Structural & Functional Neurovascular Coupling

esfMRI

Currently the fMRI method cannot directly detect and map electrical neural activity. Instead it produces images of activated brain regions by detecting the indirect effects of neural activity on cerebral hemodynamics [1]. The latter is tightly coupled to neural activity because of the high energy demands of the brain and its immense dependence on a continuous blood supply. This combination of energy demands with intolerance to ischemia is most likely the very reason for existence of so-called neurovascular coupling (NVC), that is, the reason that cerebral blood flow (CBF) is so perfectly regulated on all spatial scales.

Nonetheless, despite its fine tuning, NVC sets certain constraints on spatiotemporal resolution and the specificity of the fMRI signal. Both resolution and specificity rely on the cascade of neurovascular signaling and the vascular architecture and spatial level of blood flow regulation. Little is known about the principles of flow regulation on different vascular scales, the spatial distribution of vascular densities, and the dependence of vasculature on various brain sites. Similarly, little is known about the actual neural elements and events underlying the increases in energy metabolism or the neurovascular signaling processes that ultimately induce CBF changes.

In an attempt to better understand the above processes we have been studying structural and functional NVC using a number of different techniques over the last ten years, including very high resolution fMRI, immunohistochemistry, vascular casts, X-ray microtomography [2], neuropharmacology [3], and combined electrophysiology with BOLD imaging [4] in anesthetized and alert rhesus monkeys.

Structural Neurovascular Coupling

We combined corrosion casts, immunohistochemistry, and cytochrome oxidase (COX) staining. Our detailed measurements of regional vascular length density, volume fraction, and surface density revealed a similar vascularization in different visual areas. Interestingly the highest correlations were found between vascular density and the steady-state metabolic demand as measured by COX activity, rather than between vascular parameters and the density of neuro-glia elements. This observation suggests that although the number of neurons and synapses determines an upper bound of an area’s integrative capacity, its vascularization reflects the neural activity of those subpopulations that represent a “default” mode of brain steady state.

An attempt is currently underway to generate a precise map of the vascular system of the monkey cortex using scanning electron microscopy (SEM) with large-range stage motorization that permits the scanning of large samples (Figure 1). In addition, a framework is being developed that can model the flow of blood through the cerebral vasculature based on principles of simple fluid dynamics. Three-dimensional advective transport, vasculature-tissue exchange and diffusion within the tissue make it possible to simulate oxygen transport, drug delivery, etc. The framework provides a means of computing blood pressure, flow and scalar transport.

Momentan wird außerdem versucht das vaskuläre System des Affenkortex präzise zu kartieren mittels Rasterelektronenmikroskop (REM) mit großer, motorisierter Probenbühne, das es möglich macht, auch große Proben zu scannen (Abbildung 1). Zusätzlich wird ein System entwickelt, das den Blutfluss durch das zerebrale Gefäßsystem auf der Basis von einfachen flüssigkeitsdynamischen Prinzipien im Modell abbildet. Der dreidimensionale advektive Transport, der Austausch zwischen Gefäßsystem und Gewebe und die Diffusion innerhalb des Gewebes machen es möglich, den Transport von Sauerstoff, die Verabreichung von Medikamenten und ähnliches zu simulieren. Dieses Bezugssystem bietet die Möglichkeit, Blutdruck, Blutfluss und den skalaren Transport zu berechnen.

Functional Neurovascular Coupling

The fMRI signal predominantly reflects regional perisynaptic activity, i.e. the classical events of synaptic transmission with its respective population excitatory or inhibitory postsynaptic potentials, as well as a number of integrative processes, including somatic and dendritic spikes with their ensuing afterpotentials, and voltage-dependent membrane oscillations [1, 4, and 5]. To some extent these processes underlie different components of the comprehensive neural signal. Specifically, dendro-somatic integrative processes determine the power modulation of various low-frequency bands (<150Hz) of the field potentials (LFPs), while the population spiking of stimulus/task-selective neurons (multiple-unit activity, MUA) is captured by higher frequency bands (>1kHz) or by the activity of isolated units, although these are of little help in trying to understand the changes in the fMRI signals that typically reflect mass action.

Because LFP and MUA correlate with each other, the details of the relationship between the fMRI signal and the underlying neural events are studied best in cases of a response dissociation between the two. Such dissociations can be induced by certain types of visual stimulation, by pharmacological manipulations [3], or by electrical microstimulation. The first type was reported in the primary visual cortex of both anesthetized and alert animals [4] and most recently in area V5 (MT). BOLD responses could be elicited in the absence of any MUA activity. A similar dissociation was found during electrical stimulation (ES). We recently combined ES with fMRI [6] to study in vivo connectivity. The technique was also used to study ES-induced signal propagation in cortex. Stimulation of dLGN induced strong BOLD activation in V1, whose thalamocortical synapses (input and local processing) are driven by the electrical pulses despite the fact that the V1 output is entirely suppressed.
Because LFP and MUA correlate with each other, the details of the relationship between the fMRI signal and the underlying neural events are studied best in cases of a response dissociation between the two. Such dissociations can be induced by certain types of visual stimulation, by pharmacological manipulations [3], or by electrical microstimulation. The first type was reported in the primary visual cortex of both anesthetized and alert animals [4] and most recently in area V5 (MT). BOLD responses could be elicited in the absence of any MUA activity. A similar dissociation was found during electrical stimulation (ES). We recently combined ES with fMRI [6] to study in vivo connectivity. The technique was also used to study ES-induced signal propagation in cortex. Stimulation of dLGN induced strong BOLD activation in V1, whose thalamocortical synapses (input and local processing) are driven by the electrical pulses despite the fact that the V1 output is entirely suppressed.

Input-output dissociations like the ones just described are not rare phenomena that can only be induced experimentally. When cortical areas are “feedforward” stimulated with simple sensory stimuli then field potentials and spiking are correlated, barring certain stimulation conditions like those described above. Activations due to cognitive processing, on the other hand, might be dominated by top-down and neuromodulatory signals that could increase the excitation-inhibition balance of cortical microcircuits without necessarily causing a concomitant increase in the spiking of task-selective neurons. The effects of neuromodulation on large populations can be studied in a number of ways, including investigation of spontaneous cortical activity. Finally, the study of functional neurovascular coupling may profit greatly from attempts to calibrate the BOLD signal, in order for the latter to reflect as closely as possible the actual energy metabolism.

Literature

1. Logothetis, N. K., B. A.Wandell: Interpreting the BOLD Signal. Annual Review Physiology 66, 735–769 (2004).
2. Weber, B, A. L. Keller, J. Reichold, N. K. Logothetis: Microvascular System of the Striate and Extrastriate Visual Cortex of the Macaque. Cerebral Cortex 18(10), 2318–2330 (2008).
3. Rauch, A., G. Rainer, N. K. Logothetis: The Effect of a Serotonin-induced Dissociation Between Spiking and Perisynaptic Activity on BOLD functional MRI. Proceedings of the National Academy of Sciences of the USA 105(18), 6759–6764 (2008).
4. Goense, J. B., N. K. Logothetis: Neurophysiology of the BOLD fMRI Signal in Awake Monkeys. Current Biology 18(9), 631–640 (2008).
5. Logothetis, N. K.: What We Can Do and Cannot Do with fMRI. Nature 453(7197), 869–878 (2008).
6. Tolias A, F. Sultan, M. Augath, A. Oeltermann, E. Tehovnik, P. Schiller, N. K. Logothetis: Mapping Cortical Activity Elicited with Electrical Microstimulation Using fMRI in the Macaque. Neuron 48(6), 901–911 (2005).