visual stimulus using a discrimination task. To further elucidate the role of SC in endogenous visual attention, high-resolution fMRI was used to demonstrate that SC also exhibits a retinotopically selective response for covert attention in the absence of significant visual stimulation using a threshold-contrast detection task. SC neurons have a laminar organization according to their function, with visually responsive neurons present in the superficial layers and visuomotor neurons in the intermediate layers. The results show that the response evoked by the threshold-contrast detection task is significantly deeper than the response evoked by the high-contrast speed discrimination task, reflecting a functional dissociation of the attentional enhancement of visuomotor and visual neurons, respectively. Such a functional dissociation of attention within SC laminae provides a subcortical basis for the oculomotor theory of attention.

Measurement of population receptive fields in human early visual cortex using back-projection tomography.

Properties of human visual population receptive fields (pRFs) are currently estimated by performing measurements of visual stimulation using functional magnetic resonance imaging (fMRI), and then fitting the results using a predefined model shape for the pRF. Various models exist and different models may be appropriate under different circumstances, but the validity of the models has never been verified, suggesting the need for a model-free approach. Here, we demonstrate that pRFs can be directly reconstructed using a back-projection-tomography approach that requires no a priori model. The back-projection method involves sweeping thin contrast-defined bars across the visual field whose orientation and direction is rotated through 0°-180° in discrete increments. The measured fMRI time series within a cortical location can be approximated as a projection of the pRF along the long axis of the bar. The signals produced by a set of bar sweeps encircling the visual field form a sinogram. pRFs were reconstructed from these sinograms with a novel scheme that corrects for the blur introduced by the hemodynamic response and the stimulus-bar width. pRF positions agree well with the conventional model-based approach. Notably, a subset of the reconstructed pRFs shows significant asymmetry for both their excitatory and suppressive regions. Reconstructing pRFs using the tomographic approach is a fast, reliable, and accurate way to noninvasively estimate human pRF parameters and visual-field maps without the need for any a priori shape assumption.

Laminar multi-contrast fMRI at 7T allows differentiation of neuronal excitation and inhibition underlying positive and negative BOLD responses.

A major challenge for human neuroimaging using functional MRI is the differentiation of neuronal excitation and inhibition which may induce positive and negative BOLD responses. Here we present an innovative multi-contrast laminar functional MRI technique that offers comprehensive and quantitative imaging of neurovascular (CBF, CBV, BOLD) and metabolic (CMRO2) responses across cortical layers at 7 Tesla. This technique was first validated through a finger-tapping experiment, revealing 'double-peak' laminar activation patterns within the primary motor cortex. By employing a ring-shaped visual stimulus that elicited positive and negative BOLD responses, we further observed distinct neurovascular and metabolic responses across cortical layers and eccentricities in the primary visual cortex. This suggests potential feedback inhibition of neuronal activities in both superficial and deep cortical layers underlying the negative BOLD signals in the fovea, and also illustrates the neuronal activities in visual areas adjacent to the activated eccentricities.

Global effects of aging on the hemodynamic response function in the human brain.

In functional magnetic resonance imaging, the hemodynamic response function (HRF) is a transient, stereotypical response to local changes in cerebral hemodynamics and oxygen metabolism due to briefly (< 4 s) evoked neural activity. Accordingly, the HRF is often used as an impulse response with the assumption of linearity in data analysis. In cognitive aging studies, it has been very common to interpret differences in brain activation as age-related changes in neural activity. Contrary to this assumption, however, evidence has accrued that normal aging may also significantly affect the vasculature, thereby affecting cerebral hemodynamics and metabolism, confounding interpretation of fMRI aging studies. In this study, use was made of a multisensory stimulus to evoke the HRF in ~ 87% of cerebral cortex in cognitively intact adults with ages ranging from 22-75 years. The stimulus evokes both positive and negative HRFs, which were characterized using model-free parameters in native-space coordinates. Results showed significant age trends in HRF parameter distributions in terms of both amplitudes (e.g., peak amplitude and CNR) and temporal dynamics (e.g., full-width-at-half-maximum). This work sets the stage for using HRF methods as a biomarker for age-related pathology.

Framework for Accurate Classification of Self-Reported Stress From Multisession Functional MRI Data of Veterans With Posttraumatic Stress.

Background: Posttraumatic stress disorder (PTSD) is a significant burden among combat Veterans returning from the wars in Iraq and Afghanistan. While empirically supported treatments have demonstrated reductions in PTSD symptomatology, there remains a need to improve treatment effectiveness. Functional magnetic resonance imaging (fMRI) neurofeedback has emerged as a possible treatment to ameliorate PTSD symptom severity. Virtual reality (VR) approaches have also shown promise in increasing treatment compliance and outcomes. To facilitate fMRI neurofeedback-associated therapies, it would be advantageous to accurately classify internal brain stress levels while Veterans are exposed to trauma-associated VR imagery. Methods: Across 2 sessions, we used fMRI to collect neural responses to trauma-associated VR-like stimuli among male combat Veterans with PTSD symptoms (N = 8). Veterans reported their self-perceived stress level on a scale from 1 to 8 every 15 s throughout the fMRI sessions. In our proposed framework, we precisely sample the fMRI data on cortical gray matter, blurring the data along the gray-matter manifold to reduce noise and dimensionality while preserving maximum neural information. Then, we independently applied 3 machine learning (ML) algorithms to this fMRI data collected across 2 sessions, separately for each Veteran, to build individualized ML models that predicted their internal brain states (self-reported stress responses). Results: We accurately classified the 8-class self-reported stress responses with a mean (± standard error) root mean square error of 0.6 (± 0.1) across all Veterans using the best ML approach. Conclusions: The findings demonstrate the predictive ability of ML algorithms applied to whole-brain cortical fMRI data collected during individual Veteran sessions. The framework we have developed to preprocess whole-brain cortical fMRI data and train ML models across sessions would provide a valuable tool to enable individualized real-time fMRI neurofeedback during VR-like exposure therapy for PTSD.

Characterization of the blood oxygen level dependent hemodynamic response function in human subcortical regions with high spatiotemporal resolution.

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (<4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei.

Measurement of stretch-evoked brainstem function using fMRI.

Knowledge on the organization of motor function in the reticulospinal tract (RST) is limited by the lack of methods for measuring RST function in humans. Behavioral studies suggest the involvement of the RST in long latency responses (LLRs). LLRs, elicited by precisely controlled perturbations, can therefore act as a viable paradigm to measure motor-related RST activity using functional Magnetic Resonance Imaging (fMRI). Here we present StretchfMRI, a novel technique developed to study RST function associated with LLRs. StretchfMRI combines robotic perturbations with electromyography and fMRI to simultaneously quantify muscular and neural activity during stretch-evoked LLRs without loss of reliability. Using StretchfMRI, we established the muscle-specific organization of LLR activity in the brainstem. The observed organization is partially consistent with animal models, with activity primarily in the ipsilateral medulla for flexors and in the contralateral pons for extensors, but also includes other areas, such as the midbrain and bilateral pontomedullary contributions.

Topography of covert visual attention in human superior colliculus.

Experiments were performed to examine the topography of covert visual attention signals in human superior colliculus (SC), both across its surface and in its depth. We measured the retinotopic organization of SC to direct visual stimulation using a 90° wedge of moving dots that slowly rotated around fixation. Subjects (n = 5) were cued to perform a difficult speed-discrimination task in the rotating region. To measure the retinotopy of covert attention, we used a full-field array of similarly moving dots. Subjects were cued to perform the same speed-discrimination task within a 90° wedge-shaped region, and only the cue rotated around fixation. High-resolution functional magnetic resonance imaging (fMRI, 1.2 mm voxels) data were acquired throughout SC. These data were then aligned to a high-resolution T1-weighted reference volume. The SC was segmented in this volume so that the surface of the SC could be computationally modeled and to permit calculation of a depth map for laminar analysis. Retinotopic maps were obtained for both direct visual stimulation and covert attention. These maps showed a similar spatial distribution to visual stimulation maps observed in rhesus macaque and were in registration with each other. Within the depth of SC, both visual attention and stimulation produced activity primarily in the superficial and intermediate layers, but stimulation activity extended significantly more deeply than attention.

High-resolution imaging reveals highly selective nonface clusters in the fusiform face area.

A region in ventral human cortex (fusiform face area, FFA) thought to be important for face perception responds strongly to faces and less strongly to nonface objects. This pattern of response may reflect a uniform face-selective neural population or activity averaged across populations with heterogeneous selectivity. Using high-resolution functional magnetic resonance imaging (MRI), we found that the FFA has a reliable heterogeneous structure: localized subregions within the FFA highly selective to faces are spatially interdigitated with localized subregions highly selective to different object categories. We found a preponderance of face-selective responses in the FFA, but no difference in selectivity to faces compared to nonfaces. Thus, standard fMRI of the FFA reflects averaging of heterogeneous highly selective neural populations of differing sizes, rather than higher selectivity to faces. These results suggest that visual processing in this region is not exclusive to faces. Overall, our approach provides a framework for understanding the fine-scale structure of neural representations in the human brain.

Dynamics of the cerebral blood flow response to brief neural activity in human visual cortex.

The blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal depends on an interplay of cerebral blood flow (CBF), oxygen metabolism, and cerebral blood volume. Despite wide usage of BOLD fMRI, it is not clear how these physiological components create the BOLD signal. Here, baseline CBF and its dynamics evoked by a brief stimulus (2 s) in human visual cortex were measured at 3T. We found a stereotypical CBF response: immediate increase, rising to a peak a few second after the stimulus, followed by a significant undershoot. The BOLD hemodynamic response function (HRF) was also measured in the same session. Strong correlations between HRF and CBF peak responses indicate that the flow responses evoked by neural activation in nearby gray matter drive the early HRF. Remarkably, peak CBF and HRF were also strongly modulated by baseline perfusion. The CBF undershoot was reliable and significantly correlated with the HRF undershoot. However, late-time dynamics of the HRF and CBF suggest that oxygen metabolism can also contribute to the HRF undershoot. Combined measurement of the CBF and HRF for brief neural activation is a useful tool to understand the temporal dynamics of neurovascular and neurometabolic coupling.

Brainstem BOLD response to visual and acoustic stimuli.

Understanding the fundamental roles of brainstem function resulting in proper motor control is critical to motor-rehabilitation after brain injuries. In particular, vestibular and reticular formation nuclei are thought to be associated with spasticity in chronic stroke patients. We used two kinds of stimuli in 10 healthy subjects to activate these nuclei while collecting high-resolution (1.5-mm) fMRI across the majority of brainstem. Optokinetic stimuli evoked illusory self-motion to activate the vestibular nuclei. Acoustic-startle stimuli were sets of loud tones designed to activate of the reticular formation. We summarized the response represented in a form of activation volume, mean percent signal change, and the phase delay (time lag) following the stimulus. We observed patterns of significant activations in the brainstem but did not find significant differences between the stimulus. We conclude that more sensitive measurement techniques are needed to reliably detect vestibular and reticular formation nuclei responses.

Right temporal pole volume reduction in PTSD.

Previous magnetic resonance imaging studies of post-traumatic stress disorder (PTSD) have reported cortical volume alterations in the parahippocampal, anterior cingulate cortex, and temporal pole. It is unclear, however, if these cortical regions are specifically associated with PTSD or associated with common comorbidities. Here, we present the result of cortical volume differences between PTSD and healthy and psychiatric controls. In this study, healthy controls (n = 67) were matched for demographic characteristics (age, sex, race) and psychiatric controls (n = 67) were matched for demographic characteristics plus all other psychiatric diagnoses (past and current) to a group of PTSD patients (N = 67). We assessed group differences of 34 bilateral cortical structure volumes using statistically defined brain regions-of-interest from FreeSurfer between PTSD patients and healthy controls. We found 10 regions to be significantly different between PTSD and healthy controls and analyzed the group differences between PTSD and psychiatric controls within these regions. The right temporal pole volume in PTSD was found to be significantly smaller than both healthy and psychiatry controls. Our finding suggests only right temporal pole volume reduction is specifically associated with PTSD, and also highlights the need for using appropriate controls in psychiatry research.