Coupling of the cortical hemodynamic response to cortical and thalamic neuronal activity

Abstract

Accurate interpretation of functional MRI (fMRI) signals requires knowledge of the relationship between the hemodynamic response and the neuronal activity that underlies it. Here we address the question of coupling between pre- and postsynaptic neuronal activity and the hemodynamic response in rodent somatosensory (Barrel) cortex in response to single-whisker deflection. Using full-field multiwavelength optical imaging of hemoglobin oxygenation and electrophysiological recordings of spiking activity and local field potentials, we demonstrate that a point hemodynamic measure is influenced by neuronal activity across multiple cortical columns. We demonstrate that the hemodynamic response is a spatiotemporal convolution of the neuronal activation. Therefore, positive hemodynamic response in one cortical column might be explained by neuronal activity not only in that column but also in the neighboring columns. Thus, attempts at characterizing the neurovascular relationship based on point measurements of electrophysiology and hemodynamics may yield inconsistent results, depending on the spatial extent of neuronal activation. The finding that the hemodynamic signal observed at a given location is a function of electrophysiological activity over a broad spatial region helps explain a previously observed increase of local vascular response beyond the saturation of local neuronal activity. We also demonstrate that the oxy- and total-hemoglobin hemodynamic responses can be well approximated by space-time separable functions with an antagonistic center-surround spatial pattern extending over several millimeters. The surround "negative" hemodynamic activity did not correspond to observable changes in neuronal activity. The complex spatial integration of the hemodynamic response should be considered when interpreting fMRI data.

Fig. 1.

Spatiotemporal evolution of the hemodynamic reponse. (a) Full-field time series of HbO, Hb, and HbT signals (an average of the six strongest stimulus amplitudes) were calculated from six wavelength data. Each image represents an individual frame (average of ≈1,400 trials). Time between consecutive images is 200 msec. (b) A continuation of the time series shown in a. The signal for Hb and HbO is expressed in percent change relative to its own baseline concentration (40 and 60 μM, respectively, were assumed for all animals). HbT was calculated as a sum of Hb and HbO.

Fig. 2.

The hemodynamic response has an antagonistic center-surround spatial pattern. (a) An image of HbO at the peak of the response. (b) Integral HbO (red) and HbT (black) responses as a function of stimulus intensity in the center (principal barrel, ROI_in) and surround (>3 mm away from the recording electrode, ROI_out). Data from five animals were averaged, and all amplitudes are shown. The error bars reflect the intersubject standard error. The center and surround response amplitudes in every animal were normalized to the maximal response amplitude in the center ROI for that animal before averaging the data across animals. Note that the magnitude of the negative surround response is on average ≈10% of that in the center. (c) The locations of electrophysiological recordings are superimposed on the image of the vasculature corresponding to the functional map in a. Recordings from locations m1 and m2 were performed after recordings from C3 and D1 barrels (the electrodes are visible on the image). The indicated approximate location of the Barrel field was determined by fitting the position, size, and orientation of a typical histology sample based on the locations of two identified barrel columns (C3 and D1). (d) Time courses of HbT response averaged from 300 × 300 μm ROIs around recording electrodes. The locations are color coded in a and c. (e) MUA recorded from the locations marked in c. Responses to seven largest stimulus amplitudes are averaged in d and e. The vertical scales for the top and bottom plots in d and e differ by factor of 5. The arrow denotes stimulus delivery.

Fig. 3.

The local hemodynamic response increases beyond saturation of local neuronal activity. (a) Integral HbO (red) and HbT (black) responses averaged from 300 × 300 μm ROI around the electrode recording from the principal barrel as a function of stimulus intensity. Data from eight animals were averaged, and all amplitudes are shown. The error bars reflect the intersubject standard error. (b) MUA (Left), LFP (Right) peak (red), and integral (black) responses as a function of stimulus amplitude. The data were averaged across the same subjects as in a. The curves were fitted by using the function ax/(1-bx)^c.

Fig. 4.

Thalamic VPM and cortical responses saturate with an increase in stimulus intensity. (a1) MUA activity was recorded simultaneously in thalamus (VPM) by using a single metal electrode and in the cortex by using a laminar electrode array. Responses for different stimulus amplitudes (Inset) are superimposed for VPM (Upper) and cortical layer IV (a2). An input impedance of recording electrodes, 7 MΩ in the VPM and 0.2 MΩ in the cortex, explains differences in signal-to-noise ratio. (b1) VPM (black) and cortical layer IV (red) peak response as a function of stimulus intensity. The curves were fitted by using the function ax/(1-bx)^c.(b2) Granule (layer IV, red), supragranule (blue) and infragranule (green) peak responses as a function of stimulus amplitude.

Fig. 5.

Neither lemniscal nor paralemniscal inputs increase beyond saturation of the postsynaptic activity. (a) MUA activity was simultaneously recorded from VMP and POm by using two laminar electrode arrays. Responses for different stimulus amplitudes (Inset) are superimposed for VPM (a) and POm (b). The peak (black) and integral (red) response as a function of stimulus intensity was fitted by using the function ax/(1-bx)^c.

Fig. 6.

Neuronal activity in neighboring cortical columns increases throughout the stimulus range. MUA (a) and LFP (b) responses are plotted for the principal barrel (δ) and two neighboring barrels (D2 and D3). Responses to different amplitudes are superimposed (Inset). The arrow denotes stimulus delivery. (c) MUA (Left) and LFP (Right) peak responses as a function of stimulus amplitude. The curves were fitted by using the function ax/(1-bx)^c. (d) Locations of electrophysiological recordings are superimposed on the image of the vasculature. Recordings from barrel columns δ and D3 (the electrodes are visible on the image) were performed after recordings from δ and D2 barrels.