Differential functional connectivity underlying asymmetric reward-related activity in human and nonhuman primates

The orbitofrontal cortex (OFC) is a key brain region involved in complex cognitive functions such as reward processing and decision making. Neuroimaging studies have reported unilateral OFC response to reward-related variables; however, those studies rarely discussed this observation. Nevertheless, some lesion studies suggest that the left and right OFC contribute differently to cognitive processes. We hypothesized that the OFC asymmetrical response to reward could reflect underlying hemispherical difference in OFC functional connectivity. Using resting-state and reward-related functional MRI data from humans and from rhesus macaques, we first identified an asymmetrical response of the lateral OFC to reward in both species. Crucially, the subregion showing the highest reward-related asymmetry (RRA) overlapped with the region showing the highest functional connectivity asymmetry (FCA). Furthermore, the two types of asymmetries were found to be significantly correlated across individuals. In both species, the right lateral OFC was more connected to the default mode network compared to the left lateral OFC. Altogether, our results suggest a functional specialization of the left and right lateral OFC in primates.</jats:p

Ultrasound modulation of macaque prefrontal cortex selectively alters credit assignment–related activity and behavior

Contains fulltext : 242467.pdf (Publisher’s version ) (Open Access)Credit assignment is the association of specific instances of reward to the specific events, such as a particular choice, that caused them. Without credit assignment, choice values reflect an approximate estimate of how good the environment was when the choice was made - the global reward state - rather than exactly which outcome the choice caused. Combined transcranial ultrasound stimulation (TUS) and functional magnetic resonance imaging in macaques demonstrate credit assignment–related activity in prefrontal area 47/12o, and when this signal was disrupted with TUS, choice value representations across the brain were impaired. As a consequence, behavior was no longer guided by choice value, and decision-making was poorer. By contrast, global reward state-related activity in the adjacent anterior insula remained intact and determined decision-making after prefrontal disruption.14 p

The macaque anterior cingulate cortex translates counterfactual choice value into actual behavioral change

The neural mechanisms mediating sensory-guided decision making have received considerable attention but animals often pursue behaviors for which there is currently no sensory evidence. Such behaviors are guided by internal representations of choice values that have to be maintained even when these choices are unavailable. We investigated how four macaque monkeys maintained representations of the value of counterfactual choices – choices that could not be taken at the current moment but which could be taken in the future. Using functional magnetic resonance imaging, we found two different patterns of activity co-varying with values of counterfactual choices in a circuit spanning hippocampus, anterior lateral prefrontal cortex, and anterior cingulate cortex (ACC). ACC activity also reflected whether the internal value representations would be translated into actual behavioral change. To establish the causal importance of ACC for this translation process, we used a novel technique, Transcranial Focused Ultrasound Stimulation, to reversibly disrupt ACC activity

Amygdala-prefrontal cortex interactions in the primate brain and the neural basis of credit assignment

An important adaption for life in changeable environments, such as those occupied by many primate species, is the ability to learn the contingencies that prevail between events and their consequences. Credit assignment consists in the capacity to correctly associate the value of an outcome to the event or choice that led to it. Interactions between amygdala and prefrontal cortex have been suggested to support credit assignment. Chapter 1 reviews the anatomy and function of areas supporting value-guided learning and decision making that may contribute to credit assignment mechanisms. This chapter also reviews a group of methodological approaches that have been used or are currently being optimized to investigate these mechanisms. Chapter 2 focuses on the reconstruction of the anatomical pathways supporting value-guided computations and that may provide the scaffolding for credit assignment to take place. Both macaque monkeys and humans are investigated using the same methodological approach which additionally makes possible direct comparison of anatomical and connectional features in the two species. Chapter 3 demonstrates the potential of an offline focused transcranial ultrasound stimulation protocol applied at low-intensity to reversibly and minimally-invasively modulate the activity coupling of subcortical and deep cortical areas like the amygdala and anterior cingulate cortex of the primate brain without the necessity for surgical intervention. Chapter 4 exploits these properties of focused transcranial ultrasound stimulation to investigate the behavioural deficits in credit assignment caused by the disruption of activity in the primate lateral orbitofrontal cortex. The behavioural results reported in this chapter suggest that ultrasound stimulation targeted to this area impairs the capacity to correctly assign credit to a previous choice, specifically following positive feedback, thereby disrupting the impact that the integrated history of choice option-outcome contingencies has on future behaviour. Chapter 5 highlights the neural basis of credit assignment and the consequence of interfering with activity in lateral orbitofrontal cortex. After stimulation, brain activity encoding the choice-option outcome contingencies through credit assignment was disrupted but the response to reward only was not. Chapter 6 reviews the results reported throughout the thesis aiming to connect them together in a similar framework and discuss them with reference to the current scientific literature on amygdala-prefrontal cortex connectivity and credit assignment

White matter tract transcranial ultrasound stimulation, a computational study

Low-intensity transcranial ultrasound stimulation (TUS) is poised to become one of the most promising treatments for neurological disorders. However, while recent animal model experiments have successfully quantified the alterations of the functional activity coupling between a sonicated target cortical region and other cortical regions of interest (ROIs), the varying degree of alteration between these different connections remains unexplained. We hypothesise here that the incidental sonication of the tracts leaving the target region towards the different ROIs could participate in explaining these differences. To this end, we propose a tissue level phenomenological numerical model of the coupling between the ultrasound waves and the white matter electrical activity. The model is then used to reproduce in silico the sonication of the anterior cingulate cortex (ACC) of a macaque monkey and measure the neuromodulation power within the white matter tracts leaving the ACC for five cortical ROIs. The results show that the more induced power a white matter tract proximal to the ACC and connected to a secondary ROI receives, the more altered the connectivity fingerprint of the ACC to this region will be after sonication. These results point towards the need to isolate the sonication to the cortical region and minimise the spillage on the neighbouring tracts when aiming at modulating the target region without losing the functional connectivity with other ROIs. Those results further emphasise the potential role of the white matter in TUS and the need to account for white matter topology when designing TUS protocols

Mapping multiple principles of parietal-frontal cortical organization using functional connectivity

Item does not contain fulltextResting state functional connectivity has been promoted as a promising tool for creating cortical maps that show remarkable similarity to those established by invasive histological methods. While this tool has been largely used to identify and map cortical areas, its true potential in the context of studying connectional architecture and in conducting comparative neuroscience has remained unexplored. Here, we employ widely used resting state connectivity and data-driven clustering methods to extend this approach for the study of the organizational principles of the macaque parietal–frontal system. We show multiple, overlapping principles of organization, including a dissociation between dorsomedial and dorsolateral pathways and separate parietal–premotor and parietal–frontal pathways. These results demonstrate the suitability of this approach for understanding the complex organizational principles of the brain and for large-scale comparative neuroscience

Modelling transcranial ultrasound neuromodulation: an energy-based multiscale framework

Several animal and human studies have now established the potential of low intensity, low frequency transcranial ultrasound (TUS) for non-invasive neuromodulation. Paradoxically, the underlying mechanisms through which TUS neuromodulation operates are still unclear, and a consensus on the identification of optimal sonication parameters still remains elusive. One emerging hypothesis based on thermodynamical considerations attributes the acoustic-induced nerve activity alterations to the mechanical energy and/or entropy conversions occurring during TUS action. Here, we propose a multiscale modelling framework to examine the energy states of neuromodulation under TUS. First, macroscopic tissue-level acoustic simulations of the sonication of a whole monkey brain are conducted under different sonication protocols. For each one of them, mechanical loading conditions of the received waves in the anterior cingulate cortex region are recorded and exported into a microscopic cell-level 3D viscoelastic finite element model of a neuronal axon embedded in extracellular medium. Pulse-averaged elastically stored and viscously dissipated energy rate densities during axon deformation are finally computed under different sonication incident angles and are mapped against distinct combinations of sonication parameters of the TUS. The proposed multiscale framework allows for the analysis of vibrational patterns of the axons and its comparison against the spectrograms of stimulating ultrasound. The results are in agreement with literature data on neuromodulation, demonstrating the potential of this framework to identify optimised acoustic parameters in TUS neuromodulation. The proposed approach is finally discussed in the context of multiphysics energetic considerations, argued here to be a promising avenue towards a scalable framework for TUS in silico predictions. Statement of significance Low-intensity transcranial ultrasound (TUS) is poised to become a leading neuromodulation technique for the treatment of neurological disorders. Paradoxically, how it operates at the cellular scale remains unknown, hampering progress in personalised treatment. To this end, models of the multiphysics of neurons able to upscale results to the organ scale are required. We propose here to achieve this by considering an axon submitted to an ultrasound wave extracted from a simulation at the organ scale. Doing so, information pertaining to both stored and dissipated axonal energies can be extracted for a given head/brain morphology. This two-scale multiphysics energetic approach is a promising scalable framework for in silico predictions in the context of personalised TUS treatment