Elsevier

Neuropsychologia

Volume 145, August 2020, 106571
Neuropsychologia

Causal mapping of emotion networks in the human brain: Framework and initial findings

https://doi.org/10.1016/j.neuropsychologia.2017.11.015Get rights and content

Highlights

  • a novel causal discovery algorithm is used.

  • concurrent electrical stimulation and fMRI reveal amygdala connections.

  • a framework and initial data show causal emotion networks.

Abstract

Emotions involve many cortical and subcortical regions, prominently including the amygdala. It remains unknown how these multiple network components interact, and it remains unknown how they cause the behavioral, autonomic, and experiential effects of emotions. Here we describe a framework for combining a novel technique, concurrent electrical stimulation with fMRI (es-fMRI), together with a novel analysis, inferring causal structure from fMRI data (causal discovery). We outline a research program for investigating human emotion with these new tools, and provide initial findings from two large resting-state datasets as well as case studies in neurosurgical patients with electrical stimulation of the amygdala. The overarching goal is to use causal discovery methods on fMRI data to infer causal graphical models of how brain regions interact, and then to further constrain these models with direct stimulation of specific brain regions and concurrent fMRI. We conclude by discussing limitations and future extensions. The approach could yield anatomical hypotheses about brain connectivity, motivate rational strategies for treating mood disorders with deep brain stimulation, and could be extended to animal studies that use combined optogenetic fMRI.

Introduction

How do networks of brain structures generate human emotions? Affective neuroscience has documented a wealth of data, primarily from activations observed in neuroimaging studies in response to emotional stimuli. This has provided us with an inventory of brain structures that participate in emotions, but little knowledge of their precise causal role. Studies in humans with direct electrical stimulation of structures such as the amygdala have shown causal links between brain regions and emotional responses, but these additional findings still leave us with scant knowledge of how emotions are implemented at the network level in the brain. The question is pressing for translational reasons as well. Deep-brain stimulation is being explored for a large number of neurological and psychiatric diseases, but with quite variable success. There are clear case studies of remarkable amelioration of depression, for instance—but only in some cases, limiting the generalizability of the results (Kennedy and al, 2011; Mayberg et al., 2005).

We think of emotions as functional, central brain states defined by their cause-and-effect relationships with other brain processes, and with stimuli and behaviors. Which stimuli reliably cause emotions? How do emotions in turn cause behavioral responses? And -- the topic of this paper -- how do different brain regions interact with one another during emotion processing? The basic problem can be sketched in relation to the amygdala as schematized in Fig. 1. The amygdala is activated by threat-related stimuli, lesions of the amygdala impair threat-related responses and (in humans) aspects of the experience of fear, and stimulation of the amygdala produces defensive behaviors (very roughly). Nobody nowadays would conclude that “fear is in the amygdala”. Instead, the amygdala helps to orchestrate the many different causal effects of a fear state. To understand these effects we need to map the causal relations between the amygdala and other brain regions, through which such effects are mediated. We know almost nothing about these causal relations in the human brain.

Studies in animals have begun to dissect the circuits responsible for processing emotion, and of course offer methodological tools that are unavailable in humans. For instance, experimental manipulation of brain activity in rodents and monkeys has provided insights into the causal roles of particular circuits, such as the extended amygdala (Amaral and Adolphs, 2016, Shackman and Fox, 2016) and the hypothalamus (Lin et al., 2011). Behavioral dependent measures, while they need to be interpreted carefully, have given us strong evidence for how specific neuronal populations can cause specific emotional behaviors related to fear and aggression. One main limitation with these animal studies has been achieving a whole-brain field-of-view. Although specific circuits can be manipulated, e.g. through optogenetic or chemogenetic activation, the downstream effects are typically measured in only a very small subset of brain regions. One exciting future combination of methods is concurrent optogenetic stimulation with whole-brain fMRI (Lee et al., 2010, Liang et al., 2015), or with ultrasound imaging. However, the homology to human emotions remains a major limitation (Adolphs and Anderson, 2018).

Elucidating the causal networks that underlie emotion processing is one of the most important but also most difficult challenges faced by affective neuroscience. It is important because only an account at the level of causal mechanisms can really explain brain processing, and because only such an account can yield insights that allow us to manipulate brain function (for instance, with interventions aimed to treat mood disorders). Yet it is difficult because most of the data from the human brain are correlational in nature, making it unclear how to infer causality from typical neuroimaging and electrophysiological studies. Here we demonstrate the promise of a new technique – concurrent electrical stimulation and fMRI – and a new method in causal discovery – the fast greedy equivalence search – to obtain large-scale causal models that describe how different brain regions interact. We begin by briefly reviewing some of the findings from affective neuroscience, with an emphasis on the amygdala, and then outline the logic of causal discovery, before presenting our approach and pilot data to support it.

Section snippets

Emotion and the amygdala

Data from lesion studies and fMRI in humans, and from a range of approaches in animals, consistently implicate the amygdala (Fig. 2), the medial prefrontal cortex, the insula, the hypothalamus, and the periaqueductal gray in emotions. These structures function as components of considerably more distributed systems, and attempts to localize particular emotions (fear, sadness, etc.) to any one of these structures have been largely unsuccessful (Lindquist et al., 2012), even though specific

Causal discovery

The range of methods for analyzing brain function at the network level vary from essentially descriptive (such as looking at correlations between regions, i.e., standard functional connectivity approaches) to methods for inferring parameters of pre-specified models (such as dynamic causal modeling (DCM) (Friston, 2011; Friston et al., 2013)). All of these have tradeoffs: standard “functional connectivity” from correlations does not provide a causal model; DCM is limited by our knowledge of the

Methods

Our approach is roughly hierarchical in nature (Fig. 4) and consists of three main steps. These three steps are based on the analysis of existing resting-state data from large databases, comparison to resting-state data from individual neurosurgical patients, and comparison with the patient's graph using direct electrical stimulation-fMRI data from that patient. Future extensions beyond the scope of the present paper include (in red): formally integrating information from the large datasets as

Parameter setting for causal discovery and reproducibility across datasets

We first determined the reproducibility of our causal discovery analysis by deriving causal graphs from high-quality, large-sample size, statistically independent datasets. We began by using the HCPs dataset, which maximizes sample size, cross-subject generalizability, and statistical independence of the datasets. Comparing across 11 independent datasets from the HCPs, we obtained graphs at 10 different sparsity settings (Fig. 6). As expected, increasing the sparsity parameter resulted in

Summary of findings

We outlined a workflow for discovering causal connections in the human brain, and provided initial validation, measures of reliability, and comparisons across datasets. We then demonstrated the application of this workflow to the connectivity of the amygdala, as a case study for the investigation of causal networks that subserve emotion processing. However, our approach is quite general and we intend it to be applicable to the investigation of any brain structure, not just the amygdala (and

Acknowledgments

Supported by NIMH grant 2P50MH094258, NINDS grant 1U01NS103780-01, and grant 542941 from the Simons Foundation Collaboration on the Global Brain to R.A.; and by NSF grant 1564330 to F.E.

Data sharing

The HCP and MCP datasets are publicly available. All other data and analyses are available from the authors upon request.

Author contributions

J. Dubois conducted most of the analyses and generated all data figures in the main text. H. Oya and M. Howard conducted the electrical stimulation-fMRI experiments, and H. Oya processed the resulting data and conducted GLM analyses. J.M. Tyszka provided help with analysis of fMRI data. F. Eberhardt conducted all causal discovery analyses. All authors discussed and planned

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