Impact of Altered Cholinergic Tones on the Neurovascular Coupling Response to Whisker Stimulation.

Brain imaging techniques that use vascular signals to map changes in neuronal activity rely on the coupling between electrophysiology and hemodynamics, a phenomenon referred to as "neurovascular coupling" (NVC). It is unknown whether this relationship remains reliable under altered brain states associated with acetylcholine (ACh) levels, such as attention and arousal and in pathological conditions such as Alzheimer's disease. We therefore assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex, measured by cerebral blood flow (CBF) and neurophysiological recordings (local field potentials, LFPs). We found that acutely enhanced ACh tone significantly potentiated whisker-evoked CBF responses through muscarinic ACh receptors and concurrently facilitated neuronal responses, as illustrated by increases in the amplitude and power in high frequencies of the evoked LFPs. However, the cellular identity of the activated neuronal network within the responsive barrel was unchanged, as characterized by c-Fos upregulation in pyramidal cells and GABA interneurons coexpressing vasoactive intestinal polypeptide. In contrast, chronic ACh deprivation hindered whisker-evoked CBF responses and the amplitude and power in most frequency bands of the evoked LFPs and reduced the rostrocaudal extent and area of the activated barrel without altering its identity. Correlations between LFP power and CBF, used to estimate NVC, were enhanced under high ACh tone and disturbed significantly by ACh depletion. We conclude that ACh is not only a facilitator but also a prerequisite for the full expression of sensory-evoked NVC responses, indicating that ACh may alter the fidelity of hemodynamic signals in assessing changes in evoked neuronal activity.SIGNIFICANCE STATEMENT Neurovascular coupling, defined as the tight relationship between activated neurons and hemodynamic responses, is a fundamental brain function that underlies hemodynamic-based functional brain imaging techniques. However, the impact of altered brain states on this relationship is largely unknown. We therefore investigated how acetylcholine (ACh), known to drive brain states of attention and arousal and to be deficient in pathologies such as Alzheimer's disease, would alter neurovascular coupling responses to sensory stimulation. Whereas acutely increased ACh enhanced neuronal responses and the resulting hemodynamic signals, chronic loss of cholinergic input resulted in dramatic impairments in both types of sensory-evoked signals. We conclude that ACh is not only a potent modulator but also a requirement for the full expression of sensory-evoked neurovascular coupling responses.

1D Current Source Density (CSD) Estimation in Inverse Theory: A Unified Framework for Higher-Order Spectral Regularization of Quadrature and Expansion-Type CSD Methods.

Estimation of current source density (CSD) from the low-frequency part of extracellular electric potential recordings is an unstable linear inverse problem. To make the estimation possible in an experimental setting where recordings are contaminated with noise, it is necessary to stabilize the inversion. Here we present a unified framework for zero- and higher-order singular-value-decomposition (SVD)-based spectral regularization of 1D (linear) CSD estimation from local field potentials. The framework is based on two general approaches commonly employed for solving inverse problems: quadrature and basis function expansion. We first show that both inverse CSD (iCSD) and kernel CSD (kCSD) fall into the category of basis function expansion methods. We then use these general categories to introduce two new estimation methods, quadrature CSD (qCSD), based on discretizing the CSD integral equation with a chosen quadrature rule, and representer CSD (rCSD), an even-determined basis function expansion method that uses the problem's data kernels (representers) as basis functions. To determine the best candidate methods to use in the analysis of experimental data, we compared the different methods on simulations under three regularization schemes (Tikhonov, tSVD, and dSVD), three regularization parameter selection methods (NCP, L-curve, and GCV), and seven different a priori spatial smoothness constraints on the CSD distribution. This resulted in a comparison of 531 estimation schemes. We evaluated the estimation schemes according to their source reconstruction accuracy by testing them using different simulated noise levels, lateral source diameters, and CSD depth profiles. We found that ranking schemes according to the average error over all tested conditions results in a reproducible ranking, where the top schemes are found to perform well in the majority of tested conditions. However, there is no single best estimation scheme that outperforms all others under all tested conditions. The unified framework we propose expands the set of available estimation methods, provides increased flexibility for 1D CSD estimation in noisy experimental conditions, and allows for a meaningful comparison between estimation schemes.

Laminar Distribution of Phase-Amplitude Coupling of Spontaneous Current Sources and Sinks.

Although resting-state functional connectivity is a commonly used neuroimaging paradigm, the underlying mechanisms remain unknown. Thalamo-cortical and cortico-cortical circuits generate oscillations at different frequencies during spontaneous activity. However, it remains unclear how the various rhythms interact and whether their interactions are lamina-specific. Here we investigated intra- and inter-laminar spontaneous phase-amplitude coupling (PAC). We recorded local-field potentials using laminar probes inserted in the forelimb representation of rat area S1. We then computed time-series of frequency-band- and lamina-specific current source density (CSD), and PACs of CSD for all possible pairs of the classical frequency bands in the range of 1-150 Hz. We observed both intra- and inter-laminar spontaneous PAC. Of 18 possible combinations, 12 showed PAC, with the highest measures of interaction obtained for the pairs of the theta/gamma and delta/gamma bands. Intra- and inter-laminar PACs involving layers 2/3-5a were higher than those involving layer 6. Current sinks (sources) in the delta band were associated with increased (decreased) amplitudes of high-frequency signals in the beta to fast gamma bands throughout layers 2/3-6. Spontaneous sinks (sources) of the theta and alpha bands in layers 2/3-4 were on average linked to dipoles completed by sources (sinks) in layer 6, associated with high (low) amplitudes of the beta to fast-gamma bands in the entire cortical column. Our findings show that during spontaneous activity, delta, theta, and alpha oscillations are associated with periodic excitability, which for the theta and alpha bands is lamina-dependent. They further emphasize the differences between the function of layer 6 and that of the superficial layers, and the role of layer 6 in controlling activity in those layers. Our study links theories on the involvement of PAC in resting-state functional connectivity with previous work that revealed lamina-specific anatomical thalamo-cortico-cortical connections.