FMRI activity in the macaque cerebellum evoked by intracortical microstimulation of the primary somatosensory cortex: evidence for polysynaptic propagation

Abstract

Simultaneous electrical microstimulation (EM) and functional magnetic resonance imaging (fMRI) is a useful tool for probing connectivity across brain areas in vivo. However, it is not clear whether intracortical EM can evoke blood-oxygenation-level-dependent (BOLD) signal in areas connected polysynaptically to the stimulated site. To test for the presence of the BOLD activity evoked by polysynaptic propagation of the EM signal, we conducted simultaneous fMRI and EM in the primary somatosensory cortex (S1) of macaque monkeys. We in fact observed BOLD activations in the contralateral cerebellum which is connected to the stimulation site (i.e. S1) only through polysynaptic pathways. Furthermore, the magnitude of cerebellar activations was dependent on the current amplitude of the EM, confirming the EM is the cause of the cerebellar activations. These results suggest the importance of considering polysynaptic signal propagation, particularly via pathways including subcortical structures, for correctly interpreting 'functional connectivity' as assessed by simultaneous EM and fMRI.

Figure 1. Simultaneous fMRI and electrical stimulation of S1.

(a) Left panel, schematic drawing of a monkey brain with a microelectrode inserted in S1. Right panel, anatomical MRI image (FLASH) showing a monkey brain with a microelectrode inserted. ele, microelectrode. cs, central sulcus. ips, intraparietal sulcus. (b) Coronal sections of a representative t-score map of BOLD activation in Monkey 1 in one session (250 µA, 30 runs). In Monkey 1, right S1 was stimulated. A5, the area 5. Cb, cerebellum. S1, primary somatosensory cortex. S2, secondary somatosensory cortex. Thal, thalamus. stim, the site of EM. (c) Time courses of BOLD activations in S1 and Thal (30 runs, 240 EM blocks). Baseline signal [mean of 2 frames (6 sec) before the onset of EM block] was subtracted before averaging. White bars indicate 30 sec blocks of EM.

Figure 2. BOLD activations in the cerebellum induced by electrical stimulation of S1.

(a)–(b) A representative t-score map of BOLD activation in Monkey 1 in one session (250 µA, 30 runs). (a) BOLD activation at the site of EM. In Monkey 1, right S1 was stimulated (arrow). (b) BOLD activations in the cerebellum. Cb5, cerebellar lobule V. Cop, copula myramidis. (c)–(d) A representative t-score map of BOLD activation in Monkey 2 in one session (500 µA, 9 runs). Conventions are the same as in (a) and (b). (c) BOLD activation at the site of EM. In Monkey 2, left S1 was stimulated (arrow). (d) BOLD activations in the cerebellum.

Figure 3. Current amplitude dependence of the response magnitude of the cerebellar activation.

(a) Average time course of the cerebellar activation in response to an individual EM block. The shaded region indicates the EM block. For each time course, the baseline signal [mean of 2 frames (5 sec) before the onset of EM block] was subtracted before averaging. Error bars indicate standard error (SE). Red, 750 µA (240 blocks). Green, 500 µA (264 blocks). Blue, 250 µA (240 blocks). (b) Response magnitude for each current amplitude. Colored lines indicate data for individual monkeys (gray solid line, Monkey 1; gray dotted line, Monkey 2). Error bars indicate SE. *, P<0.02. **, P<0.0002. ***, P<10⁻⁸.

Figure 4. Current amplitude dependence of the size of the cerebellar activation.

(a) Representative t-score maps (P<0.001, uncorrected) showing enlargement of activation with increasing current amplitude. Monkey 1, data from one session (250 µA, 6 runs. 500 µA, 9 runs. 750 µA, 6 runs). (b) Number of significantly activated voxels (P<0.001, uncorrected) in the contralateral cerebellum. Colored lines indicate data for individual monkeys (gray solid line, Monkey 1; gray dotted line, Monkey 2). Error bars, SE. +, P<0.005.