Prefrontal Cortex and Cognitive Function Research Paper

1. Behavioral Evidence Of Improvements In Cognitive Functions That Depend On PFC During The First Year Of Life

Piaget’s ‘A-not-B’ task has been widely used to study infant cognitive development (Wellman et al. 1987). Under the name ‘delayed response,’ the almost identical task has been widely used to study the functions of a subregion of PFC in rhesus monkeys (GoldmanRakic 1987). The subregion is dorsolateral PFC (DLPFC). A participant watches as a reward is hidden to the left or right in one of two identical hiding places. A few seconds later the participant is encouraged to find the hidden treat. The participant must hold in mind over those few seconds where the treat was hidden and, over trials, must update his or her mental record to reflect where the treat was hidden last. The participant is rewarded for reaching correctly by being allowed to retrieve the treat. In this way, the behavior of reaching to that location is reinforced and hence the tendency to make that response is strengthened. When the reward is then hidden at the other location, the participant must inhibit the natural tendency to repeat the rewarded response and instead respond according to the representation held in mind of where the reward was hidden last. Hence, this task requires an aspect of working memory (holding information in mind) plus inhibition of a prepotent action tendency (the tendency to repeat a positively reinforced response).

By roughly 7 to 8 months of age, infants reach correctly to the first hiding location with delays as long as two or three seconds (Diamond 1985). When the reward is then hidden at the other hiding place, however, infants err by going back to the first location (called the ‘A-not-B error’). Infants show marked improvements in their performance of the A-not B delayed response task at 7 to 12 months of age. For example, each month they can withstand delays approximately two seconds longer, so that by 12 months of age delays of roughly 10 seconds or longer are needed to see the A-not-B error (Diamond 1985).

In a transparent barrier detour task called ‘object retrieval’ (Diamond 1991) a toy is placed within easy reach in a small, clear box, open on one side. There is a very strong pull to reach straight for the toy through the side one is looking, which must be inhibited when an infant is looking through a closed side of the box. At 6 to 8 months of age, infants reach only at the side through which they are looking. They must look through the opening, and continue to do so, to reach in and retrieve the toy. As they get older, the memory of having looked through the opening is enough; infants can look through the opening, sit up, and reach in while looking through a closed side. By 11 or 12 months of age, infants do not need to look along the line of reach at all. Infants progress through a well-demarcated series of five stages in performance of this task from 6 to 12 months of age (Diamond 1991).

Although the A-not-B delayed response and object retrieval tasks share few surface similarities, human infants improve on these tasks during the same age period (6–12 months) and so do infant rhesus monkeys (1 –4 months; Diamond 1991). Despite wide individual differences in the rate at which infants improve on these tasks, the age at which a given infant reaches ‘Phase 1B’ on the object retrieval task is remarkably close to the age at which that same infant can first uncover a hidden object in the A-not-B delayed response paradigm (Diamond 1991).

There is no behavioral task more firmly linked to DL-PFC than the A-not-B/delayed response task (Goldman-Rakic 1987, Fuster 1989). This is one of the strongest brain–behavior relations in all of cognitive neuroscience. DL-PFC lesions in the monkey also disrupt performance on the object retrieval task (Diamond 1991). MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injections, which reduce the level of dopamine in PFC, also produce deficits on the task (Taylor et al. 1990, Schneider and Roeltgen 1993). (MPTP also affects the level of dopamine in the striatum, but lesions of the striatum do not impair performance on the object retrieval task (Crofts et al. 1999).)

Hum an infants of 7 to 9 months, infant monkeys of 1 1/ 2to 2 1/2 months, adult monkeys in whom DL-PFC has been removed, infant monkeys of 5 months in whom DL-PFC was removed at 4 months, and adult monkeys who have received MPTP injections to disrupt the prefrontal dopamine system all fail the A-not-B delayed response and object retrieval tasks under the same conditions and in the same ways (Diamond 1991). In human infants, changes in the pattern of electrical activity detected by electroencephalogram (EEG) over frontal cortex and in the coherence of electrical activity detected by EEG over frontal cortex and parietal cortex (A-not-B: Bell and Fox 1992, object retrieval: N A Fox, personal communication 1992) correlate closely with developmental improvements on the A-not-B/delayed response and object retrieval tasks. This does not prove that developmental improvements on these tasks rely in part on maturational changes in DL-PFC, but it is consistent with that hypothesis.

2. Anatomical And Biochemical Evidence Of Maturational Changes In PFC During The First Year Of Life

Nerve cells consist of axons, dendrites, and a cell body. Dendrites, which branch off from the cell body, represent the largest part of the receptive surface of a neuron. In humans, the period of marked growth in the length and extent of the dendritic branches of pyramidal neurons in layer III of DL-PFC is 7 1/2 to 12 months (Koenderink et al. 1994), exactly coinciding with the period when human infants are improving on the A-not-B/delayed response and object retrieval tasks. Pyramidal neurons of this PFC region have a relatively short dendritic extent in 7 1/2 -month-old infants. By 12 months of age, they have reached their full mature extension. The surface of the cell bodies of these neurons also increases between 7 and 12 months (Koenderink et al. 1994). The level of glucose metabolism in DL-PFC increases during this period as well, and approximates adult levels by 1 year of age (Chugani et al. 1987).

Dopamine is an important neurotransmitter in PFC. During the period that infant rhesus monkeys are improving on the A-not-B/delayed response and object retrieval tasks (1.5–4 months), the level of dopamine is increasing in their brain (Brown and Goldman 1977), the density of dopamine receptors in their PFC is increasing (Lidow and Rakic 1992), and the distribution within their DL-PFC of axons containing the rate-limiting enzyme (tyrosine hydroxylase) for the production of dopamine is changing markedly (Rosenberg and Lewis 1994).

Acetylcholinesterase (AChE) is an enzyme essential for metabolizing another neurotransmitter, acetylcholine. In humans, the pattern of AChE staining in DL-PFC changes dramatically during the first year of life (Kostovic et al. 1988).

3. Behavioral Evidence Of Improvements In Cognitive Functions That Depend On PFC From Age 1–3 Years

This is the period for which we know the least about changes in PFC anatomy or in cognitive functions dependent on PFC. Kochanska et al. (2000) report that the ability to inhibit a prepotent response in order to perform a modulated or different response improves markedly from 22 to 33 months of age and that the consistency across their various measures of inhibition also increases between 22 and 33 months.

Using a lazy susan to bring a toy within reach requires relating the lazy susan and its movement to the toy and its movement. It also requires inhibition of trying to reach on a direct line of sight (as the younger children try to do) and inhibition of the tendency to push the lazy susan in the direction you want the toy to go (you must push left to get the toy to approach on the right). Children improve in their ability to do this between 12 and 24 months (Koslowski and Bruner 1972). Case (1992) similarly reports marked improvements on a simple balance beam problem be- tween 1 1/2 and 2 1/2 years.

4. Evidence Of Maturational Changes In PFC From Age 1–3 Years

Almost nothing is known about changes in prefrontal cortex during this period. AChE reactivity of layer III pyramidal neurons begins to develop at this time (Kostovic et al. 1988), but that is surely not the only change in prefrontal cortex between 1 and 3 years of age.

5. Behavioral Evidence Of Improvements In Cognitive Functions That Depend On PFC From Age 3–7 Years

Clear improvements in tasks that require holding information in mind plus inhibition are seen between 3 and 7 years of age. Three-year-olds make an error reminiscent of infants’ A-not-B error, but with a more difficult task. On this task, 3-year-olds sort cards correctly by the first criterion (whether it is color or shape: Zelazo et al. 1995), just as infants and prefrontally lesioned monkeys are correct at the first hiding place, and just as adults with PFC damage sort cards correctly according to the first criterion (Wisconsin Card Sort test: Milner 1964, Stuss et al. 2000). Three-year-olds err when they must switch to a new sorting criterion, e.g., when cards previously sorted by color must now be sorted by shape, just as infants of 7 1/2 to 9 months and prefrontally lesioned monkeys err when required to switch and search for the reward at the other location, and just as adults with PFC damage err when required to switch to a new sorting criterion. Although 3-year-old children fail to sort by the new sorting criterion, they can correctly state the new criterion (Zelazo et al. 1996), as is sometimes seen with adult patients who have sustained damage to PFC (Luria and Homskaya 1964, Milner 1964). Infants, too, sometimes indicate that they know the correct answer on the A-not-B task, by looking at the correct well, although they reach back incorrectly to the well that was previously correct (Hofstadter and Reznick 1996).

Another example of apparently knowing the correct answer, but not being able to act in accord with it is provided by work with ‘go/no-go’ tasks (Tikhomirov 1978, Livesey and Morgan 1991). Here, the participant is to respond to one stimulus but do nothing when shown another. Children between 3 and 4 years old repeat the instructions correctly, but they cannot get themselves to act accordingly; they respond even to the ‘no-go’ stimulus. By 5 years, they perform well on the card sort and go no-go tasks.

The problem on the card sort task appears to be in (a) integrating two dimensions of a single stimulus (e.g., if children are used to focusing on whether stimuli are red or blue, they have trouble refocusing and concentrating instead on whether the same stimuli are trucks or stars) and (b) inhibiting the tendency to repeat their previously correct response. Similarly, children of 3 years have difficulty with ‘appearance– reality’ tasks (e.g., Flavell 1986) where, for example, they are presented with a sponge that looks like a rock. Three-year-olds typically report that it looks like a rock and really is a rock, whereas children of 4 or 5 years correctly answer that it looks like a rock but really is a sponge. The problem for the younger children is in relating two conflicting identities of the same object (e.g., Rice et al. 1997) and in inhibiting the response that matches their perception. Manipulations that reduce perceptual salience, by removing the object during questioning, enable children of 3 or 4 years to perform much better (e.g., Heberle et al. 1999).

‘Theory of mind’ and ‘false belief’ tasks are other tasks that require holding two things in mind about the same situation (the true state of affairs and the false belief of another person) and inhibiting the impulse to give the veridical answer. Here, as well, manipulations that reduce the perceptual salience of the true state of affairs aid children of 3 to 4 years (e.g., Zaitchik 1991). Carlson et al. (1998) reasoned that pointing veridically is likely to be a well- practiced and reinforced response in young children, and that children of 3 to 4 years have trouble inhibiting that tendency when they should point to the false location on false belief tasks. Carlson et al. (1998) found that when they gave children a novel response by which to indicate the false location, children of 3 to 4 years performed much better.

Many of the advances of Piaget’s ‘preoperational’ child of 5 to 7 years over a child of 3 to 4 years, who is in the stage of ‘concrete operations,’ similarly reflect the development of the ability to hold more than one thing in mind and to inhibit the strongest response tendency of the moment. For example, children of 3 or 4 years fail tests of liquid conservation (they do not attend to both height and width, attending only to the most perceptually salient of the two dimensions) and they fail tests of perspective-taking where they must mentally manipulate a scene to indicate what it would look like from another perspective and must inhibit the tendency to give the most salient response (i.e., their current perspective). By 5 or 6 years, they can do these things. Since part of the difficulty posed by Piaget’s liquid conservation task is the salience of the visual perception that the tall, thin container contains more liquid, placing an opaque screen between the child and the containers before the child answers enables younger children to perform better (Bruner 1964).

In the ‘delay of gratification’ paradigm, when faced with the choice of a smaller, immediate reward or a later, larger reward, children of 3 to 4 years are unable to inhibit going for the immediate reward although they would prefer the larger one. By 5 or 6 years of age, children are better able to wait for the preferred reward (Mischel and Mischel 1983).

Between 4 and 5 years of age children show improvement on several tests in the CANTAB battery that are designed to assess frontal lobe function (Luciana and Nelson 1998). For example, their improved ability to retain temporal order information in memory is demonstrated by better performance at 5 years on (a) a test of spatial memory span that is similar to the children’s game, Simon, or the Corsi block task (the child must touch boxes displayed on a computer screen in the order in which he or she just saw them change color); and on (b) a spatial self- ordered pointing task where the child must keep track of which squares he or she has already touched.

The ‘day–night’ task (Gerstadt et al. 1994) requires that children hold two rules in mind and inhibit the tendency to say what the stimuli really represent; instead they must say the opposite (‘Say ‘‘night’’ when shown a white card with a picture of the sun, and say ‘‘day’’ when shown a black card with a picture of the moon and stars’). Children of 3 to 4 years find the task very difficult; by 6 or 7 years it is trivially easy. If abstract designs are used as the stimuli, even children of 3 1/2 have no difficulty correctly saying ‘day’ to one and ‘night’ to the other (Gerstadt et al. 1994). Hence, the need to learn and remember two rules is not in itself sufficient to account for the poor performance of young children on the task.

Luria’s ‘tapping’ test (Luria 1966) also requires (a) remembering two rules and (b) inhibiting a prepotent response, making the opposite response instead. Here, one needs to remember the rules, ‘Tap once when the experimenter taps twice, and tap twice when the experimenter taps once,’ and one needs to inhibit the tendency to mimic what the experimenter does. Adults with large frontal lobe lesions fail this task (Luria 1966). Children improve on the task over the same age range at which they improve on the day–night task (Diamond and Taylor 1996). Moreover, performance on the two tasks is correlated so that children whose performance on the day–night task is delayed or accelerated show a corresponding delay or acceleration in their performance on the tapping task (Diamond et al. 1997, Diamond 2001).

The ‘counting span’ and ‘spatial span’ tasks of Case (1972) require finding target stimuli, counting them or remembering their locations, holding that information in mind while finding target stimuli in new arrays, and keeping track of the answers computed on each trial so that they can be repeated back in order at the end. Thus, these tasks require temporal order memory and resisting interference from prior and interpolated activity. A meta-analysis of 12 cross-sectional studies revealed strong linear improvements on both tasks between 4 1/2 and 6 1/2 years (Case 1992). Performance on these tasks is highly correlated with performance on Piaget’s ‘balance beam’ task, ‘Raven’s matrices,’ and ‘concept acquisition.’ On the balance beam and Raven’s matrices tests, 4-year-olds tend to answer accordingly to what is perceptually salient. By 7 or 8 years of age, they are able to take two dimensions, or two perspectives, into account and relate one to the other. They can mentally manipulate, combine, recombine, order, and reorder information.

6. Anatomical Evidence Of Maturational Changes In PFC From Age 3–7 Years

The density of neurons in human DL-PFC is highest at birth and declines thereafter. At 2 years of age it is 55 percent above the adult mean, but by 7 it is only 10 percent above adult levels (Huttenlocher 1990). Thus there is a dramatic change in neuronal density in DLPFC between the ages of 2 and 7. The synaptic density of layer III pyramidal cells in DL-PFC increases after birth and reaches its maximum at about 1 year of age; by 7 years of age the decrease in synaptic density is significant, though not yet down to adult level (Huttenlocher 1979). Another change during this period is a marked expansion in the dendritic trees of layer III pyramidal cells in human DL-PFC between 2 and 5 years of age (Mrzlijak et al. 1990). In addition, the density of neuropeptide Y-immunoreactive neurons in human DL-PFC increases between the ages of 2 and 4 years and 6 to 7 years (DeLalle et al. 1997).

7. Behavioral Evidence Of Improvements In Cognitive Functions That Depend On PFC From 7 Years To Adulthood

Some abilities dependent on DL-PFC appear to reach their adult levels by about 11 years of age. The Wisconsin Card Sort test is one of the classic tests for studying PFC function in adults (Milner 1964, Stuss et al. 2000). Here, the participant must deduce the rule for sorting cards, which can be sorted by color, shape, or number. Children do not begin to reach adult levels of performance on this task until they are about 11 years old (Chelune and Baer 1986). Continuous, marked improvement is seen on the counting and spatial span tasks through age 8, and then improvement is less steep until performance asymptotes around 10 or 11 years of age (Case 1972, 1992). Pascual-Leone’s tasks (the compound stimulus visual information and the digit placement tests) show similar developmental progressions (Pascual-Leone 1970, Case 1972). Hale et al. (1997) report that resistance to interference improves from 8 to 10 years, when it approximates adult levels.

Other abilities dependent on PFC continue to show improvement into adulthood. Zald and Iacono (1998) report that spatial working memory improves from 14 to 20 years of age. They found that 20-year-olds were significantly more accurate than 14-year-olds at indicating the location of an object in space using memory even after brief delays of only half a second. (There was no age difference in the ability to accurately indicate an object’s location using visual feedback.) The improvement with age was in the ability to accurately get the information into working memory, not in the ability to hold it in mind for a longer period. Indeed, they found little difference over age in the rate of degradation of the memory.

Another task that requires precise spatial memory is the pattern span task (Wilson et al. 1987). On any given trial some of the squares in a grid pattern are filled and some unfilled. After a quick look, the participant is presented with the grid with one change; the participant is to find that change. Performance on this task improves dramatically between 5 and 11 years, when it reaches adult levels (Wilson et al. 1987).

Several bodies of work indicate that the ability to inhibit a prepotent response tendency continues to improve until early adulthood. In the ‘directed forgetting’ paradigm, participants are directed to forget some of the words they are shown and to remember others. Even children as old as roughly 11 years show more intrusions of the to-be-forgotten words than do adults (e.g., Harnishfeger and Pope 1996, Lehman et al. ). The ‘anti-saccade’ task requires the participant to suppress the tendency to reflexively look to a visual stimulus in the periphery, and instead look away in the opposite direction. It depends especially on the frontal eye fields, and the supplementary eye fields and DLPFC (O’Driscoll et al. 1995, Luna et al. ). Performance on the task improves continuously from 8 until about 20 to 25 years of age (Munoz et al. 1998, Luna et al. (in press)). Luna et al. (in press) report that while activation in the frontal eye fields, supplementary eye fields, and DL-PFC increased during anti-saccade performance in participants of all ages, increased activation of the thalamus, striatum, and cerebellum was seen only in adults, suggesting that the circuit connecting PFC with subcortical regions might mature late.

8. Anatomical Evidence That PFC Is Not Fully Mature Until Adolescence Or Early Adulthood

One of the functions of glial cells is to provide an insulating sheath, called myelin, around the axons of neurons, which increases the speed of transmission of communication between neurons and which acts as an electrical insulator, decreasing lateral transmission and interference, thus improving the signal:noise ratio. Myelination of PFC is protracted and does not reach adult levels until adolescence (Huttenlocher 1970, Giedd et al. 1999). For example, using MRI and following the same children longitudinally, Giedd et al. (1999) were able to show that the amount of white matter (i.e., myelinated axons) increased linearly in frontal cortex from 4 to 13 years of age.

Portions of the neuron that are unmyelinated, such as the cell body, have a gray appearance. In their longitudinal study, Giedd et al. (1999) found that gray matter in frontal cortex increased until adolescence, reaching its maximum extent at 12 years of age for males and 11 years for females. However, in cross-sectional volumetric studies, Jernigan et al. (1991) and Sowell et al. (1999a) report reductions in gray matter volume between childhood and adolescence, with the most dramatic changes occurring in dorsal frontal and parietal cortex. Sowell et al. (2001) related these gray matter changes to cognitive performance and found that, between 7 and 16 years of age, gray matter in frontal cortex (which included in their analyses not only PFC, but motor cortex, and all cortex in between) decreased in size, and the ability to accurately remember which words had and had not been presented earlier (i.e., the ability to remember which words had been seen in the present context and to discriminate them from other familiar words) improved. Impressively, gray matter thinning in frontal cortex was significantly correlated with this source memory, independent of age. Indeed, while the relation between frontal cortex gray matter thinning and this ability remained significant controlling for age, the relation between age and source memory was no longer significant controlling for frontal gray matter changes.

Synaptogenesis occurs concurrently with myelination. Huttenlocher (1979) reports that the synaptic density of layer III pyramidal cells in DL-PFC increases until about the age of 1 year, and then decreases, finally reaching adult levels at about 16 years of age. Huttenlocher and Dabholkar (1997) report that the formation of synaptic contacts in DLPFC reaches its maximum after 15 months of age, and synapse elimination occurs late in childhood, ex-tending to mid-adolescence for DL-PFC.

Developmental changes in PFC continue into adult- hood. Sowell et al. (1999b) report a reduction in the density of gray matter in frontal cortex between adolescence (12–16 years) and adulthood (23–30 years). Kostovic et al. (1988) report that acetylcholinesterase (AChE) reactivity of layer III pyramidal cells in DL-PFC, which begins to develop after the first postnatal year, reaches its peak intensity in young adults.

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