Dopamine-induced dissociation of BOLD and neural activity in macaque visual cortex

Neuromodulators determine how neural circuits process information during cognitive states such as wakefulness, attention, learning, and memory [1]. fMRI can provide insight into their function and dynamics, but their exact effect on BOLD responses remains unclear [2, 3 and 4], limiting our ability to interpret the effects of changes in behavioral state using fMRI. Here, we investigated the effects of dopamine (DA) injections on neural responses and haemodynamic signals in macaque primary visual cortex (V1) using fMRI (7T) and intracortical electrophysiology. Aside from DA’s involvement in diseases such as Parkinson’s and schizophrenia, it also plays a role in visual perception [5, 6, 7 and 8]. We mimicked DAergic neuromodulation by systemic injection of L-DOPA and Carbidopa (LDC) or by local application of DA in V1 and found that systemic application of LDC increased the signal-to-noise ratio (SNR) and amplitude of the visually evoked neural responses in V1. However, visually induced BOLD responses decreased, whereas cerebral blood flow (CBF) responses increased. This dissociation of BOLD and CBF suggests that dopamine increases energy metabolism by a disproportionate amount relative to the CBF response, causing the reduced BOLD response. Local application of DA in V1 had no effect on neural activity, suggesting that the dopaminergic effects are mediated by long-range interactions. The combination of BOLD-based and CBF-based fMRI can provide a signature of dopaminergic neuromodulation, indicating that the application of multimodal methods can improve our ability to distinguish sensory processing from neuromodulatory effects

Two distinct profiles of fMRI and neurophysiological activity elicited by acetylcholine in visual cortex

Cholinergic neuromodulation is involved in all aspects of sensory processing and is crucial for processes such as attention, learning and memory, etc. However, despite the known roles of acetylcholine (ACh), we still do not how to disentangle ACh contributions from sensory or task-evoked changes in functional magnetic resonance imaging (fMRI). Here, we investigated the effects of local injection of ACh on fMRI and neural signals in the primary visual cortex (V1) of anesthetized macaques by combining pharmaco-based MRI (phMRI) with electrophysiological recordings, using single electrodes and electrode arrays. We found that local injection of ACh elicited two distinct profiles of fMRI and neurophysiological activity, depending on the distance from the injector. Near the injection site, we observed an increase in the baseline blood oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) responses, while their visual modulation decreased. In contrast, further from the injection site, we observed an increase in the visually induced BOLD and CBF modulation without changes in baseline. Neurophysiological recordings suggest that the spatial correspondence between fMRI responses and neural activity does not change in the gamma, high-gamma, and multiunit activity (MUA) bands. The results near the injection site suggest increased inhibitory drive and decreased metabolism, contrasting to the far region. These changes are thought to reflect the kinetics of ACh and its metabolism to choline

Dopamine is signaled by mid-frequency oscillations and boosts output-layers visual information in visual cortex

Neural oscillations are ubiquitously observed in cortical activity, and are widely believed to be crucial for mediating transmission of information across the cortex. Yet, the neural phenomena contributing to each oscillation band, and their effect on information coding and transmission, are largely unknown. Here, we investigated whether individual frequency bands specifically reflect changes in the concentrations of dopamine, an important neuromodulator, and how dopamine affects oscillatory information processing. We recorded the local field potential (LFP) at different depths of primary visual cortex (V1) in anesthetized monkeys (Macaca mulatta) during spontaneous activity and during visual stimulation with Hollywood movie clips while pharmacologically mimicking dopaminergic neuromodulation by systemic injection of L-DOPA (a metabolic precursor of dopamine). We found that dopaminergic neuromodulation had marked effects on both spontaneous and movie-evoked neural activity. During spontaneous activity, dopaminergic neuromodulation increased the power of the LFP specifically in the [19–38 Hz] band, suggesting that the power of endogenous visual cortex oscillations in this band can be used as a robust marker of dopaminergic neuromodulation. Moreover, dopamine increased visual information encoding over all frequencies during movie stimulation. The information increase due to dopamine was prominent in the supragranular layers of cortex that project to higher cortical areas and in the gamma [50–100 Hz] band that has been previously implicated in mediating feedforward information transfer. These results thus individuate new neural mechanisms by which dopamine may promote the readout of relevant sensory information by strengthening the transmission of information from primary to higher areas

Fine-Scale Spatial Organization of Face and Object Selectivity in the Temporal Lobe: Do Functional Magnetic Resonance Imaging, Optical Imaging, and Electrophysiology Agree?

The spatial organization of the brain's object and face representations in the temporal lobe is critical for understanding high-level vision and cognition but is poorly understood. Recently, exciting progress has been made using advanced imaging and physiology methods in humans and nonhuman primates, and the combination of such methods may be particularly powerful. Studies applying these methods help us to understand how neuronal activity, optical imaging, and functional magnetic resonance imaging signals are related within the temporal lobe, and to uncover the fine-grained and large-scale spatial organization of object and face representations in the primate brain

Cortical lamina-dependent blood volume changes in human brain at 7T

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6 mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans

Trajectories of charged particles trapped in Earth's magnetic field

I outline the theory of relativistic charged-particle motion in the magnetosphere in a way suitable for undergraduate courses. I discuss particle and guiding center motion, derive the three adiabatic invariants associated with them, and present particle trajectories in a dipolar field. I provide twelve computational exercises that can be used as classroom assignments or for self-study. Two of the exercises, drift-shell bifurcation and Speiser orbits, are adapted from active magnetospheric research. The Python code provided in the supplement can be used to replicate the trajectories and can be easily extended for different field geometries.Comment: 10 pages, 7 figures. Submitted to American Journal of Physic

Effects of lactate on the early visual cortex of non-human primates, investigated by pharmaco-MRI and neurochemical analysis

In contrast to the limited use of functional magnetic resonance imaging (fMRI) in clinical diagnostics, it is currently a mainstay of neuroimaging in clinical and basic brain research. However, its non-invasive use in combination with its high temporal and spatial resolution would make fMRI a perfect diagnostic tool. We are interested in whether a pharmacological challenge imposed on the brain can be reliably traced by the blood oxygen level-dependent (BOLD) signal and possibly further exploited for diagnostics. We have chosen a systemic challenge with lactate and pyruvate to test whether the physiological formation of these monocarboxylic acids contributes to the BOLD signal and can be detected using fMRI. This information is also of interest because lactate levels in the cerebrospinal fluid rise concomitantly with reduced vascular responsiveness of the brain during the progression of Alzheimer disease (AD). We studied the BOLD response after a low-dose lactate challenge and monitored the induced plasma lactate levels in anesthetized non-human primates. We observed reliable lactate-induced BOLD responses, which could be confirmed at population and individual level by their strong correlation with systemic lactate concentrations. Comparable BOLD effects where observed after a slow infusion of pyruvate. We show here that physiological changes in lactate and pyruvate levels are indeed reflected in the BOLD signal, and describe the technical prerequisites to reliably trace a lactate challenge using BOLD-fMRI

Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7T

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms

Sub-millimeter fMRI reveals multiple topographical digit representations that form action maps in human motor cortex

The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. Compared to previous methods, in this study, we could capture locally specific blood volume changes across entire brain regions along the cortical curvature. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 ​mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits’ muscles are used for different motor actions such as flexion movements, like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for non-invasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging

High-resolution CBV-fMRI allows mapping of laminar activity and connectivity of cortical input and output in human M1

Layer-dependent fMRI allows measurements of information flow in cortical circuits, as afferent and efferent connections terminate in different cortical layers. However, it is unknown to what level human fMRI is specific and sensitive enough to reveal directional functional activity across layers. To answer this question, we developed acquisition and analysis methods for blood-oxygen-level-dependent (BOLD) and cerebral-blood-volume (CBV)-based laminar fMRI and used these to discriminate four different tasks in the human motor cortex (M1). In agreement with anatomical data from animal studies, we found evidence for somatosensory and premotor input in superficial layers of M1 and for cortico-spinal motor output in deep layers. Laminar resting-state fMRI showed directional functional connectivity of M1 with somatosensory and premotor areas. Our findings demonstrate that CBV-fMRI can be used to investigate cortical activity in humans with unprecedented detail, allowing investigations of information flow between brain regions and outperforming conventional BOLD results that are often buried under vascular biases