Combining Brain Perturbation and Neuroimaging in Non-human Primates

Abstract

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesions. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state-of-the-art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods.

Effective connectivity and spatial selectivity-dependent fMRI changes elicited by microstimulation of pulvinar and LIP

“…Microstimulation elicited strong local BOLD activity in the targeted dPul or LIP ( Figure 2 ). The extent of activation around and below the electrode tip was substantially larger than expected from a passive current spread within 0.5-1 mm radius at 100-250 μA (Klink et al, 2021; Thier and Andersen, 1998). Dorsal pulvinar stimulation affected mainly the medial pulvinar (MPul, including the anterior portion of the medial pulvinar, APul), but the edges of activation extended ventromedially to the superior colliculus (SC), and a weaker activity was found in the adjacent lateral pulvinar and ventral pulvinar (vPul) ( Figure 2A,B,C , see Figure S15 for dPul activation close-up with overlaid atlas regions).…”

“…Confirming and extending these findings, these STS regions and the adjacent area called PITd have recently emerged as consistently being activated in monkey fMRI studies employing visual attention and delayed saccade tasks (Bogadhi et al, 2018; Caspari et al, 2015; Kagan et al, 2010; Patel et al, 2015). It is worth noting that inactivation-induced changes in these STS regions were also a common denominator of LIP, dPul and superior colliculus inactivation studies, accompanying contralesional saccade selection and attentional deficits (Bogadhi et al, 2019; Klink et al, 2021; Melanie Wilke et al, 2010; Wilke et al, 2013, 2012).…”

“…Notably, MT and FST were still weakly activated with the lower current, in line with their known anatomical connectivity to parts of dPul (Gutierrez et al, 2000). Furthermore, differences of distal activation patterns due to vPul or dPul stimulation even with higher currents suggest that notwithstanding the apparent partial overlap of the local activation spread, typically more extensive when measured with fMRI than with other techniques (Klink et al, 2021; Tehovnik et al, 2006), es-fMRI connectivity is strongly site-specific. Such specificity was also reported for the behavioral effects of dPul vs. vPul stimulation with comparable currents (Dominguez-Vargas et al, 2017).…”

“…The combination of electrical microstimulation and fMRI (es-fMRI) has emerged as a powerful technique to probe the effective connectivity of a local cortical or subcortical stimulation site to distal brain regions in vivo (Field et al, 2008; Logothetis et al, 2010; Matsui et al, 2011; Moeller et al, 2008; Murayama et al, 2011; Petkov et al, 2015; Sultan et al, 2012), as recently summarized in an extensive review (Klink et al, 2021). Es-fMRI allows the mapping of anatomical connections in a living animal with a precision that cannot be achieved with other in-vivo methods such as diffusion tensor imaging or resting state connectivity (Honey et al, 2009; Schilling et al, 2019).…”

Optogenetic stimulation of primate V1 reveals local laminar and large-scale cortical networks related to perceptual phosphenes

“…Crucially, while electrical stimulation is routinely used with great success in research and clinical settings to influence sensory-motor function and cognition, optogenetic manipulation of behaviour in NHP remains challenging (Galvan et al, 2017; Tremblay et al, 2020). Delineating how optogenetic stimulation affects the primate functional circuitry, both at the local and global level is crucial for achieving a deeper understanding of how optogenetic methods may influence behaviour (Ju et al, 2018; Klink et al, 2021). Among several promising approaches, optogenetics has been combined with multi-contact electrophysiology to investigate optogenetic influences on primate cortical circuits with laminar resolution (Klein et al, 2016).…”