3717

fMRI investigation of the role of interhemispheric interactions in cortical sensory processing
Eddie C. Wong1,2, Alex L. T. Leong1,2, Xunda Wang1,2, Celia M. Dong1,2, and Ed X. Wu1,2

1Laboratory of Biomedical Imaging and Signal Processing, The University of Hong Kong, Hong Kong, China, 2Department of Electrical and Electronic Engineering, The University of Hong Kong, Hong Kong, China

Synopsis

Effective sensory communications require massive interconnected interhemispheric cortico-cortical projections. However, little is known at present regarding the exact interactions that occur bilaterally between sensory cortices across the brain hemispheres and how they influence cortical processing. Here, we employ optogenetic stimulation of the whisker-related thalamic excitatory neurons in combination with the somatosensory forepaw stimulation. We demonstrate a novel platform to investigate the interhemispheric interactions underlying cortical sensory processing.

Purpose

Interhemispheric communication is one of the vital forms of interactions that occur to maintain normal brain functions. To achieve effective communication between the two cortical hemispheres, thalamo-cortical and interhemispheric cortico-cortical projections are crucial1,2. Numerous studies have shown that interhemispheric cortical activities could be initiated from thalamic input through the thalamo-cortical pathway3-5. However, little is known on how interhemispheric activities interact bilaterally and modulate the corresponding cortical sensory processing at each hemisphere. Our recent fMRI study demonstrated that specific neural patterns initiated from the somatosensory thalamus, ventral posteromedial thalamus (VPM), could selectively confine somatosensory activity to the stimulated hemisphere (i.e., ipsilateral) or drive somatosensory activity propagation to the contralateral cortex6. Here, we document the strategic use of optogenetic stimulation at the whisker thalamus VPM in combination with forepaw electrical stimulation/ tactile sensation, to investigate the interhemispheric interactions of somatosensory cortical processing.

Method

Animal preparation: 3μl AAV5-CaMKIIα::ChR2(H134R)-mCherry was injected to the right VPM of adult rats (200-250g, SD strain, male, n = 6). Four weeks after injection, an opaque optical fiber cannula (d=450μm) was implanted at the injection site as a means to deliver optical stimulation.

Optogenetic and Forepaw Stimulation: Blue light (473nm) was presented to animals expressing ChR2 with a 4-pulse paradigm (10ms pulse width, interstimulus interval, ISI=125ms or 50ms, 40mW/mm2). To map out the responses evoked by VPM optogenetic stimulation, blue light was presented once every 30s, and repeated 20 times. Two needle electrodes were subcutaneously inserted into the right forepaw: one between the first and second digits and the other between the third and fourth digits. The electrodes were fixed using surgical tape and the stimulus effectiveness was first qualitatively confirmed by digit twitching. Electrical stimulation was given via a constant voltage stimulator at 8V with a 4Hz square wave and 3ms pulse duration in a block design paradigm (5s ON, 25s OFF) to evoke robust BOLD responses in primary somatosensory cortex (S1). To investigate the effects of optogenetic stimulation of VPM on the forepaw somatosensory processing, the optogenetic and forepaw stimulation were paired with one another.

fMRI Acquisition and Analysis: fMRI data was acquired at 7T using GE-EPI (FOV=32×32mm2, matrix=64×64, α=56°, TE/TR=20/1000ms, and 10 contiguous slices with 1mm thickness). Data were preprocessed before applying GLM and coherence analysis to identify significant BOLD responses (P<0.001).

Results

BOLD activations evoked by either optogenetic stimulation or forepaw electrical stimulation: 4-pulse optogenetic stimulation at the VPM thalamocortical excitatory neurons activated the ipsilateral primary somatosensory cortex (S1). Optogenetic stimulation with the ISI of 125ms evoked a stronger BOLD response (2.5% vs 1%) with a prolonged BOLD profile when compared to the 4-pulse OG stimulation with an ISI of 50ms. Moreover, BOLD activation in contralateral S1 barrel field (S1BF) was observed when the ISI was 125ms, but not 50ms. As expected, electrical stimulation at forepaw evoked robust positive BOLD response in the contralateral forelimb region of S1 (S1FL).

Optogenetically-evoked contralateral S1 activation suppress the forepaw evoked response: When optogenetic stimulation was presented together with the forepaw electrical stimulation, we observed that the responses in S1FL was significantly reduced only when the ISI of optogenetic stimulation was 125ms, and not 50ms. This suggests the optogenetic stimulation with an ISI of 125ms is capable of evoking BOLD response at the contralateral S1BF, which could likely influence the somatosensory activation in S1FL evoked by forepaw stimulation.

Discussion & Conclusion

In this study, we demonstrate that by probing the somatosensory thalamo-cortical network with specific 4-pulse optogenetic stimulation paradigms, unilateral or bilateral primary somatosensory cortical responses can be selectively evoked. We found that the OG stimulation with ISI 125ms evoked stronger and longer BOLD responses in ipsilateral S1 when compared to ISI 50ms. Moreover, OG stimulation with 125ms evoked responses at contralateral S1BF. This suggests that specific neural activity pattern could mediate long-range propagation across the cerebral hemispheres7,8. Interestingly, the optogenetically-evoked contralateral S1BF responses influenced and suppressed the forepaw-evoked BOLD responses in left S1FL. This observation suggests the existence of unique underlying neural mechanism(s) that can dynamically adjusts cortical excitability9 when the somatosensory cortical regions across both hemispheres receive multiple somatosensory inputs, such as the whisker-related and forepaw inputs in this study. In summary, we demonstrate a novel approach to investigate the interactions underlying interhemispheric somatosensory cortical processing. The platform develop here could be vital for revealing key characteristics of cortical interhemispheric interactions, which at present remains poorly understood.

Acknowledgements

This work was supported by the Hong Kong Research Grant Council (C7048-16G and HKU17103015 to E.X.W.).

References

1. van der Knaap, L. J., & van der Ham, I. J. (2011). How does the corpus callosum mediate interhemispheric transfer? A review. Behavioural brain research, 223(1), 211-221.

2. Roland, J. L., Snyder, A. Z., Hacker, C. D., Mitra, A., Shimony, J. S., Limbrick, D. D., ... & Leuthardt, E. C. (2017). On the role of the corpus callosum in interhemispheric functional connectivity in humans. Proceedings of the National Academy of Sciences, 114(50), 13278-13283.

3. Ahissar, E., Sosnik, R., & Haidarliu, S. (2000). Transformation from temporal to rate coding in a somatosensory thalamocortical pathway. Nature, 406(6793), 302.

4. Lu, S. M., & Lin, R. C. S. (1993). Thalamic afferents of the rat barrel cortex: a light-and electron-microscopic study using Phaseolus vulgaris leucoagglutinin as an anterograde tracer. Somatosensory & motor research, 10(1), 1-16.

5. Koralek, K. A., Jensen, K. F., & Killackey, H. P. (1988). Evidence for two complementary patterns of thalamic input to the rat somatosensory cortex. Brain research, 463(2), 346-351.

6. Leong, A. T., Wang, X., Chan, R. W., Hallaoui, K. E., & Wu, E.X. (2018). Neural activity pattern(s) underlying brain interhemispheric propagation: An optogenetic fMRI study. Proceedings of the 25th Annual Meeting of ISMRM, Paris, p.2935, 2018

7. Roland, P. E. (2017). Space-time dynamics of membrane currents evolve to shape excitation, spiking, and inhibition in the cortex at small and large scales. Neuron, 94(5), 934-942.

8. Jazayeri, M., & Afraz, A. (2017). Navigating the neural space in search of the neural code. Neuron, 93(5), 1003-1014.

9. Pais-Vieira, M., Kunicki, C., Tseng, P. H., Martin, J., Lebedev, M., & Nicolelis, M. A. (2015). Cortical and thalamic contributions to response dynamics across layers of the primary somatosensory cortex during tactile discrimination. Journal of neurophysiology, 114(3), 1652-1676

Figures

Figure 1. (A). Histological characterization of ChR2 expression in VPM (left) and T2-weighted anatomical image (right) showing the fiber implantation site. (B) Illustration of optogenetic fMRI stimulation setup (left) and forepaw electrical stimulation setup (right). (C) Optogenetic fMRI experiment employing the 4-pulse optogenetic paradigm. Twenty stimulation blocks equally spaced at 30s were presented in each trial. Each of the blocks consisted of 4 optogenetic stimulation pulses spaced at interstimulus interval, ISI=125ms or 50ms. Forepaw stimulation at 4Hz, 3ms pulse width was presented 5s following 25s rest. Twenty simulation cycles were presented per trial. Combined stimulation paradigm was used for optogenetic-forepaw fMRI experiments.

Figure 2. (A) Averaged BOLD activation maps during 4-pulse optogenetic stimulation (ISI=125ms or 50ms), forepaw electrical stimulation and combined stimulation. (B) ROIs defined based on rat brain atlas. Abbrevations: Left/Right S1BF: barrel field, primary somatosensory cortex; Left/ Right S1FL: forelimb region, primary somatosensory cortex. (C) BOLD signal profiles extracted from the atlas-based defined ROIs. (Grey area indicate forepaw stimulation period; Light blue line indicate OG stimulation period) (D) Averaged coherence values within the atlas based defined ROI. Coherence of 0.1 corresponds to P<0.001. Pair t-test was performed to identify the statistical significance.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
3717