Does the pre-frontal cortex have a unitary function?

The frontal lobe has long been ascribed higher, intellectual or executive functions � this tradition can be traced back to the well-known 1848 case of Phineas Gage (from Damasio, 1994). After miraculously surviving an iron rod passing straight through his skull, Gage was transformed as a person. The rod caused most damage to his left frontal lobe, and left the formerly religious, friendly and competent foreman unable to hold down a job, disreputable and prone to inappropriate swearing and social behaviour.

what makes humans special, different and at an advantage is our ability to store and process sensory information, so that we use it better in making effecitve responses to our environment

not only has our neocortex grown through evolution, but the proportions have changed radically

very little of a rat�s cortex is not either primary motor or a projection area for one of the senses

by contrast: in humans, most of the cortex neither reponds in an obvious way to simple sensory stimulation, nor produces movements when electrically activated (= �silent areas�)

large number of diverse + seemingly unrelated facts � apparently multiple functions � but the basic funcitons seem to be essentially few, and are represented over the cortical surface according to a certain topological pattern

interrelated, mutually supporting and complementing functions in the purposive behaviour of the organism

prefrontal � ugly, misuses �pre�, aka frontal granular cortex (cytoarchitectonic features in primates) and frontal association cortex (ambiguities of the word �association�)

often referred to as �frontal�, implicitly excluding the motor and premotor areas

in rodents and carnivores, is also called the �orbitofrontal cortex�, easily confused with �orbital frontal cortex� (which in primates = the ventral aspect of the frontal lobe which forms part of the prefrontal cortex)

primates: cerebral cortex of both hemispheres is divided by the central sulcus (Rolandic fissure) into 2:

posterior � sensation, perception, perceptual memory

frontal � action and motor memory

both are hierarchically organised in terms of development, connectivity, memory and processing of sensory and motor information

Main

Anatomy of the frontal lobes

The frontal lobe includes all the tissue in front of the central sulcus (approximately 20% of the entire neocortex), and can be divided functionally into three main categories: the motor, premotor and prefrontal.

There are parallel cortical motor systems for movements of the limbs and eyes. There are also two premotor systems, both with a map of the whole body. These play a role in the selection of movements, and differ in their reliance on information about the external context.

motor (area 4)

The motor cortex (Brodmann�s area 4)

the motor cortex is specialised for the control of the movements of limb and face (�manipulative movements�).

it is not essential for the control of non-learned movements, such as reaching and walking

although motor cortex is active during the normal performance of such movements, subcortical mechanisms have some control over them even in the absence of motor cortex

motor cortex provides a mechanism for the execution of the fine behavioural variants which are selected in voluntary action

the ability to perform discrete movements depends on the direct connections from motor cortex to the motor neurons in the spinal cord

premotor (areas 6 + 8)

premotor cortex - lateral area 6

lateral premotor area has expanded as Broca�s area (44) has developed

Like the lateral premotor cortex, the medial premotor cortex plays a role in the selection of movement;

but the two areas differ in their specialisation. The lateral premotor cortex makes the greater contribution when the subject uses external cues to direct the movements, and the medial premotor cortex when no such cues are available. However, the specialisation is a matter of degree � it is by no means total.

The evidence comes from the analysis of the effects of lesions, from PET scanning and from unit recording. Considering first tasks with no external cues, monkeys with MPC but not LPC lesions are severely impaired at performing self-paced arm movements, and at relearning motor sequences. This contrasts with the pattern of results for tasks on which performance is directed by external cues. Monkeys� with LPC but not MPC lesions are impaired at relearning a visual conditional motor task, and monkeys with MPC lesions are only slightly impaired at making arm movements cued by an external signal.

In PET scanning experiments, the medial premotor cortex is activated when subjects perform a well-rehearsed sequence from memory, but there is more activation in the lateral premotor cortex when subjects must rely on external feedback to learn new sequences.

Recordings from single cells in monkeys show the same pattern. More cells are active in the medial premotor cortex when repetitive movements are self-paced, and in the lateral premotor cortex when these movements are externally triggered. Similarly, more cells are active in the medial premotor cortex when the animals perform motor sequences from memory and in the lateral premotor cortex when they learn new sequences as directed by visual cues.

supplementary motor cortex - medial area 6

frontal eye field � area 8

Motor cortex governs movements of the limbs and face ,and the frontal eye fields the movements of the eyes. Just as the selection of limb and face movements depends on the premotor mechanisms of area 6, so the selection of eye movments depends on the premotor mechanims of the rest of area 8. Both monkeys and patients with lesions in lateral area 8 are poor at directing their eye on the basis of a learned context.

The selection of eye movements is to be described in terms of the objects of the search, the things or locations that we look for. Whereas area 6 selects our limb movements, area 8 selects things in the outside world. It is for this reason that area 6 receives proprioceptive information, and area 8 information from the external senses.

Area 8 forms part of the lateral premotor cortex and the dorsomedial eye field part of the medial (supplementary) motor cortex. It is proposed that area 8 is specialised for the selection of eye movements made when targets have been presented and the dorsomedial eye field for the selection of eye movements that are not determined by visual targets.

supplementary eye field - area 8a

Frontal lobes � overview of function

example of: shopping for various ingredients to cook a meal for friends after work in a hurry

frontal lobe injury cannot manage this. fundamental requirements are:

plan behaviour in advance, selecting from many options

time constraint, so ignore stimuli and persists in the taks at hand

keep track of where we have been and done

general function of the frontal lobe:

behavioural requirements = temporal organisation of behaviour

Anatomy of the prefrontal

curious name � Rose + Woolsey�s observation that it received projections from the dorsomedial nucleus of the thalamus

divisions within the prefrontal

primates 3 regions:

dorsolateral prefrontal cortex (areas 9, 46)

Areas 9 and 46 receive their main input from the parietal lobe which processes information about the animal itself, and about the space in which it moves and manipulates things.

Monkeys with lesions in area 46 fail to learn delayed response tasks. These are conditional tasks on which the animal must choose between locations on the basis of information in working memory. These impairments can be demonstrated on an oculomotor version of the DR task on which monkeys must direct their eye movements on the basis of locations in which they recently saw a spot of light. During the delay on this task, many cells in area 46 change their activity selectively according to the location of the target.

Monkeys with lesions in area 9 and 46 are impaired at selecting between objects on the basis of their past responses, and also at generating a series of actions. In PET scanning expeirments with human subjects, the dorsal prefrontal cortex is activated when the subjects generate a series of actions at will. In patients there is also a relation between psychomotor retardation and a decrease in regional cerebral blood flow the dorsal prefrontal cortex. This suggests a role for the dorsal prefrontal cortex in generating actions.

inferior (or ventral) prefrontal cortex (areas 11, 12, 13, 14)

= orbital frontal cortex (11, 13, 14) because the orbit (socket) of the eye

The ventral prefrontal cortex receives a multimodal input from the temporal lobe. Monkeys are impaired at learning what response to make, irrespective of the modality of the cue. There is also evidence suggesting that it may not be essential that there is a delay between the presentation of the cue and the opportunity to respond; however, this evidence is not conclusive. It is argued that the ventral prefrontal cortex selects the goal � e.g. an object � given the current context.

When monkeys learn visual concurrent discriminations, they can solve the problems by learning only about the associations between the stimuli and reward. Monkeys with ventral prefrontal lesions can learn such problems at a normal rate. Furthermore, when human subjects make perceptual judgements, there is no activation in the prefrontal cortex.

The ventral prefrontal cortex is heavily interconnected with the amygdala. Monkeys will learn to deliver rewarding stimulation to the orbital cortex or to deliver rewarding drugs. It is argued that the connections between the ventral prefrontal cortex and the amygdala are involved in the process by which responses are selected on the basis of their success.

medial frontal cortex (areas 25, 32)

= sometimes considered part of the anterior cingulate region rather than prefrontal cortex

orbit(o)(al)(medial)etc. ???

the 2 multimodal areas of the frontal lobe = the lateral premotor cortex (area 6) and area 46

The prefrontal cortex is one of the most recently evolved and massively developed areas of the primate, and especially, human brain.

Connections of the prefrontal areas

prefrontal areas � endpoints of the dorsal + ventral visual streams

Felleman & van Essen included the prefrontal as part of the visual cortex

dorsolateral prefrontal area (areas 9 + 46)

reciprocal connections with the posterior parietal areas and the superior temporal sulcus

extensive connections to the same areas the posterior parietal projects to, incl:

the cingulate cortex, basal ganglia and superior colliculus

inferior frontal area (areas 11-14)

receives its main afferents from:

the temporal lobe (incl the auditory regions of the superior temporal gyrus), the visual regions of TE, and the superior temporal sulcus, and amygdala

there are also connections from:

the somatosensory cortex (area 43), gustatory cortex (in the insula), and olfactory regions of the pyriform cortex

the gustatory + olfactory connections are localised in the orbital cortex

the visual, auditory + somatosensory connections go largely to area 12

projects subcortically to the amygdala and hypothalamus

this provides a route for influencing the autonomic system (important in emotional responses)

receive a significant input from dopaminergic cells in the tegmentum

(plays an important role in regulating how prefrontal neurons react to stimuli, incl stressful ones) � abnormalities in this projection play a central role in schizophrenia

frontal cortex has important connections with the basal ganglia

perhaps expected: basal ganglia lesions �/span> similar spatial memory impairments

Ingle & Hoff: frogs impaired in this way

visible barrier placed beside frog, then removed,

delay, then large dark object looms towards frog, which leaps away

normal frogs avoided leaping into or around the barrier�s previous location

frogs with basal ganglia lesions: behaved as if they failed to remember where the barrier had been, though they avoided it when it was present

diverse output:

extends to the hypothalamus as well as to the striatum, subthalamus and midbrain

receives afferents from:

the correspondingly large dorsomedial nucleus of the thalamus

(which receives from the frontal lobe, but also the hypothalamus and other parts of the limbic system)

Functions of the prefrontal cortex

prefrontal cortex: controls the cognitive processes so that appropriate movements are selected at the correct time + place

this selection may be controlled by internalised information, or may be made in response to context

the internalised record of what has just occurred is independent of the existing sensory information = the STM

temporal memory = neural record of recent events

events = either things or places

thus information is derived from the object-recognition or spatial streams of sensory processing

(both project to the prefrontal cortex, though to different parts)

i.e. spatial + object information are stored in temporal memory � but localised in different places in the frontal cortex

dorsolateral areas = especially involved in the selection of behaviour based on temporal memory (if defective, become dependent on environmental cues)

so frontal lobe injury �/span> difficulty inhibiting behaviour directed to external stimuli, as opposed to being controlled by internalised knowledge

behaviour = context-dependent

Goodall: the current make-up of the social group dictates the behaviour of each chimpanzee (e.g. bold + relaxed vs quiet + nervous with a different group of animals)

can be serious consequences in wrongly evaluating context

primates: highly social, hence the need for large frontal lobe

choice of behaviour in context requires detailed sensory information:

conveyed to the inferior frontal cortex from the temporal lobe

amygdala supplies the affective context

inferior frontal lesoins �/span> difficulty with context, especially in social situations

Asymmetry of frontal lobe function

functional asymmetry in parietal + temporal association cortex � similar in frontal lobes

left: preferential role in language-related movements, incl speech

right: greater role in other movements, e.g. facial expression

however, both frontal lobes play roles in nearly all behavoiur

laterality of function = relative, not absolute

Lesions

Leucotomies (B&E)

prefrontal lobotomies, pioneered by Moniz (Moniz, 1936; Fulton, 1951) � argued that anxiety, irrational fears and emotional hyperexcitabilty in humans might be treated by damage to the frontal lobes

widespread use of this procedure � although irrational anxiety or emotional outbursts were sometimes controlled � but intellectual deficits and other side effects were often apparent (Rylander, 1948; Valenstein, 1974)

still had pain, but it no longer bothered them (Freeman & Watts, 1950; Melzack & Wall, 1996)

Summary table - frontal lesions

*Most probable symptom*	*Lesion site*	*Basic reference*
Disturbances of motor function
loss of fine movements loss of strength poor movement programming poor voluntary eye gaze poor corollary discharge Broca�s aphasia	area 4 areas 4, 6; dorsolateral premotor dorsolateral frontal eye fields dorsolateral, premotor area 44	Kyupers, 1981 Leonard et al., 1988 Roland et al., 1980 Kolb & Milner, 1981 Guitton et al., 1982 Teuber, 1964 Brown, 1972
Loss of divergent thinking
reduced spontaneity poor strategy formation	orbital dorsolateral?	Jones-Gotman and Milner, 1977 Shallice & Evans, 1978
Environmental control of behaviour
poor response inhibition risk-taking and rule-breaking impaired associative learning	prefrontal prefrontal dorsolateral	Milner, 1964 Milner, 1985 Petrides, 1982
Poor temporal memory
poor recency memory poor frequency estimate poor self-order recall poor delayed response	dorsolateral dorsolateral dorsolateral dorsolateral	Milner, 1974 Smith & Milner, 1985 Petrides and Milner, 1982 Freedman & Oscar-Berman, 1986
Impaired social behaviour	orbital; dorsolateral	Blumer & Benson, 1975
Altered sexual behaviour	orbital	Walker & Blumer, 1975
Impaired olfactory discrimination	orbital	Potter & Butters, 1980
Disorders associated with damage to the face area	face	Taylor, 1979

Kolb & Whishaw � spatial behaviour in the frontal cortex

frontal cortex = important for spatial discriminations

Nakamura � monkeys: spared all the visual areas of the posterior cortex, but removed all the cortex anterior to it

the monkeys failed to show any signs of vision, but recordings of single cell activity in the visual areas showed the cells to be functioning normally

i.e. removal of the frontal cortex �/span> chronically blind, even though the visual system is functioning

restricted lesions in the visual cortex �/span> more selective impairments:

Haaxma & Kuypers: if the finger area of the motor cortex is disconnected from the visual centers

then a monkey cannot use the pincer grasp to pick up food

difficult to distinguish: impairments object detection from impairments of memory

Goldman-Rakic: rhesus monkeys, lesions in the frontal cortex along the principal sulcus

the monkeys were trained to direct their gaze and fixate on a spot of light flashed in their visual field, once the spot had disappeared

unilateral lesions: could only direct their gaze to direct when no delay, not even with short delays

selective deficits in different parts of the visual field (by varying the location of the lesion)

demonstrates that:

the principal sulcus contains a mechanism for guiding responses on the basis of stored information, when there are no external cues

the memory for the location of objects may be mapped in visuospatial coordinates

parallel set of experiments: monkeys have to reach to a target

lesions to the principal sulcus:

delayed-response taks: location of the object is the relevant task variable

�/span> impairments after short delays

but other discrimination tasks that don�t require memory are not impaired

Passingham rhesus monkeys with principal sulcus lesions:

monkeys trained to retrieve peanuts from behind 25 different doors in the shortest number of trials, without returning to a door twice

tested spatial memory for doors it had opened

monkeys with lesions: severely impaired

Petrides & Milner: patients presented with a set of pages containing the same array of visual stimuli, but varied positions on the page

point to one of the stimuli on each page, but not to the same place twice

needed to remember the selections they had made previously

frontal lobe damage �/span> impairments

Phineas Gage

�fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires, at times pertinaciously obstinate, yet capricious and vacillating�

his friends even said that he was actually happier: more carefree + less inhibited afterwards

Experiments on animals

lesions in the frontal lobes seem to �/span> � anxiety

monkeys worry less when they make mistakes in learning tasks

thought it might help schizophrenics or depressive patients:

1935 = frontal leucotomy

pharmacological agents (more reversible) in 1960s

alleviation of tension + anxiety, better adjustment to work (???), increased weight + energy

sometimes: changes of personality too far (euphoria, tactlessness, lackadaisical approach, lack of social inhibitions)

helped with intractable pain � not analgesia, but loss of the �affekt� of the pain, its unpleasant/emotional quality

�Oh doctor, it�s absolutely appalling, unbearable� � yet smiling, and apparently not really feeling it despite being able to sense it

Models & function

Misc

Shallice etc.

Fuster

defined as the part of the cerebral cortex that receives projections from the mediodorsal nucleus of the thalamus (applicable to all mammalian brains)

though coincides with the �frontal granular cortex� cytoarchitectonic demarcation in primates anyway

network model

dorsal and lateral frontal cortex � segregated action domains for:

� skeletal movement

� eye movement

� speech

actions are represented by increasing order of complexity + novelty in higher interconnected areas

abstract schemas = gestalts of actions + goals; novel plans, structures of behaviour

automatic + routine actions are represented in lower levels of motor hierarchies

plans: motor hierarchy in the dorsolateral frontal cortex:

connectivity flows downwards from prefrontal � premotor � premotor

all stages within each action domain are reciprocally connected, as well as with each other through subcortical loops through the basal ganglia

sequential action: parallel + serial processing

orbitomedial frontal cortex � action domain for emotional behaviour + visceral manifestations

transmits information of limbic origin about the internal milieu � dorsal cortex

plays a role in decision-making

important cortical depository of emotional memory

frontal lobe cortex � initation and execution of deliberate actions

�executive� functions � decision-making, attention, planning and working memory

= phenomena of neural processing, without unique locations of their own

organism�s basic drive + motivations

arrive in frontal cortex from diencephalic and limbic formations

other inputs from sensory receptors and areas of the posterior cortex

attention = ability to select sensory inputs and actions, and to inhibit others

widely distributed in the frontal cortex

dorsolateral = selective

orbital = exclusionary/inhibitory

perception-action cycle = circular flow of organism-environment interactions

sensory processing + consequent action

in cognitive + emotional behaviour

highest level: cycle completed by reciprocal connections between posterior association and prefrontal cortex

prefrontal � mediates cross-temporal contingencies

i.e. bridges time gaps in a structure of behaviour

3 temporal integrative functions of the prefrontal cortex:

working memory / active short-term memory

= the provisional retention of (sensory or motor) information for prospective action

mainly a function of the action domains of the dosolateral prefrontal cortex

maintained active in neuronal networks by reverberation through reentrant circuits

set

i.e. motor attention = selection of particular motor acts (from an established repertoire of motor memory) and preparing the sensory/motor systems for them

essential for execution of plans (temporally extended set)

also based in the dorsolateral prefrontal corte � though probably under influences from the anterior medial cortex

inhibitory control

exclusionary role of attention

i.e. protects behavioural structures from external/internal interference (e.g. similar but inappropriate sensory/motor memories)

based primarily in the orbitmedial prefronal cortex � exerted on a variety of cortical + subcortical regions

Rolls

Passingham misc prefrontal

As in monkeys, the prefrontal cortex is also crtiically involved in the process by which the human brian generates and selects actions. Human beings can select between ideas, and the prefrontal cortex has been elaborated to allow the selection of mental responses.

Human beings can also plan future actions and select between them by mental trial and error. The consequences of this development are far-reaching, because it means that human beings can set themselves goals other than simply promoting their genes in the next generation. Human beings are capable of �voluntary� action in the most restrictive sense.

The prefrontal cortex as a whole selects actions when the subject must make a new decision as to what to do. It is not yet clear whether prefrontal cortex is only engaged when there is no external cue at the time of the response.

If new decisions are required when a task is learned, prefrontal cortex is activated. But if the task can later be run off automatically, prefrontal cortex need no longer be engaged.

The exact role played by the basal ganglia is not clear. In animals without neocortex, such as amphibians, the basal ganglia form the telencephalic mechanism for determining responses. In mammals, the frontal cortical and basal ganglia are closely interrelated via a system of loops. There are suggestions that the ventral striatum may play a role in the process by which the probability of a response is altered as a result of positive or negative outcomes.

Neuroimaging branching study in nature

Using imaging technology, scientists from the National Institute of Neurological Disorders and Stroke (NINDS) found that a specific type of multitasking behavior, called branching, can be mapped to a certain region of the brain that is especially well developed in humans compared to other primates. The study will appear in the May 13, 1999, issue of the journal Nature.¹

"The results of this study suggest that the anterior prefrontal cortex, the area of the brain that is most developed in humans, mediates the ability to depart temporarily from a main task in order to explore alternative tasks before returning to the main task at the departed point," says Jordan Grafman, Ph.D., Chief of the Cognitive Neuroscience Section at the NINDS and a co-author of the study.

The investigators used functional magnetic resonance imaging (fMRI), which measures changes in blood flow to the brain, to view the brains of volunteers while they performed branching tasks. The region of the brain that is involved in multitasking is called the fronto-polar prefrontal cortex (FPPC).

Tasks performed by the volunteers involved exercises to test working memory, attentional focus, and a combination of the two. All of the subjects, who were healthy, normal volunteers, participated in all of the task groups. The task groups consisted of a control task, a delayed-response task, a dual-task, and a branching conditions task. Dual-task involves changing focus between alternative goals successively. The investigators predicted that subject performance on the individual delayed-response task and dual-task conditions would not activate the FPPC. They did predict that the branching task which involves problem solving and planning would stimulate activity in the FPPC. According to the fMRI data, their predictions were correct. The FPPC was activated only during those tasks that involved an interaction between working memory and attentional focus decisions.

The FPPC is the region of the brain that controls complex problem solving and is especially well developed in humans as compared to other primates. The study showed that the FPPC selectively mediates the human ability to multi-task.

Conclusion

Summary of prefrontal functions

frontal lobe � endpoint for the spatial and object-recognition functions initiated in the occiptal lobe

the frontal lobe�s function = to select behaviours with respect to context and internalised knowledge

3 distinct functional zones:

motor cortex � responsible for making movements

premotor cortex � selects movements

lateral � selects behaviours in response to environmental cues

supplementary � selects behvaiorus on the basis of internalised knowledge

prefrontal cortex � controls the cognitive processes so that appropriate movements are selected at the right time and place

dorsolateral zone � selects behvaoiur with respect to temporal memory

inferior � selects behaviour with respect to context (current + based on knowledge)

Unitary function?

whatever the criteria for tracing its boundaries, no demarcation can be said to outline a structural entity with unitary function

on morphological grounds alone: the anatomical complexity (especially in higher animals), makes its functional homogeneity implausible

behavioural study of animals with selective lesions of this cortex �/span> rules out such homogenity

untiary role: also inconsistent with clinical findings in patients with injuries to this part of the brain

unitary function � but at different levels (Fuster, 1996)

�doer� cortex

organises action in the time domain

it is only with regard to this commonality of cognitive functions at the service of assorted actions that the prefrontal cortex may be considered functionally �homogenous�

only minor effect on ordinary intelligence, except:

difficulties in carrying out more than one program of activity simultaneously

inability to organise actions in proper temporal sequence, e.g. trying to prepare a meal

e.g. monkeys, delayed reaction test

monkey behind glass partition in cage

shown a reward in one of two boxes, then both closed

interval of 10 minutes � partition raised

normal monkeys go to the correct box to receive reward

frontal lesion animals: cannot, unless they spend the waiting period concentrating single-mindedly on the correct doors

unit recordings in prefrontal areas during delayed response trials indicate that these are areas are in some sense �waiting to do something�

activity in many units starts up on receipt of the command, then firing is sustained until the response is finally made

= defects in the ability to store a program of action for deferred use

anxiety = side effect of the sense that something has to be done in the future

lack of anxiety sometimes = lack of forethought

similarly, by stripping pain of its significance and meaning for the future, we also relieve its emotional threat