Ventromedial and orbital frontal cortex

Goals

To discuss valuation and neuromarketing
To extend our discussion of the ventral and medial prefrontal cortex
To discuss the amygdala, vmPFC and psychopaths
To discuss the neuroscience of morality
To discuss psychosurgery: frontal lobotomies and cingulotomies

Topic slide

Antonio Egas Moniz (1884-1955) was a neurosurgeon in Portugal who won the Nobel Prize in 1949 for his invention of the frontal lobotomy.

From the PBS website:

'In 1935 at an international neurology conference he saw a presentation on the frontal lobes of the brain and the effects of removing them from chimpanzees. Moniz later claimed he had been thinking about similar methods before the conference, but it went into scientific mythology that the calm behavior of the presenter's formerly temperamental chimp had inspired him to develop the lobotomy to treat mental illness.

Moniz had an idea that some forms of mental illness were caused by an abnormal sort of stickiness in nerve cells, causing neural impulses to get stuck and the patient to repeatedly experience the same pathological ideas. There was no empiric evidence for his theory, but Moniz pressed on. If the nerve fibers causing these morbidly fixed ideas could be destroyed, the patient might improve. In November 1935, he and his assistants made the first attempts at this type of psychosurgery. First they gave a series of alcohol injections to the frontal lobe (through holes drilled in the skull). After seven patients, they switched to cutting the lobe with a wire. Nothing was removed; connections were just severed.'

Walter Freeman YC'1916 (1895-1972) was an American physician who popularized a version of the frontal lobotomy (transorbital frontal lobotomy) that did not require the skull to be opened, but rather introduced a surgical tool through the eye socket. Although he was not trained as a surgeon, he personally performed some 3400 of these lobotomies. He charged $25. per surgery. A 1980 article from the Washington Post about Freeman and lobotomy can be found here.

Reading

Reading: There are no readings assigned for today’s lecture.

Valuation

These notes were carried over from Lecture 23 and revised.

Several studies have implicated ventromedial prefrontal cortex in preference. In some theories, the vmPFC compares two rewards and responds proportionally to the difference in their value.

Neural basis of preference

The vmPFC activates more to stimuli that are more preferred relative to others. I first described the anatomy of vmPFC and orbital frontal cortex. These abutting anatomical regions are often combined into the term orbital frontal cortex.

I discussed a monkey study by Padoa-Schioppa and Assad that showed single neurons in the monkey orbital frontal cortex appear to code the relative amounts of more preferred 'A' and less preferred 'B' drink rewards. Prior to recording, the relative value of each reward 'A' and 'B' was assessed with behavioral testing and the 'point of indifference' between the two rewards was calculated (~4 units of 'B' = 'A'). The units responded greater to the difference in reward value between competing 'A' and 'B' offers.

I then reviewed a 2013 meta-analysis by Bartra et al. that combined 206 individual studies of subjective value* using functional MRI. The results that a system responding linearly to increasing positive subjective value included the ventral striatum and vmPFC. This system responded to primary and secondary rewards, did not respond also to negative rewards (as responding to extreme values would suggest that something other than subjective value was operating – e.g., salience or arousal, and responded to both the delivery of the reward, and a cue predicting cue delivery.

The subjective theory of value is a theory of value which advances the idea that the value of a good is not determined by any inherent property of the good, nor by the amount of labor necessary to produce the good, but instead value is determined by the importance an acting individual places on a good for the achievement of his desired ends. (from Wikipedia).

Neuromarketing

Some companies are interested in the results of such studies described above to determine subject's responses to different products. This work was stimulated by a study that contrasted the vmPFC response to Coke and Pepsi in individuals displaying a strong preference for one or the other drink. The vmPFC response (measured by fMRI) was stronger for a subject receiving Coke who had a strong preference for Coke, and weaker for a Coke reward in subjects with a less strong preference for Coke. This suggests (to some) that the vmPFC response is a veridical measure of 'liking'.

I also discussed a study by Antonio Rangel and colleagues at Cal Tech who investigated whether ‘marketing’ (here represented by the dollar value assigned to a wine) influenced both preference (as measured by behavior) and neural activity in the vmPFC and OFC. Subjects preferred cheap wines when labeled as expensive, and did not prefer expensive wines when labeled as cheap. OFC and vmPFC activity tracked these preferences. The authors suggest that the pleasure associated with the wine (as indexed by vmPFC and OFC) was partly determined by its expense.

Reconciling subjective valuation and somatic markers

I find it unsatisfying when the same* brain regions are implicated in what appears on the surface to be very different behaviors. Such it is for ventromedial PFC, which we discussed in the domain of emotions and 'somatic markers' and in the domain of economic choice based upon valuation. [and it gerts worse, we will further link vmPFC to the realm of abnormal social behavior and psychopathy.]

One way to link valuation to somatic markers is through the subjective experience that the potential rewards evoke. The 'as if' feeling associated with a high value reward is presumably stronger than the 'as if' feeling associated with a lesser value reward.

It is sometimes difficult to determine what are same brain regions with fMRI and lesion studies. Both of these require spatial separation of differing functions. If two or more functions are spatially interdigitated, then the blood oxygenation response of fMRI will be indistinguishable for all of those functions. We have already seen in the striatum (both dorsal and ventral) that medium spiny neurons that are part of the direct (D1) pathway and indirect (D2) pathway are spatially interdigitated. I showed a slide from a 2017 study indicating that there are functionally dissociable but spatially interdigitated D1 and D2 microcircuits in vmPFC associated with different aspects of decision-making.

Although we discussed the somatic marker hypothesis in some detail already, I came across this concise summary of the theory by Antoine Bechara who worked on developing this theory with Damasio.

Summary of Somatic Marker Hypothesis (SMH) provided in Sobhani and Bechara (Social Neuroscience, 2011).

Damasio proposed the SMH … which posits that the neural basis of the decision-making impairment characteristic of patients with VMPFC damage is defective activation of somatic states (emotional signals) that attach value to given options and scenarios. These emotional signals (which are perceived by specific neural regions in the brain) function as covert, or overt, biases for guiding decisions. Deprived of these emotional signals, patients may resort to deciding based on the immediate reward of an option. The failure to enact somatic states, and consequently to decide advantageously, results from dysfunction in a neural system in which the VMPFC is a critical component.

… the amygdala, as well as the VMPFC, is a critical structure in triggering somatic states, but the amygdala seems more important in triggering somatic states from emotional events that occur in the environment (i.e., primary inducers), whereas the VMPFC region seems more important in triggering somatic states from memories, knowledge, and cognition (i.e., secondary inducers) … Decision-making is a complex process that relies on the integrity of at least two sets of neural systems: (1) one set is important for memory (e.g., the hippocampus), and especially working memory (e.g., the dorsolateral prefrontal cortex), in order to access knowledge and information used during the deliberation of a decision; (2) another set is important in triggering emotional responses. This set includes effector structures such as the hypothalamus and autonomic brainstem nuclei, which produce changes in internal milieu and visceral structures, along with other effector structures, such as the ventral striatum, periacqueductal gray, and other brainstem nuclei…

Ventral and medial prefrontal cortex

Across studies, the terminology for the ventral aspect of the frontal lobes is not consistent. Some differentiate three regions: ventromedial prefrontal cortex (vmPFC), medial prefrontal cortex (mPFC), orbital frontal cortex (OFC). Others refer to all of ventral cortex as orbital frontal cortex. Lesions to this area are frequently large and all encompassing, so distinctions among these regions are less relevant. However, functional MRI studies have been generally more specific with regard to these adjacent brain regions.

In lecture, I showed a figure illustrating where vmPFC and OFC are located in the brain, and emphasized the connectivity between vmPFC and amygdala through the fiber pathway called the uncinate fasciculus. The vmPFC and amygdala are frequently co-activated in different imaging tasks.

While I just discussed vmPFC and orbital frontal cortex in the context of valuation, other literatures (e.g., Somatic Marker hypothesis) have linked decision-making to emotions (or somatic markers) linked to those decisions. Still other literatures have emphasized the role of vmPFC and orbital frontal cortex in emotion regulation and psychopathic behaviors. We will consider these latter studies below.

Recall in my lecture on dorsolateral PFC, patients with dlPFC lesions were shown to excel on certain 'out of the box' logic tasks, such as the Matchstick problems. The suggestion was that the dlPFC helped sculpt a response space for a problem set that constrained individuals with intact dlPFC from seeing unusual solutions. An interesting question is whether lesions of vmPFC (and related limbic structures like the amygdala) improve performance on any tasks.

A study by Damasio's group showed that individuals with vmPFC lesions (and lesions to limbic structures such as amygdala and insula) performed better on risky decision tasks where a loss aversion strategy in normal individuals prevailed. In this task, subjects were given an endowment of $20. On each trial they could choose to invest $1 on a bet, or keep $1 without betting. If they chose to bet, a coin was flipped. Heads meant that they were credited with $2.50, while tails involved a loss of their $1 investment. Despite the fact that each trial had a positive expected value, and that the best way to win the most money was to bet on every trial, normal subjects were loss averse and tended to keep the $1 and not bet. The patients with vmPFC lesions were not loss averse, bet on nearly every trial, and won the most money. This result was consistent with the Somatic Marker theory, in that these subjects presumably did not experience the somatic marker, or emotion, associated with losing (or winning) when deciding to invest.

Recall from an earlier lecture that vmPFC lesioned-subjects showed bad decision-making on the Iowa Gambling task – frequently choosing from the risky deck while not generating anticipatory skin conductance responses (SCRs). The behaviors in both tasks were consistent – the vmPFC lesioned subjects made risky bets. In the preceding task, the risky bet was a winning strategy, while in the Iowa Gambling Task, it was a poor strategy.

Clinical syndromes

I reviewed a 2012 study by Avram Holmes (of Yale) and his colleagues that discovered an inverse relationship between cortical thickness in vmPFC and amygdala volume that was associated with negative affect and impaired social functioning in a large sample of non-psychiatric college-age students.

Orbito-medial syndrome (combines both vmPFC and OFC):

Disruption of emotional and inhibitory mechanisms
Impulsive and socially inappropriate behavior
Confabulation
Go/No Go deficits
Disinhibited personality, jocularity, lack of concern, poor decision making
Anosmia (loss of olfactory function) – damage to olfactory nerve.
Hypersensitivity to pain

Orbital frontal (OFC) lesions:

Can lead to deficits in self-insight.
- I discussed a study in which OFC patients made socially inappropriate comments during an interview. However, when viewing their interview later on a video, the OFC patients were embarrassed by their behavior. This suggests that OFC patients can observe and detect socially inappropriate behavior, but that they have little control over, or insight into, their behavior in the moment.

Lesions of vmPFC are often associated with the following:

Normal intellect and IQ
Decisions are markedly different from premorbid state
Decisions are against interests, leading to financial and social losses
Patients do not learn from their poor decisions
Abnormalities in feeling and expressing emotions
Say the “right thing” but do the “wrong thing”
- Evident in the Iowa Gambling task – those vmPFC patients who learn the payoffs still make the bad bets (discussed above)

Psychopathy, vmPFC, and amygdala

Psychopathy is a developmental disorder that involves emotional dysfunction, characterized by reduced guilt, empathy and attachment to significant others, and anti-social behavior including impulsivity and poor behavioral control.

Acquired Psychopathy

I discussed three case studies of acquired psychopathy with lesions to the vmPFC (‘acquired’ means that some injury or disease caused the deficit – not congenital):

The case studies demonstrated a pattern of lying, stealing, aggression, risk decision-making, promiscuity, low empathy (e.g., ignoring one’s infant), inability to keep a job, financial dependence.

Blair's model for psychopathy

The neuropsychological literature on psychopathy has identified two core neural regions that seem to be dysfunctional in psychopathy: the amygdala and the vmPFC.

I discussed Blair’s model for psychopathy that involves both the amygdala and vmPFC. The following is quoted from his TICS review:

the amygdala, through … reinforcement learning, enables the association of actions that harm others with the aversive reinforcement of the victims’ distress.
information on reinforcement expectancy, fed forward to the ventromedial prefrontal cortex, can guide the healthy individual away from moral transgressions.
In psychopathy, dysfunction in these structures means that care-based moral reasoning is compromised and the risk that antisocial behavior is used instrumentally to achieve goals is increased.

I reviewed recent findings from the literature with regard to psychopaths:

Individuals with psychopathy show reduced autonomic responses to the distress of others
- SCRs to visual distress signals of others were smaller in psychopaths than controls.
Reduced amygdala response to fearful expressions and greater endorsement of fear-causing phrases like “I could hurt you”.
- Showed fMRI study by Marsh
They also make significantly less of a moral–conventional distinction than do comparison individuals.
Lower amygdala volume in males is associated with psychopathic traits, and also with violence (past and future).
The uncinate fasciculus (which connects the amygdala to ventral frontal cortex) is smaller in psychopaths than in normals (this resonates with the Holmes et al. 2012 study discussed above that was carried out in normal subjects).

Psychopathy compared to vmPFC lesions in economic games

In the ultimatum game, player A receives a sum of money while player B receives nothing. Player A then offers player B a proportion of the money – for example, if Player A received $10, she might offer player B $2. Player B can accept or reject this offer. If Player B rejects Player A's offer, then Player A loses her money, and Player B receives nothing. That is, both end up with nothing. Although it would appear that Player B should accept any offer of money above zero dollars, in many experiments they will reject offers below a 50% split.

The dictator game is similar to the ultimatum game, except that Player B cannot reject the offer, and so Player A 'dictates' exactly the percentage that Player B receives. In such experiments, the rationale response would be for Player A to offer zero dollars to Player B. However, in most situations, Player A makes a positive offer to Player B.

Both psychopaths and patients with vmPFC lesions make lower offers than control subjects in the Dictator Game, and both groups reject more unfair offers in the Ultimatum Game than controls. This further emphasizes the similarities between developmental primary psychopaths and behavioral traits of patients with vmPFC lesions.

Fronto-temporal dementia (FTD)

I did not discuss these results in lecture.

PET scans from patients with FTD that demonstrated hypo-metabolism in ventral frontal lobe. I reviewed how some patients with FTD show signs of sociopathy (often used interchangeably with psychopathy):

‘moral agnosia’
loss of both cognitive and emotional empathy
abnormal somatic markers
poor impulse control
abnormal theory of mind

Morality and the brain

Moral reasoning

Judgment of harmful intent task:

Task involves a 2×2 matrix of an agent’s intent (Neutral or Harmful) by the outcome (Neutral or Harmful). The focus was on a Harmful Intent combined with a Neutral Outcome (e.g., Grace thought she was poisoning her friend, but what she thought was poison was sugar, and her friend was fine).
Individuals with damage to vmPFC endorsed these ‘harmful intent’ scenarios as acceptable at a higher rate than healthy controls or controls with brain damage to other brain regions than vmPFC.

Utilitarian vs. Deontological theories of morality

An enduring question about Moral Decisions now investigated using neuroscience techniques: are Moral Decisions driven by Emotion (Hume) or Reason (Kant)?

Outcomes of Moral Decisions:

“Utilitarian” outcomes maximize a certain variable, such as the number of lives saved
“Deontological” outcome is consonant with a moral rule, such as “do not cause harm to others”.

Josh Greene (Harvard) Dual Process Theory

Moral judgments about personal actions are driven by social-emotional processing performed by the vmPFC, which prompts the rejection of direct personal harms.
Moral judgments about impersonal harms are driven by the more cognitive operations of the dorsolateral PFC, which prompts the endorsement of a utilitarian outcome.

Evidence from Greene et al.: The Trolley Moral Dilemma

Throw switch to divert trolley from a track that will kill five people to a track that will kill only one person. (most people endorse this)
- Activates executive processing and working memory areas – this moral decision is ‘cold’ processing, or utilitarian – driven by number of lives saved.
Personally throw a fat guy off a bridge to stop the trolley from killing five people. (very few people endorse this)
- Activates ‘emotional processing’ areas of the brain (according to Greene). This is an example of ‘hot’ processing moral decision-making in that it is personal.

Damage to vmPFC increases the endorsement of throwing the fat guy off the bridge – the absence of vmPFC (and its somatic markers?) makes the vmPFC-lesioned individual very ‘utilitarian’ in their moral decision-making. It is interesting to note that psychopaths tend to make 'utilitarian' judgments in Trolley Moral Dilemmas.

Lobotomies

I discussed the popularity of the lobotomy procedure during the 1940s and early 1950s in the realm of mental illness. It is estimated that between 40,000 and 50,000 such surgeries were performed in the USA during that period. The rationale for including a discussion of this surgery here is that lesions to the white matter connecting OFC and vmPFC to thalamic projections was the surgical goal of a transorbital frontal lobotomy. What were the behavioral sequelae of a lobotomy and are they explicable by what we understand of of OFC and vmPFC function?

One of Freeman’s rationales for the lobotomy was that ‘the lobotomy got them home’. This reflected the poor state of mental health care in the heyday of the lobotomy, the lack of effective drugs to treat serious mental illness, and the huge underfunded mental institutions. The lobotomy made the individuals more easily managed. Indeed, the placidity of many individuals post-lobotomy was the explicit goal.

I raised the issue as to the mechanism of the lobotomy. Why did the lobotomized patients not become psychopaths?

I quoted extensively from a 1939 paper by Freeman and Watts published in the Yale Journal of Biology and Medicine entitled "An Interpretation of the functions of the frontal lobe based upon observations in forty-eight cases of prefrontal lobotomy." I think that these descriptions illustrate a number of phenomena that we have discussed concerning the frontal lobes, and orbital/ventromedial frontal lobes in particular. These phenomena include abulia and lack of motivation, somatic markers, and the absence of emotional responses. There were also indications that subjects performed aggressive acts without being able to foresee the consequences.

From Freeman and Watts (all emphasis is mine):

"These patients present a placidity and indifference that forms a striking contrast to their previous apprehensive state. They answer questions pertaining to their condition mostly in monosyllables, but correctly. They make no effort to eat the food that is placed before them, but continue accepting food as long as the nurse feeds them, chewing and swallowing with precision. There is a peculiar flattening of the voice, with abrupt termination of sentences and inability to carry on a consecutive conversation.”

“When examination is carried out a month after operation it is found that there is a certain inertia present. The patient responds courteously and accurately, but volunteers little. The relatives state that the patient spends most of his time sitting in a chair, not reading or playing games; apparently perfectly at ease, but merely unoccupied. He reacts usually in a satisfactory manner to demands within his capacity, caries on a conversation addressed directly to him, but in a general conversation he is apt to remain silent”

"He may … carrying through routine procedures more or less automatically, but when one task is finished he does not go on to the next. He just sits. If he makes any complaint it is about fatigue. He seems to lack sufficient energy to carry him onward. On the other hand, this lackadaisical behavior is unaccompanied by any feeling of distress … The patients make plans for tomorrow, but somehow, tomorrow never comes. They do enough for today, and then stop.”

"They are not distressed by failure. … she completed correctly some of the test problems. After operation she was unable to complete the same problems, but continued far beyond the patience of the examiner, making mistake after mistake with not the least indication of embarrassment.”

“They … are able to discuss their sensations and emotions quite dispassionately. They can often bring back certain sensorial and ideational activities that were present during the pre-operative phase, but their attitude toward those activities is altered by the absence of any strong emotional component.”

After describing the sequelae of the lobotomy, Freeman and Watts hazard a hypothesis about PFC related to projecting an individual into the future. We will encounter a similar concept espoused by Randy Buckner of Harvard next week.

“…the rest of the frontal cortex is, according to our hypothesis, concerned with the projection of the whole individual into the future. With the intact brain the individual is able to foresee, to see before, to forecast the results of certain activities that he is to initiate in the future. And he can visualize what effect those actions will have upon himself and upon his environment. One patient expressed this concept almost directly. He was the man who slapped his nurses and pulled the fire alarm. "Now that I have done it,” he said, ”I can see it was not the thing to do, but beforehand I couldn’t say whether or not it would be alright." A patient with intact frontal lobes can presumably define the goal toward which he is working, and estimate more or less dearly the nearness with which he approaches it. By projecting himself into the future in his "mind's eye" he is calling upon his cortical mechanisms to synthesize past experience as a guide, and upon his emotional mechanisms for driving force, the search for satisfaction, and the avoidance of distress."

The Human Brain

Professor Gregory McCarthy

Lecture 24