Being able to quickly detect and respond to potential threats is essential for survival. Fear and threat trigger a range of responses in the body, which are controlled by different regions in the brain. For example, a structure located deep within the brain called the amygdala is connected to other parts of the brain that regulate hormones, senses and muscles. The amygdala is highly responsive to signs of threat, and research in rodents has shown that it plays a role in transmitting sounds that indicate danger. However, so far it has remained unclear if this was also the case for visual information.

This is particularly challenging to study in humans because it has been difficult to image the deeper regions in the human brain. Now, McFadyen et al. reconstructed the pathways between the deeper brain regions important for processing vision and the amygdala using the brain scans of 622 participants. Then, they tested whether there was any connection between these pathways and the ability to recognise emotional expressions. To do so, fMRI brain scanning was used to measure the blood flow in the brain of volunteers looking at 40 faces that were either happy, sad, angry, fearful or neutral.

The results showed that when people were looking at pictures of fearful and angry faces, the blood flow between visual areas and the amygdala increased, especially in individuals with stronger connections, such denser nerve fibres, between the involved regions. The denser those fibres were, the better the people were at recognising when a face was fearful.

These discoveries suggest that the amygdala also plays a role in transmitting signals from deep-brain visual areas indicating danger and is likely to be one of the first areas to trigger a fear response in the brain. People with autism respond less to fearful faces, while people with anxiety respond more. Future research could investigate if the pathways to the amygdala differ in these people.

Decades ago, rodent research uncovered a subcortical pathway to the amygdala that rapidly transmits auditory signals of threat even when the auditory cortex is destroyed (Ledoux, 1998). Since this discovery, researchers have sought an equivalent visual pathway that might explain how it is that people with a lesioned primary visual cortex can still respond to affective visual stimuli that they cannot consciously see (Tamietto et al., 2010). The superior colliculus, pulvinar, and amygdala have been identified as nodes of a human subcortical route to the amygdala that bypasses the cortex (Morris et al., 1999). These subcortical areas consistently coactivate in cortically blind patients (Pegna et al., 2005) – as well as in healthy adults (Vuilleumier et al., 2003; Morris et al., 1999) – when they view emotional stimuli, such as angry or fearful faces. Magnetoencephalography studies using computational modelling have investigated whether the activation of these subcortical nodes is causally related. These studies have consistently found evidence for a forward connection between the pulvinar and amygdala (McFadyen et al., 2017; Garvert et al., 2014; Rudrauf et al., 2008). The dynamic causal relationship between the superior colliculus and the pulvinar, however, remains unexplored in the human brain (Soares et al., 2017). The pulvinar also has several functional and cytoarchitectural subregions (Barron et al., 2015) and it is unclear how these connect to the superior colliculus and the amygdala and what roles these subregions may play in mediating transmission along the subcortical route (Koller et al., 2018; Pessoa and Adolphs, 2010). As such, the hypothesis that the subcortical route rapidly transfers information from the retina to the amygdala without interference has been heavily criticised (Pessoa and Adolphs, 2010; Pessoa and Adolphs, 2011). Furthermore, the pulvinar is highly connected with a widespread network of cortical regions that may contribute to transmission along the subcortical route (Bridge et al., 2016; Zhou et al., 2016). Hence, it remains unknown whether the functional activation of the human superior colliculus, pulvinar and amygdala during affective processing bears any relation to an underlying structural pathway (Pessoa and Adolphs, 2010).

Recent animal research has revealed several potential direct subcortical pathways that have a causal relationship with fearful behaviour in response to visual threats (Zhou et al., 2017; Wei et al., 2015; Shang et al., 2015). In the absence of relevant postmortem human research, however, our anatomical knowledge of the human subcortical route to the amygdala can only be derived from tractography of diffusion-weighted images (DWI). Tamietto et al., 2012 examined DWIs from a blindsight patient whose left primary visual cortex was destroyed. The white matter structure of the subcortical route was estimated for the patient and for ten healthy, age-matched controls. Critically, the subcortical route had greater fractional anisotropy in the patient’s damaged hemisphere, suggesting a neuroplastic increase in structural connectivity to compensate for the disrupted cortical pathways (Tamietto et al., 2012). In a similar study, Rafal et al. (2015) used tractography to investigate the subcortical route in 20 healthy humans and eight macaques. The subcortical route was reconstructed in both hemispheres for 19 of the 20 human participants and 7 of the eight macaques (Rafal et al., 2015). Notably, this sample of human participants was recently expanded and re-examined, further demonstrating that individuals with greater fractional anisotropy along the subcortical route also had a stronger bias toward threat when making saccades to scenes (Koller et al., 2018).

Diffusion tractography may grant insight into the strength of anatomical connectivity between regions, but it cannot reveal the direction of information transfer nor can it be used as direct evidence alone for the anatomical existence of a neural pathway. The anatomical presence and the direction-specific neural flow of emotional visual information along the subcortical route has never been concurrently investigated in humans to definitively show that the subcortical route is a direct, afferent pathway specifically associated with fear (Pessoa and Adolphs, 2010; Pessoa and Adolphs, 2011). Such a finding would have important implications for the very foundation of visual threat perception, given this pathway’s potential for rapid information transfer (McFadyen et al., 2017; Silverstein and Ingvar, 2015) and unconscious processing (Tamietto et al., 2010). Here, we aimed to comprehensively investigate this putative amygdala pathway in a large sample of over 600 healthy human adults from the Human Connectome Project (HCP) dataset using a multimodal imaging approach to encompass structure, function and behaviour. First, we used DWI to reconstruct the subcortical route from the superior colliculus to the amygdala, via the pulvinar, and estimated its fibre density in a large sample. Next, we modelled the direction-specific flow of haemodynamic responses to faces, testing whether a functional subcortical route is recruited to transmit information toward the amygdala. Finally, we asked whether the fibre density of the subcortical route predicts both fearful face recognition as well as the strength of dynamic coupling between the superior colliculus, pulvinar, and amygdala.

The elusive subcortical route to the amygdala has posed a unique challenge in studies of the human brain, due to its depth and its fast activation. Evidence has accumulated over recent years across many studies using various neuroimaging modalities showing that this pathway may underlie primitive threat-related behaviour. These studies, however, often take a unimodal approach on typically small samples, making it difficult to relate the specific structural connections between superior colliculus, pulvinar, and amygdala to observed functional brain activity and behavioural output. Our study, which used a large sample of participants from the HCP, supports the existence of a subcortical pulvinar connection to the amygdala in the healthy human adult brain that facilitates dynamic coupling between these regions and also enhances fear recognition. We reconstructed the subcortical route to the amygdala using sophisticated tractography methods and found that the white matter fibre density of the pulvinar-amygdala connection significantly predicted individuals’ ability to recognise fearful faces. We then computationally modelled the functional neural networks along this structurally connected network that were engaged while people viewed emotional faces. We found that it was more likely for the network to include a subcortical visual route to the amygdala than a cortical route alone. Finally, we revealed converging evidence from structural and effectivity connectivity, such that the fibre density of the right pulvinar to amygdala pathway was positively correlated with the strength of the dynamic coupling (i.e. effective connectivity) between these regions.

This study marks the first time that structural and effective connectivity have been concurrently investigated in the one large sample to address the controversy on the existence and functional role of the putative subcortical route to the amygdala. Up to 60% of its fibre density overlapped with major fasciculi, including the corticospinal tract, anterior thalamic radiation, inferior longitudinal fasiculus, and inferior fronto-occipital fasciculus. Tractography of diffusion images is susceptible to both false positives and false negatives and thus is seldom used in isolation to determine the existence of particular neuroanatomical pathways (Jbabdi and Johansen-Berg, 2011). We established the validity of our tractographically reconstructed subcortical route by directly relating our measures of fibre density to both behaviour and effective connectivity, as well as by using two different tractography methods. Had the fibre density measures been simply due to noise, we would not have expected these theoretically relevant relationships with fearful face processing to emerge within this large sample of individuals. Notably, these intermodal relationships were only found for the pulvinar-amygdala connection, despite there being greater fibre density between the superior colliculus and the pulvinar and this connection being present in the winning dynamic causal model. One explanation for this is that we had relatively less BOLD signal-to-noise ratio in the superior colliculus due to its small size and proximity to major blood vessels in the brain stem (Wall et al., 2009), thus weakening the likelihood of finding consistent covariance of its functional coupling with fibre density. Another explanation, particularly regarding the behaviour-tractography relationship, is that the pulvinar plays a significant functional role in the subcortical route to the amygdala. Research on macaques has demonstrated the pulvinar’s response to emotional faces (Soares et al., 2017; Maior et al., 2010) and its role in modulating attention (Soares et al., 2017) and so we would indeed expect the strength of the pulvinar-amygdala connection to be more predictive of fearful face recognition. Future research could more deeply investigate the relative contribution of each half of the subcortical route to emotional face processing by using an optimised fMRI approach (Wall et al., 2009) and contrasting different types of stimuli – for example, low vs. high spatial frequency (Gomes et al., 2017) or moving stimuli (Berman and Wurtz, 2011).

Our decision to reconstruct the two halves of the subcortical route separately was motivated by our interest in the relative contribution of each connection to face-related processing (as described above) but was also a limitation imposed by anatomically-constrained tractography, where reconstructed fibres are terminated at boundaries between grey and white matter (Smith et al., 2012). Given that the pulvinar is made up of thalamic cell bodies (grey matter), the likelihood of reconstructing a continuous streamline of axon bundles traversing the pulvinar’s grey matter may have been restricted by these boundary constraints. Previous studies that have not imposed these constraints have successfully traced a continuous pathway from the superior colliculus to the amygdala via the pulvinar (Rafal et al., 2015; Tamietto et al., 2012), supporting animal research showing that inferior-lateral pulvinar neurons receiving superior colliculus afferents also have efferent connections to the lateral amygdala (Day-Brown et al., 2010). Our investigation into pulvinar and amygdala subregions support these findings, such that we found the superior colliculus to project predominantly onto the inferior (and anterior) pulvinar, which was the same subregion to receive the vast majority of fibres from the amygdala (see Figure 1). Furthermore, pulvinar fibres terminated predominantly within the basolateral amygdala, which is known to process visual information about threat and faces (Hortensius et al., 2016). Further studies could use both anatomically constrained tractography and this subregion-specific approach with ultra-high-resolution imaging to better differentiate grey-white matter boundaries and more accurately determine if and where a continuous, subcortical route might traverse the pulvinar.

While our results suggest that the inferior pulvinar may serve as a disynaptic connection point between the superior colliculus and amygdala, the continuity of information flow along the subcortical route is still a disputed feature due to the strong cortical influences on the pulvinar (Bridge et al., 2016; Pessoa and Adolphs, 2011). This dispute has also arisen from prior work investigating the spatial frequency content of information conveyed along the subcortical route. Research on blindsight patients has found evidence only for low spatial frequencies which suggests that such information originated from magnocellular cells in the superior colliculus (Burra et al., 2017; Méndez-Bértolo et al., 2016). On the other hand, work in healthy participants has found no such spatial frequency preference, which suggests that rapid pulvinar-amygdala transmission might include input from other parvocellular pathways (McFadyen et al., 2017). We did not exhaustively explore the extent to which the cortex contributes information to the pulvinar-amygdala connection. The winning effective connectivity model, however, did not include cortical connections between the pulvinar and the inferior occipital gyrus. Hence, it is unlikely that the primary visual cortex contributed (either via direct anatomical connections or functional coupling along the ventral visual stream; Pessoa and Adolphs, 2010) to the information transmitted along the subcortical route. The winning model did, however, include input to the superior colliculus as well as directly to the pulvinar, which could reflect direct retinal input or input from areas not explicitly included in the model, such as the parietal cortex, temporal cortex, or the LGN (Bridge et al., 2016), that may transmit both low and high spatial frequency information. Furthermore, it remains to be shown how interactions between the pulvinar and other cortical areas, such as the inferotemporal cortex (Zhou et al., 2016), may directly influence activity along the pulvinar-amygdala connection.

Our findings open avenues for future studies on how this subcortical pathway might influence threat-related behaviour. While our findings demonstrated that greater pulvinar-amygdala fibre density related to better fearful face recognition, it remains to be seen how this might compare with structural connectivity of other cortical networks. In other words, would the fibre density of this subcortical connection explain fearful face recognition above and beyond, say, structural connections between the inferior temporal or orbitofrontal cortex and the amygdala (Pessoa and Adolphs, 2011) or between the thalamus and the superior temporal sulcus (Leppänen and Nelson, 2009)? Evidence from blindsight patients suggests that this subcortical connection ensures redundancy and compensation, such that it strengthens when cortical connections are destroyed (Tamietto et al., 2012). Taking this in conjunction with our findings, we might consider that the pulvinar-amygdala connection contributes to fear recognition in faces (and effective connectivity underlying face perception) in healthy participants but can increase or decrease its influence depending on the functioning of other networks. Such increases and decreases are already evident in certain clinical populations. For example, structural connectivity between the superior colliculus, pulvinar, and amygdala is weakened in individuals with autism compared to healthy controls (Hu et al., 2017), and BOLD signal to fearful faces is reduced in these areas (Kleinhans et al., 2011; Green et al., 2017), unless participants are explicitly instructed to fixate on the eyes (Hadjikhani et al., 2017). On the other hand, people who suffer from anxiety show hyperactive activity along the subcortical route compared to non-anxious individuals (Hakamata et al., 2016; Tadayonnejad et al., 2016; Nakataki et al., 2017). How and why this subcortical visual pathway to the amygdala is altered in these clinical populations remains a significant and relatively unexplored avenue of research.

We observed hemispheric lateralisation of the pulvinar-amygdala connection, such that both the local and global tractography showed greater fibre density along the right than the left, and there were stronger tractography-behaviour and tractography-connectivity relationships for the right than the left. Early studies on the subcortical route observed specifically right-sided BOLD responses during non-conscious fearful face viewing (Morris et al., 1999; Morris et al., 1998), and a previous tractography study has also found that only the fractional anisotropy of the right subcortical route was significantly related to threat-biased saccades (Koller et al., 2018). There is mounting evidence for right-sided specialisation for ordered (Wyczesany et al., 2018) and disordered (McDonald, 2017) emotion processing, particularly for non-conscious signals transmitted along the subcortical route (Gainotti, 2012). Thus, our results lend support to this theory by demonstrating evidence for the right pulvinar-amygdala connection’s stronger fibre density and its relationship to emotional face viewing and fearful face recognition. Our understanding of this lateralisation may be deepened by future exploration of left- vs. right-sided structural connectivity and function along the subcortical route during conscious vs. non-conscious emotion processing in healthy participants.

One limitation of the present study is the discrepancy between how local and global measures of fibre density related to other measures; namely, that local tractography covaried with fearful face recognition scores while global tractography covaried with effective connectivity. While the reconstructed fibres shared many similarities (e.g. the pattern of findings for each connection across hemispheres and subregions, as well as the overlap with major fasciculi; see Figure 1) even after accounting for head motion, it is possible that the local tractography’s relatively greater susceptibility to noise may have decreased its relationship to corresponding effective connectivity parameters. Indeed, global tractography has been shown to better reflect local connection architecture (Jbabdi and Johansen-Berg, 2011), such as the subcortical connections we have investigated. Such discrepancies between global and local tractography have been reported in other work (Anastasopoulos et al., 2014) and so further research (particularly those that only recruit a single tractograpy method) will benefit from specific investigations into why these discrepancies might arise.

In conclusion, our study has made substantial progress towards settling the long-held debate over the existence and function of a subcortical route to the amygdala in the human brain. Our multimodal neuroimaging approach, leveraged by computational modelling, provides convergent evidence for a fundamental and conserved pulvinar-amygdala pathway that is specifically involved in fear. We demonstrate that the white matter tracts that form the subcortical structural pathway from the pulvinar to the amygdala enables functional, dynamic interactions involved in emotional face perception. Critically, we show that structural connectivity between the pulvinar and the amygdala leads to better recognition of fearful expressions.

The data analysed in this study came from the publicly-available Human Connectome Project S900 release: https://www.humanconnectome.org/study/hcp-young-adult/document/900-subjects-data-release. Restricted access was obtained through the HCP to acquire specific participant ages (in years) and drug/alcohol information. Computer code used to produce the results is available on GitHub (https://github.com/jjmcfadyen/hcp-diffusion-dcm; copy archived at https://github.com/elifesciences-publications/hcp-diffusion-dcm).

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Author details

1. Jessica McFadyen

   1. Queensland Brain Institute, University of Queensland, Brisbane, Australia
   2. Australian Research Council of Excellence for Integrative Brain Function, Clayton, Australia

   Contribution

   Data curation, Software, Formal analysis, Validation, Visualization, Methodology, Writing—original draft

   For correspondence

   j.mcfadyen@uq.edu.au

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1415-2286

2. Jason B Mattingley

   1. Queensland Brain Institute, University of Queensland, Brisbane, Australia
   2. Australian Research Council of Excellence for Integrative Brain Function, Clayton, Australia
   3. School of Psychology, University of Queensland, Brisbane, Australia
   4. Canadian Institute for Advanced Research (CIFAR), Toronto, Canada

   Contribution

   Supervision, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0929-9216

3. Marta I Garrido

   1. Queensland Brain Institute, University of Queensland, Brisbane, Australia
   2. Australian Research Council of Excellence for Integrative Brain Function, Clayton, Australia
   3. School of Mathematics and Physics, University of Queensland, Brisbane, Australia
   4. Centre for Advanced Imaging, University of Queensland, Brisbane, Australia

   Contribution

   Conceptualization, Methodology, Supervision, Funding acquisition, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0679-4959

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