Ventromedial prefrontal cortex and amygdala, cognitive-emotional integration in one pathway – the Uncinate Fasciculus
By Jenay Bartlett UA’25 (JB), Judah Weathers (JW), and Jim Stellar (JS)
This blog is a collaboration of JB who is a senior undergraduate, JW a past student of JS who is now an MD/PhD working as a Psychiatrist at Yale, and JS who is a Professor
We begin this blog with two points:
1) A previous blog briefly discussed the uncinate fasciculus (UF), a pathway from the frontal lobe to the amygdala. The key observation there was that in normal people, not patients, if the UF was a more dense connection the subjects tended to be somewhat less anxious.
2) The UF supports communication between the ventromedial prefrontal cortex (vmPFC) and the amygdala (AMG), two key brain regions involved in the decision making and emotion regulation. A published 2018 neuroscientific study by one of our co-authors (JW, a psychiatrist and former undergraduate student of JS from long ago) showed that if UF developed in adolescents with reduced structural integrity, they were more likely to develop bipolar disorder and have problems in emotion regulation. Thus, the healthy development of the UF is likely a key structure in the distributed brain circuitry involved in healthy cognitive-emotional integration with increasing age.
This study of the UF fits with the general theme of the entire blog series – about cognitive-emotional integration processes in college students when they combine academic learning with direct experience (e.g. internships). In these students, we can even look for the beginning of what we call professional wisdom and that helps with confidence in the college years and success after graduation.
But first, what is the UF and how does it illustrate cognitive-emotional integration particularly between the ventromedial prefrontal cortex and the amygdala?
The uncinate fasciculus (UF)
Anatomy: The UF is a bidirectional white matter tract that interconnects the functions of the vMPFC and the AMG. This tract is a major pathway that allows integration of emotions (AMG) and value-based planning and decision-making (vMPFC). We also believe the UF is potentially a key structure subserving the ‘somatic marker hypothesis’, as described by Damiso and Bechara in 2004, and that we will discuss later.
Studies on the UF were driven by basic findings from diffusion tensor imaging (DTI) imaging in humans. They have generally shown that the entire UF has a hook-shape as shown in the figure below.
While the UF has many anatomical components beyond the vMPFC (e.g. the orbital frontal cortex) and AMG (e.g. anterior temporal pole) and has differences between the left and right hemispheres, we will restrict ourselves here to the basic vMPFC and AMG connections and focus on the relevant cognitive-emotional integration properties. However, to give a bit more anatomical detail, the UF is divided into three sections – 1) temporal, 2) insular, and 3) frontal. 1) The temporal portion begins in the front or anterior part of the middle temporal gyrus, with branches fanning from the AMG, the uncus, and the temporal pole. Findings from an older paper in 1992 and a more recent one from 2013, shows that these areas are known to play roles in emotion processing, episodic and object memory, and semantic and social-emotional memory. 2) The UF pathway continues through the limen insulae (the anteroinferior aspect of the insular cortical surface), before splitting off into two significant branches in the ventrolateral frontal cortex and the rostral middle frontal cortex. 3) The pathway continues on to connect to the orbitofrontal cortical region. With other prefrontal cortex regions, the orbital frontal cortex is known to have a role in decision-making, reward, and emotional processing. While the UF is a rich area for study, specifically, again this blog will focus on the UF connection from the neocortical-vmPFC to the limbic-AMG regions of the brain.
Development: UF development can be measured from DTI scanning by fractional anisotropy, which is a quantitative biomarker of white matter integrity. Fractional anisotropy increases with development and such values reflect increases in the structural integrity associated with fiber track and presumably functional maturation. We note that the UF doesn’t appear to reach full development until around 30 years of age, which may significantly influence decision making and susceptibility to emotion regulation deficits in children, adolescents, and even young adults. The UF is one of the last white matter brain pathways to mature in humans, suggesting that it is also one of the most recently evolved. Of course the largest changes in UF structure are early in development. Numerous studies have reported differences in structural integrity of the UF in patients with mental disorders including anxiety, depression, and bipolar disorder, strengthening the belief that there is a disconnect of our emotions and decision making in these conditions. The idea is that AMG and vmPFC regulate each other via the UF, and that disruption or weakness of development in this pathway may result in things such as unregulated emotions by the AMG and/or impaired decision making from the vmPFC.
AMG and vmPFC – two key connections of the UF
The Ventromedial Prefrontal Cortex (vmPFC): The vmPFC is famously implicated in the work of Damasio’s group (previously mentioned) in generating feelings that underlie decision-making and also in the somatic marker hypothesis where gut-level feelings are involved in cognitive decisions. More specifically, research indicates that first-hand learning from ones making value-based decisions is reliant on healthy functioning of the vmPFC. Individuals that have damage to this brain region fail to make decisions that reflect learning the value of their decisions, especially in the long term. A separate neuropsychological study in 2015 revealed that, while damage to the vmPFC did not impair participants from learning to make value-based decisions from outcomes of their own choices (i.e. ‘experiential learning’), damage did impair participants from learning to make value-based decisions from observed outcomes of computer choices (i.e. ‘observational learning’). Taken together, the vmPFC is not only important in value-based decision making, but value-based decision making that is learned from one’s own choices and choices observed by others. We wrote a blog about the infralimbic cortex basal lateral AMG connections in rats, and another blog discussing this and other cortical areas that seem to re-represent limbic processing in general.
The Amygdala: The AMG is a subcortical structure. It lacks the columnar organization of the neocortex that we have said before is a signature feature of the cortex’s networked operation that we speculate underlies the cortex’s ability to generate symbolic logical models of the world that go beyond learned associations. A simple example here is knowing and calculating the trajectory of an object (not just eye-tracking) that is done in all mammals. A more complex example might be human language and other high cognitive abilities. However, we also did suggest that the neocortex does re-represent subcortical limbic processes creating a value-processing cortex where the AMG’s functions can enter into cognitive planning, perhaps through a previously mentioned “somatic marker” or “embodied cognition” or some other process. In one past blog post we particularly thought the insula cortex might play a role here. Of course, the UF connects to the AMG and this connection has an important role in adolescent development as seen in another paper.
The AMG itself is a complex structure with a history of being thought to be involved in fear and emotional processing, even more recently in processing positive situations. To focus directly on the AMG and fear, and to tap into a long research history often in sub-primates, the lateral amygdala nucleus is thought to be the place where neurons receive and encode fear conditioning inputs. The basal lateral nucleus of the AMG is thought to work with other areas to bring fear conditioning to bear on other behaviors, such as operant responding. The central nucleus has been traditionally viewed as the output operation of the AMG. All of these subregions and more remain a current subject of much study including a genetic analysis of its structure.
The above discussion only briefly represents the complex internal structure of the AMG into which the UF connects. How it does that remains a mystery in humans, in part due to the inability of human brain scan data to operate (for now) at sufficient resolution. In addition, in animal studies a variety of anatomical tracers and molecular genetic studies can give even a cellular resolution to some of these AMG structural connection questions. But that discussion is now beyond the scope of this blog.
What weakens and strengthens the UF pathway?
Several studies have reported the negative impact of trauma on brain structure and health, including on the structural development of the UF and other white matter tracts. This supports the notion that ensuring our needs from the environment are met has a profound impact on our lives long-term. In a 2017 study, childhood adversity was found to be associated with reduced fractional anisotropy in tissues of certain white matter tracts in the adult brain including the UF. Reduced DTI fractional anisotropy measures were even found to still be reduced even in these now-healthy adults. The study mainly focused on childhood adversity resulting from parental maltreatment, building on a 2006 study associating reduced integrity of white matter tracts, including the UF, with childhood socioemotional deprivation. Additionally, reduced integrity in the UF has been found to occur in adults exposed to combat distress and suffering from PTSD-related symptoms.
What is it exactly about adversity that appears to weaken the UF? Consistent exposure to stress has been shown to result in long-lasting microstructural changes in the brain, with the AMG and prefrontal cortex being key regions. In a 2006 study supporting this, PTSD subjects showed a distinct pattern of medial prefrontal and AMG connectivity when exposed to a fear perception task compared to healthy subjects. Other studies have shown that the AMG may become overactive as a result of being in a constant stressful state, and the vmPFC may become reduced in its activity. Chronic stress has been found to cause a shrinking of dendritic neuron branches in the vmPFC, as well as an impaired ability to extinguish fear responses, which is the vmPFC’s ability to learn certain feared stimuli are no longer harmful. This hypoactivity of the vmPFC has been shown to elevate AMG activity. Dendritic neuron branches in the AMG have been found to grow in response to stress, which allows for stronger development of fear responses and altered emotional responses to traumatic events. Additionally, stress directly impacts the AMG through receptors that allow stress hormones to bind to the AMG. When there is an increased amount of stress hormones being produced and binding to the AMG, fear conditioning becomes heightened even further, and emotional processing altered even more. It is likely that overtime, the vmPFC’s inability to properly regulate the AMG’s reactivity to chronic stress as a result from trauma is what results in the weakened integrity of the pathway connecting the two, the UF. Trauma likely reinforces a maladaptive pattern of prefrontal and AMG connectivity, which may result in long-term learning and structural changes of this altered connectivity.
To our knowledge, research on what strengthens the UF pathway is nonexistent. Nevertheless, it is known that aerobic and anaerobic exercise, including in childhood, as well as practicing overlearned and novel skills, cognitive and working memory training, and meditation all contribute to increased brain structural integrity and particularly as measured by DTI fractional anisotropy in white matter tracts. Furthermore, higher levels of social network diversity in another DTI study (i.e. regular contact with supports from people from a range of groups, such as colleagues, family, religious, etc.) correlated with higher white matter structural integrity in adults, suggesting depth and breadth of socialization is likely important in strengthening white matter tracts. That could apply to the UF.
The UF and the Somatic Marker Hypothesis
As mentioned previously, we believe that the UF may be an integral structure in supporting the somatic marker hypothesis and therefore this form of cognitive-emotional integration as mentioned earlier in connection with Damaiso’s work. In brief, as discussed here, “The Somatic Marker Hypothesis suggests that emotions and feelings create “somatic markers” which act as signals guiding behavior towards beneficial outcomes.” As Damasio suggested, patients with vmPFC brain damage lost the ability to use these somatic markers and thus had a very difficult time making decisions while they retained much knowledge of the facts and theories of the subject under discussion. The result was a serious impairment of function in daily life.
Several studies have found the UF to play a role in reversal learning, impulsive responding, sensitivity to reward and punishment, episodic memory, social-emotional processing, and language. While all of these phenomenon seem to involve cognitive-emotional integration, how this all fits together seems complicated. A proposed model suggests that the UF influences our behavior through integrating mnemonic associations in the temporal lobe/AMG (such as the combination of a person’s name, face, and feelings towards them). This process would facilitate updates in the frontal cortex about decision making and value components of those temporal mnemonic associations. This could be the same function as in the somatic marker idea.
Application to career decisions in college: While a discussion of the cognitive components of frontal-temporal lobe UF connections is beyond the scope of this blog, the idea of integration with emotions is critical in other areas about which we write in this blog series such as a student’s evaluations of college, social, and professional experiences. So, perhaps the UF allows for people in general to make decisions based on the integration of one’s emotional responses with cognitive information. For example, when a student considers pursuing a career in basic science versus clinical medicine, does the UF supports brain functioning in reflecting upon remembered events (e.g. How well I understood physiology in my freshman year course?), current events (e.g. I really enjoy volunteering in the hospital setting.), and anticipated events (What it will be like writing a research paper with my science mentor?). These experiences, feelings, decisions and mastery, all depend on integration in memory, learning, emotions and decision making.
I’m a college student, and I don’t know what my future holds. Does this mean my brain is not developing properly?
The answer is, no.
Through the course of this blog post, we have presented a network of brain circuitry, involving the AMG, vMPFC, and the UF that connects them, that subserves the complex process of cognitive-emotional integration, which we believe extends to experiential learning and the development of ‘professional wisdom’. A reader may thus conclude that any challenges that arise in experiential learning, or barriers to achieving a personally fulfilling professional life, are due to problems in the brain based development of cognitive-emotional integration. To the contrary, this brain circuit is only one part of the story.
For example, consider the range of life experiences, experiences happening ‘external’ to the brain, that can have direct impact on academic or professional outcomes. Perhaps a student suddenly finds themself having to worry about how to finance their continued education. Or, maybe a student has an unexpected loss in their family, or finds themselves having to juggle new family responsibilities, during their academic career. Or, the effect that comes with that especially challenging prerequisite college class that is making you question whether you have the skills needed to ‘succeed’. While we understand life experiences can certainly impact cognitive and emotional processes, brain function can be extraordinarily different between individuals, as well as resilient and adaptive. What may seem like an impossible setback for one student, may feel like an opportunity to shine for another. Furthermore, individual differences on the impacts of adversity, stress, or unexpected events on cognitive-emotional development may not be ‘neatly’ encoded in the AMG-UF-vMPFC circuitry we discuss here. An ongoing important area of study, therefore, is understanding the dynamic interaction of AMG-UF-vMPC circuitry development with environmental variables, including for example access to higher education or role models, adversity and resilience, and the ever changing socialization of students with advancing technology. An improved understanding on how individual differences in life experiences, in concert with cognitive-emotion circuitry brain development leading to different outcomes and decision making, can also help educators develop experiential learning programs that are tailored to yield the greatest personal fulfillment and success for each individual student.
These are challenging questions as related to the UF, but we think they are important, and we will be back to discuss them again in a future blog.
