1. Frontal Cortex

2. Frontal Lobes Traditionally considered to be the seat of intelligence.
This is probably because:
The frontal cortex is the most recent to evolve.
Humans have particularly large frontal lobes compared to other animals.
The frontal cortex is the brain lobe least amenable to quantitative testing.
·        Traditionally considered to be the seat of intelligence: the “highest” mental functions & those which are most unique to humans.
·        The prefrontal cortex is the area of the brain that has enlarged the most in recent evolution.
·        Humans have particularly large frontal lobes compared to other animals.
·        The frontal lobes seem to be the area of the brain that are most difficult to describe functionally—thus, they may be attributed with intelligence by default.
·        Almost ½ of the total area of the cortex (frontal cortices have more sides than other brain areas—so they don’t look bigger just from the surface view) & an even higher area of the association cortex is composed of the frontal lobe.
·        After much contention in the 50’s & 60’s it was concluded that general intelligence (as measured by standard IQ tests) was not differentially impaired in frontal patients as compared to patients with other types of brain damage—suggesting that the frontal lobes ARE NOT involved in general intelligence more than other areas of the brain.
·        Are there SPECIFIC deficits produced by frontal damage? That’s what we’ll spend the rest of the lecture on.
Don’t go over:
·        As a note of historical importance, Kurt Goldstein (the same person who rama talked about before when he went over alien hand syndrome) suggested that the frontal cortices were involved in abstract thought whereas the rest of the brain was involved in concrete thought.
·        For instance, abstract thought referred to look at a situation from different perspectives, to dissect and synthesize the elements of an object (Block Design), to plan ahead, and to think symbolically.
·        Concrete thought was tied to immediate sensory data which could be derived from the object.
However, for both theoretical problems (how to define abstractness…copying block design with different colored blocks vs. interpretation of proverbs) and methodological problems (patients with posterior lesions may also fail at the test), this distinction is at best insufficient.

5. Divisions of the Frontal Cortex
Motor cortex
Premotor cortex
Prefrontal cortex
Orbitofrontal & Ventromedial prefrontal cortex
Anterior cingulate gyrus
Broca’s area
·        It is useful to divide the frontal cortex into different regions. In this lecture we’ll move from the clearest to understand to the most difficult to understand & the most intriguing:
·        *&1* Overhead of different regions. Kandel 825, 827; Beaumont 51
1.      Motor cortex (anterior to the central sulcus)
2.      Premotor cortex
3.      Prefrontal cortex
Dorsolateral prefrontal cortex (superior prefrontal convexity)
Principal sulcus
Inferior prefrontal convexity (lateral orbitofrontal cortex)
4.      Orbitofrontal cortex (medial orbitofrontal cortex)
5.      Ventromedial prefrontal cortex
6.      Anterior cingulate
7.      Broca’s area

6. Divisions of the Frontal Cortex

7. Primary Motor Cortex

8. Prefrontal Cortex

9. Working memory
Refers to the capacity to keep track of and update information at the moment
E.g.,
 Patricia Goldman-Rakic
 ODR paradigm (oculomotor delayed-response)
 Electrodes record activity from monkey neurons during the task.
 Different neurons respond to different task characteristics.
·        Patients shown a series of items one at a time, they may be able to recognize the ones that were on the list, but won’t be able to report which was presented more recently.
·        Working memory definition (Gold-R) & e.g
·        *&3* Baddeley’s diagram & Goldman Rakic’s changed diagram (rather than central executive manipulating, the same neuroanatomical area stores & manipulates)
·        *&4* Monkey delay task
·        Distinguish where from what (superior vs. inferior convexity) (mention dorsal & ventral vision feed into these areas)
·        ODR paradigm (oculomotor delayed-response)—monkey looks at a fixation point while some visuospatial stimuli are presented around the fixation point. The stimuli then disappear. The monkey must make a response (direct their eyes to the location where a specific stimuli appeared). Thus, they must make this response from memory.
·        During the task, electrodes are recording activity from neurons to see what the neurons are doing at different points in the task.
·        *&* Some neurons in the region of the principle sulcus are activated in relation to an occurrence of a target, while some respond in relation to the delay, and still others are activated in relation to the occurrence of a response.

10. Regional Specialization:
Superior prefrontal convexity (dorsal)— spatial location
Inferior prefrontal convexity (ventral)—objects, faces

12. Impaired Response Inhibition
Stroop

13. Purple Red Green Black Blue Yellow Blue Brown Red Green Yellow Orange
·        *&* Stroop example
·        My timing experiment
·        *&&* Show Pick’s disease tape
·        Note: these patients are oftentimes AWARE that they are doing this—after making a wrong selection they might comment that they knew this was wrong, but couldn’t help doing it. Then they continue making the wrong responses.
·        Is this paradoxical? Talk about amygdala case…

14. Purple Red Green Black Blue Yellow Green Yellow Red Orange Blue Brown
·        *&* Stroop example
·        My timing experiment
·        *&&* Show Pick’s disease tape
·        Note: these patients are oftentimes AWARE that they are doing this—after making a wrong selection they might comment that they knew this was wrong, but couldn’t help doing it. Then they continue making the wrong responses.
·        Is this paradoxical? Talk about amygdala case…

15. Perseveration
Carrie’s timing task with frontals

16. Shifting Difficulty Reduced fluency
Generate animals beginning with “C”
Difficulty generating hypotheses and flexibly shifting to new task demands
Generate as many animals in 3 min. beginning with “C”: most people switch categories, which frontals don’t       
Prefrontal cortex (prefrontal association cortex)
·        *&1*
Dorsolateral prefrontal cortex (superior prefrontal convexity)
Principal sulcus
Inferior prefrontal convexity (lateral orbitofrontal cortex)
·        Tertiary level of motor control
1.      Dorsolateral prefrontal syndrome
a.       Executive function deficits and motor programming abnormalities
b.      Unable to generate hypotheses and flexibly maintain or shift sets required by changing task demands (WCST)
c.       Reduced verbal & design fluency, poor organizational strategies for learning tasks, poor constructional strategies for copying complex designs
a.       Difficulty in alternating and reciprocal motor and sequential motor tasks.
·        Perform card-sorting tasks normally.
·        Planning and programming of motor acts and their flexible adaptation to particular circumstances (not specific components of movement)
Damage to prefrontal cortex results in inflexible and stereotyped motor behavior.

17. Wisconsin Card Sort Task (WCST)
Test Cards

18. The subject is shown 4 “target cards” on a surface.
These vary on the number, color, and shape of the objects on the cards.
The subject is given a deck of cards with the same sorts of objects.
The subject is asked to sort the cards, one at a time, under the target cards.
They must determine the rule they should use to sort the cards—whether to sort by number, color, or shape.
After each card is placed under a target card, the tester tells the subject whether the choice is correct or not, based on the “rule” the experimenter is using.
After 10 correct sorts, the tester changes the matching principle and the subject must test new hypotheses to figure out the new rule. This continues many times.
Normal subjects and patients with frontal injuries discover this initial rule.
Frontals perseverate (continue with a response when it is no longer appropriate. Impaired response inhibition—once certain responses have become active then it is difficult to inhibit them & change to more appropriate responses. Frontals take a long time to adapt to the new rule & many do not manage to at all.
·        The WCST really doesn’t discriminate frontal from other types of lesions very well (patients with damage in other brain areas do poorly) although people continually use the test as a measure of frontal lobe dysfunction. The reason is that right & wrong answers are scored & the type of error is not.
You CAN tell a person has frontal damage if the type of error they perform is perseveration.

19. Wisconsin Card Sorting Task (WCST)

20. Alternating & Sequencing Deficits
·        *&* Programming and planning—not impaired when imitating 1 facial expression, but impaired with multiple
·        other tasks that require multiple parts like the Porteus mazes & Block Design
Difficulty with cooking or errands because requires organizing

21. ***VIDEO: Pick’s Disease

22. Alternating & Sequencing Deficits
Motor
Planning & organizing tasks
Developing strategies for learning new tasks

23. Frontal Eye Fields

24. Exploratory Eye Movement Deficits
·        *&* Frontal eye fields
·        Voluntary eye movements, scanning the environment & inspection of objects
·        Normal subjects rapidly detect the picture’s most significant and informative elements and follow a picture’s most significant and informative elements and follow a series of glance paths between these elements when asked to extract meaning from it.
·        Frontals show a disorganized series of movements.
·        Also, problems locating a target item in a larger array of similar items.
·        Deficit in generating & operating strategies for collecting & processing info?
·        Perhaps if can’t hold a piece of info in working memory, then that info can’t be used to determine what the next piece of information one needs is & to direct a search for it.

25. Other Dorsolateral Deficits
Pseudo-depression
Perceptual deficits
Corollary discharge
·        Pseudo-depression—reduced spontaneous behavior. Sit around, almost nothing to say, engage in little activity, present a flat, emotionless expression. (relate to verbal fluency above)
·        Perceptual deficits—Show patient a picture of a person whose body parts are numbered. Name a number & have them point to that part of their own body. (Perhaps can’t manipulate the object in their head—PET studies on Shepherd’s rotation expts?)
Corollary discharge—when a movement is executed, information is not only sent to the motor output system, but also to other areas so that movements can be anticipated and accounted for. If this did not occur, then the world would appear to move everytime you move your eyes (demo? Pushing eye). Some frontal deficits may be related to a lack of compensation due to impaired corollary discharge.

26. Mirror Neurons: Characteristic Firing Properties of Inferior DLPFC
Motor
Visual
Somatosensory
Body-part centered
(Fadiga et al., 2000)

27. “Mirror” Property of Human DLPFC
(Iacoboni et al., 1999)

28. Orbitofrontal & Ventromedial Prefrontal Cortex

29. Phineas Gage
·        Orbitofrontal cortex (medial orbitofrontal cortex) [Combine with ventromedial??]
·        *&1*
·        personality & social behavior
·        Part of the limbic association cortex
·        *&5* Phineas Gage’s skull—Fuster
·        Describe Gage, p 61 Beaumont or Fuster
1.      Orbitofrontal syndrome
a.       Personality changes
b.      Common causes: anterior communicating artery aneurysms (rupture), orbitofrontal tumors, inferior frontal lobe infarction (death of neurons due to loss of blood to an area of the brain for a prolonged period of time, usually due to closure or clogging of a blood vessel) Kandel
c.       Some characteristics: worry less; more irritable; elevated mood; more tactless; alterations in interest, initiative, or conscientiousness.
d.      Bilateral anterior orbitofrontal lobe lesions  imitation, enslaved to environmental cues.
·        Phineas Gage—a construction worker on the American railroads
·        In 1848 suffered an accident with an iron bar (3 ½ ft long x 1 ¼ in thick) was blown through his cheek and exited his forehead. He survived.
·        However, prior to his accident, he was a capable & efficient worker.
·        Subsequent to the injury, he became impulsive, inconsiderate, & obstinate. He swore, which he had not previously done, and frequently changed his mind. His friends and acquaintances said he was “no longer Gage”.

32. The Case of Phineas Gage
An explosion projected a tamping rod through his left cheek.
Miraculously, he recovered and had “normal intellegence”.
Months later, however, Gage began to have startling changes in personality and in mood.
He became extravagant and anti-social, a fullmouth and a liar with bad manners, and could no longer hold a job or plan his future.  
He was quick to anger and often got into fights.
"The equilibrium between his intellectual faculties and animal propensities seems to have been destroyed.” - Harlow

33. This is hypothesized to occur as a result of impoverished social learning as a result of failure to make appropriate mappings between events and their outcomes.

34. Personality Changes Lack of concern for the future
Consistently poor decision-making 
Impulsiveness
Failure to obey rules
Lack of social graces
Disposed to imitation
·        This type of change generally only follows large, bilateral lesions (which are not uncommon results of car accidents).
·        Silliness (childishness), sing, whistle, repeat poor jokes. Impulsiveness, facetiousness, & mild euphoria; diminished anxiety and lack of concern for the future; lack of initiative & spontaneity.
·        Lack of social graces—patients engage in belching, picking their noses, urinating, exposing themselves (exhibitionism), or masturbating in public. (Also, loss of interest in sexual activity.)
·        On neuropsy tests they often fail to obey rules also—such as going through the walls of a maze.
·        Part of pseudo-depression—indifference, lack of initiative, general loss of drive—say little & exhibit no emotional expression.
·        [Distinguish between pseudodepression & mild euphoria.]
·        Damage to this region does not result in any of the deficits mentioned above & these patients can appear completely normal on neuropsy tests & have normal intelligence.
·        Tell story about patient with fairly good neuropsy profile (show) but they jump up to answer a question, can’t inhibit, & imitate the experimenter (demonstrate these)
·        Eg. Case study from clinical class last week—performed normally on the test but jumps up because know the answer
·        Loss of inhibition
·        OR decreased affect
Imitation problems? (echo apraxia?)

35. Personality Changes II
Mild euphoria
Silliness & facetiousness
Pseudo-depression
Irritability

36. Orbitofrontal Cortex Decision-Making Reinforcement Value
of Sensory Stimuli
·        Orbitofrontal (this is basically the same area as the ventromedial & produces the same sort of personality changes that Phineas Gage had & that Tony Damasio’s patients exhibited—we’ll go over these in a minute)
·        Roll’s Pict
·        2ndary odor & taste cortex (other sensory areas)
·        Primary reinforcers—neurons respond to stimuli only when something is rewarding (e.g., olfactory neurons respond to food only when hungry); in somatosensory cortex pleasant and neutral touch stimuli produce equal responses, while in OB pleasant produce much larger responses.
·        Learned reinforcers. Neurons in both the OB and BL amyg fired selectively during the anticipation of rewarding or aversive outcomes. This activity emerged early in training, before rats had learned reliably to avoid the aversive outcomes.
·        If damage, pain no longer bothers although still feel
·        Neurons differentially responsive to different faces, better responses to real faces
·        Respond differently to objects depending on reward associations
·        Phineas Gage
·        Damasio’s gambling task (ventromedial prefrontal lesions block autonomic responses to learned reinforcers—1950’s before Damasio)
·        Damage results in:
Changes in personality & interests
Silliness
Impulsiveness, facetiousness, & mild euphoria.
Lack of concern for the future
Consistently poor decision-making
Pseudo-depression
Irritability
Lack of social graces
Failure to obey rules
Disposed to imitation
Orbitofrontal cortex
·        Primary reinforcers
·        Learned (secondary) reinforcers
Lesions block autonomic responses to learned reinforcers
·        Secondary odor and taste cortices
·        Pain is perceived but not aversive
·        Cells respond better to real than to 2-D faces
·        Cells respond preferentially to specific faces
·        Cells change their responsive to particular objects when reward associations change
·        Personality changes:
Poor decision-making
Empathy

37. Orbitofrontal Cortex Secondary odor & taste cortices
Deficits in perceiving auditory or visual emotional cues
Can be Modality Specific
Cells respond to the rewarding or aversive nature of stimuli
Primary reinforcers
Learned (secondary) Reinforcers
Primary reinforcers (the aversive nature of pain, Rolls)  
The last area that I’ll talk about is the orbitofrontal cortex. This area is the horizontal underside of the frontal lobes, just above the eye sockets. Damage to the ventromedial area (split open) seems to have a similar effect in human patients. I’m sure from stories about Phineas Gage as well as Damasio’s gambling task that you’re all familiar with behavioral changes that occur with damage to this area, such as the failure to obey rules, poor decision-making, and the disposition towards imitation. There are several other very interesting characteristics of this region & I’ll talk about just a few.
First, different regions of the OFC receive the majority of their input from specific sensory modalities. For example, you can see this area of area 12 primarily receives somatosensory input, and the secondary taste and olfactory cortices are located here. The OFC seems to be involved in the subjective feelings of reward and aversion—for instance, people with damage here perceive pain but don’t find it aversive. The area is involved in learning associations????
What I find especially intriguing is that the OFC is involved I representing primary reinforcers. Primary reinforcers are stimuli that are innately rewarding or aversive, probably having been hard-wired through evolution. In primates, there is evidence that the represenation of taste is independent of its rewarding properties as far as the primary taste cortex. In the secondary taste cortex, the representation is of the food reward value of the taste, in that the taste responses of neurons are modulated by hunger, and decrease to zero when the animal is satiated, and the taste is no longer rewarding.
Cells respond better to real than to 2-D faces
Cells respond preferentially to specific faces
Cells change their response to objects when reward associations change

38. Anterior Cingulate

39. Anterior Cingulate Bilateral lesions produce:
Akinetic mutism—inability to initiate speech
 Minimal movement
 Incontinence
 No emotional display to pain
 Profound apathy
 Indifference
·        Anterior cingulate
a.       *&1*
1.      Anterior cingulate syndrome
a.       Bilateral lesions  akinetic mutism, profoundly apathetic, eyes open, don’t speak, move little, are incontinent, eat & drink only if fed, display no emotion when in pain, indifferent to their condition
Failure of response inhibition on go-no go tasks.

40. ***Striatum Pict – Sagittal?

41. 5 Frontal-Subcortical Circuits
Motor
Oculomotor
Dorsolateral prefrontal
Lateral orbitofrontal
Anterior cingulate
A.     FRONTAL LOBE SYNDROMES
B.     STRIATAL SYNDROMES
1.      Dorsolateral caudate nucleus (from dorsolateral prefrontal cortex)
a.       Executive function deficits: memory, attention, WCST deficits
b.      confused & disinterested
2.      Ventromedial region of the caudate (from orbitofrontal cortex)
a.       disinhibited, euphoric, & inappropriate
b.      memory, attention, executive function, WCST deficits
3.      Ventral striatum & nucleus accumbens (from anterior cingulate gyrus)
a.       apathy, lack of initiative
b.      Craniopharyngiomas, obstructive hydrocephalus, & third ventricle region tumors (involve ventral striatum, ventral globus pallidus, & medial thalamus) result in akinetic mutism.
a.       Describes 5 neuroanatomical frontal-subcortical circuits.
·        Motor
·        Oculomotor
·        Dorsolateral prefrontal
·        Lateral orbitofrontal
·        Anterior cingulate
b.      Point out that each circuit includes the same 4 main brain structures, although the circuits remain anatomically separate.
·        Frontal cortex
·        Striatum
·        Globus pallidus
·        Thalamus.
Frontal lobe  striatal structures (caudate, putamen, ventral striatum)  globus pallidus & substantia nigra  specific thalamic nuclei  frontal lobe
Topographic mapping

42. Frontal-Subcortical Circuits II
Frontal lobe 
Striatum (caudate, putamen, ventral striatum) 
Globus pallidus & Substantia nigra 
Specific thalamic nuclei 
Frontal lobe

43. Summary I Motor cortex Premotor cortex
Loss of voluntary control over a specific body area
Deficits of fine motor control
Reduction of strength & speed
Premotor cortex
Impairs the integration of sequences into fluid actions
Reflex changes (i.e., grasp reflex)
*&* Beaumont 64 for summary of different functions

44. Summary II Prefrontal cortex Working memory problems
(superior—where; inferior—what)
Difficulty generating new items or hypotheses
Lack of inhibition
Perseveration
Difficulty planning sequences or organizing strategies
Eye movement deficits

45. Summary III Orbitofrontal & Ventromedial prefrontal cortex
Personality & emotional changes
Disregard for rules
Imitation
No IQ or dorsolateral problems
Anterior cingulate
Problems with initiating movements
Apathy
No emotional response to pain