Cognition and Working Memory in Brain Injury and Autism

Revised 17 November 2013

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Cognition and Working Memory in Brain Injury and Autism

Alan Challoner MA (Phil) MChS

Working memory can be seriously affected by brain injury both In

terms of the structures that are damaged and the failure of some

developmental processes that follow, when the injury occurs early

in a child’s life. It is of importance for there to be a better

understanding of autistic spectrum disorder so that consideration

can be given to the possibilities that the condition may arise as a

consequence of early brain damage.1,2,3

A review of l iterature may help to understand better these issues

especially to consider research that indicates how working

memory affects our cognitive processes and how the deficits

following brain injury affect cognition and communication as a

result of damage to the prefrontal cortex and its connections to

other brain areas.

In the normal brain, the very complicated span of neural activity

which we call working memory goes on without us having to think

about it consciously. However, with subjects who have damage to

some of the areas involved, it can be seen why there is a failure of

certain cognitive and social skills and it is important to portray

these difficulties as being influenced by brain damage and not by

lack of intellect.

Attentional focus is important for many cognitive processes

including problem solving and its differential effects on analytic

and creative activity. One of the main ways in which working

memory capacity benefits analytic problem solving seems to be

that it helps to control attention, resist distraction and narrow the

search through a problem space. Conversely, several lines of

recent research show evidence that too much focus here can

actually harm performance on creative problem-solving tasks.4

Working Memory ‘Working memory’ is a form of short-term memory that

is often exemplified by the times when information is being held on line for the purpose of

performing computations on it (analogous to a mental scratch pad). Fuster 5,6 provided the

first detailed account of the role of working memory in prefrontal processes. He described

the role of the prefrontal cortex as that of integrating temporally distributed information, a

complex process which he attributed partly to short-term working memory. Contrasting this

view with supervisory attentional system (SAS)-like executive accounts of prefrontal

1 http://www.scribd.com/doc/9635846/Abnormal-Brain-Structure-and-Autism-

2 http://www.scribd.com/doc/3665740/Autism-and-Abnormalities-in-the-Brain

3 http://www.scribd.com/doc/19408267/Brain-Damage-Caused-by-Vaccination

4 Jennifer Wiley, J. & Jarosz, AF. Working Memory Capacity, Attentional Focus, and Problem

Solving. Current Directions in Psychological Science August 2012 vol. 21 no. 4 258-262.

5 Fuster JM. The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal

Lobe. New York: Raven Press, 1980.

6 Fuster JM. The prefrontal cortex and temporal integration, in Jones EG, Peters A (eds):

Cerebral Cortex: Vol 4. Association and Auditory Cortices. New York: Raven Press; 1985.


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function7, he wrote: “The prefrontal cortex would not superimpose a steering or directing

function on the remainder of the nervous system, but rather, by expanding the temporal

perspectives of the system, it would allow it to integrate longer, newer, and more complex

structures of behaviour.”

Goldman-Rakic8 has also proposed a working-memory account of frontal lobe function on

the basis of extensive research with non-human primates. Building on the well-established

relationship between the prefrontal cortex and delayed-response tasks, she argues that the

prefrontal cortex is responsible for maintaining information (“representational memory”)

that is later used to guide action. Funahashi and colleagues9,10 carried out a variety of

lesion studies and single-unit recording studies to establish the role of prefrontal cortex in

working memory, primarily with monkeys trained to perform spatial working memory tasks.

Neuro-imaging studies in humans11,12,13,14 suggest that similar working-memory processes

are located pre-frontally in the human brain. Goldman-Rakic (1987, idem) has put forward

a view that the association between prefrontal cortex and working memory can, in

principle, explain a range of human cognitive impairments following focal frontal lesions as

well as other non-focal pathologies affecting prefrontal cortex. The proposal that working

memory impairment could underlie the range of cognitive changes seen after prefrontal

damage first found direct support in the work of Cohen and Servan-Schreiber15.

Working Memory and Early Brain Injury

Treble et al have found that deficits in working memory are a common consequence of

paediatric traumatic brain injury and are believed to contribute to difficulties in a range of

cognitive and academic domains. Their research has shown that reduced integrity of the

corpus callosum (CC) after traumatic brain injury may disrupt the connectivity between

bilateral fronto-parietal neural networks underlying working memory .

They used diffusion tensor imaging (DTI) tractography to examine eight callosal subregions

(CC1-CC8) in relation to measures of verbal and visuospatial working memory in 74

children sustaining traumatic brain injury and 49 typically developing comparison children.

7 Supervisory attentional system — a loosely defined collection of brain processes that are

responsible for planning, cognitive flexibility, abstract thinking, rule acquisition, initiating

appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory

information.

8 Goldman-Rakic PS. Circuitry of primate prefrontal cortex and regulation of behavior by

representational memory, in Plum F, Mountcastle V (eds): Handbook of Physiology, The

Nervous System: V. Bethesda, MD: American Physiological Society, 1987.

9 Funahashi S; Bruce CJ & Goldman-Rakic PS. Mnemonic coding of visual space in the

monkey's dorsolateral prefrontal cortex. J Neurophysiol 61:331349,1989.

10 Funahashi S; Bruce CJ & Goldman-Rakic PS. Dorsolateral prefrontal lesions and oculomotor

delayedresponse performance: Evidence for mnemonic ‘scotomas’. J Neurosci 13:1479-

1497, 1993.

11 Cohen J; Forman S & Braver T, et al. Activation of prefrontal cortex in a nonspatial working

memory task with functional MRI. Hum Brain Mapping 1:293-304, 1994.

12 D'Esposito M; Shin RK & Detre JA, et al. Object and spatial working memory activates

dorsolateral prefrontal cortex: A functional MRI study. Soc Neurosci Abstr 21:1498, 1995.

13 D'Esposito M; Detre J & Alsop D, et al. The neural basis of the central executive system of

working memory. Nature 378:279-281, 1995.

14 Jonides J; Smith E & Koeppe R, et al. Spatial working memory in humans as revealed by PET.

Nature 363:623-625, 1993.

15 Cohen JD & Servan-Schreiber D. Context, cortex, and dopamine: A connectionist approach

to behavior and biology in schizophrenia. Psychol Rev 99:4577,1992.


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Relative to the comparison group, children with traumatic brain injury demonstrated

poorer visuospatial working memory , but comparable verbal working memory .

Microstructure of the CC was significantly compromised in brain-injured children, with lower

fractional anisotropy (FA) and higher axial and radial diffusivity metrics in all callosal

subregions. In both groups of children, lower FA and/or higher radial diffusivity in callosal

subregions connecting anterior and posterior parietal cortical regions predicted poorer

verbal WM, whereas higher radial diffusivity in callosal subregions connecting anterior and

posterior parietal, as well as temporal, cortical regions predicted poorer visuospatial

working memory.

DTI metrics, especially radial diffusivity, in predictive callosal subregions accounted for

significant variance in working memory over and above remaining callosal subregions.

Reduced microstructural integrity of the CC, particularly in subregions connecting parietal

and temporal cortices, may act as a neuropathological mechanism contributing to long-

term WM deficits. The future clinical use of neuroanatomical biomarkers may allow for the

early identification of children at highest risk for working memory deficits and earlier

provision of interventions for these children. 16

Hardan et al found that areas of the anterior sub-regions of the corpus callosum were

smaller in those with autism than in individually matched controls. 17 This may support a

view that some brain injuries can result in autistic spectrum disorder if they occur early

enough in life.

Information Processing & Brain Injury— A common deficit arising from a brain injury,

and more commonly from a head injury, is the inability to process information at the normal

rate. Whereas the child may be able to carryout a variety of mental tasks, the speed at

which these are completed in a brain-injured child may be significantly slower than it would

be for a normal child. 18 The deficit may involve the speed at which the child can

understand the task involved, learn the material, retrieve it from memory and then carry out

the mental processes involved.

Deficits in this area can severely limit the ability of the child to function in many everyday

situations and such deficits can arise following even a mild head injury. 19 In specific detail,

the child finds difficulty comprehending information at the normal rate, formulating

their thoughts and then carrying out the required actions. They may find it difficult to

understand if too much information is presented at any one occasion. They may therefore

initially start off understanding what is going on but rapidly lose their way as the amount of

information accumulates. This is particularly the case if the level of information becomes

more complex and it can occur in both the classroom and in social situations.

Borod found brain-injured children to be less competent at comprehending emotional

information. In the teaching situation this often shows itself in the child's inability to

complete written assignments or answer questions in the allotted time, and therefore

16 Treble A; Hasan KM; Iftikhar A; Stuebing KK; Kramer LA; Cox CS Jr; Swank PR & Ewing-Cobbs L.

Working memory and corpus callosum microstructural integrity after pediatric traumatic brain

injury: a diffusion tensor tractography study. J Neurotrauma. 2013 Oct 1;30(19):1609-19. doi:

10.1089/neu.2013. 2934.

17 Hardan AY; Minshew NJ & Keshavan MS. Corpus Callosum Size In Autism. Neurology 2000

Oct 10;55(7):1033-6.

18 Brooks, N. Cognitive deficits after head injury. In: Closed Head Injury: Psychosocial Social and

Family Consequences (ed. N. Brooks), pp. 44-73. Oxford: Oxford Community Press; 1984.

19 Wrightson, P., McGinn, V., & Gronwall, D. Mild head injury in pre-school children – evidence

that can be associated with a persisting cognitive defect. Journal of Neurology Neurosurgery

and Psychiatry 59, 375-80; 1995.


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never being able to answer a question directed at the class, because by the time they

raise their hand someone else has already answered before them. 20

Children who are significantly affected can find themselves severely disadvantaged at a

social level. Whereas adults will give a child a sympathetic look and the necessary time to

collect their thoughts, a more competitive adolescent group will not be so kind or so

tolerant. In the playground, the conversation moves at the pace of the group and

for those too slow to respond, they frequently find themselves left far behind; sometimes it is

easier not to even try, and the children may find themselves becoming increasingly isolated

from their peers. 21

The ability to understand, learn and then retrieve information involves a range of abilities,

including attention, short-term memory and the ability to manipulate the information in

order to place it into a more permanent memory system. Essential to this, is the ability to

organize material into a meaningful manner so that it can be recalled and subsequently

placed within some existing scheme or order. As Tromp and Mulder 22 demonstrated,

access to the memory system affects the speed at which information is processed.

Information therefore has to be organized and categorized so that it can be stored in some

permanent memory system. To do this, it is also necessary for the child to be able to

distinguish the core information and main ideas from any irrelevant information. It is

apparent that a range of strategies can be used at a simplistic level. The rate, amount and

complexity of the material may, however, exceed what the child can comfortably cope

with at a simplistic level. To help the child cope with such processing problems, it is

important that parents and teachers are aware that the child may have such difficulties.

If people are so aware, the problem can be partly resolved by altering the rate at which

work is presented. It is also very valuable if the child can be offered some basic strategies

and prompt him to say —can you please explain that again —can you go through that a

little slower, please — or, — can you let me think about that for a minute before I answer.

These sorts of responses, if approved, can give the child a second opportunity to answer

or resolve the problem and help to prevent an anxiety-producing situation.

It is possible to give children more general strategies in order to help to speed up the

processing problem within its own right. The child can be encouraged to use visual

imagery, provided that they have intact visual and perceptual skills. This visual imagery

technique has been well explained by Buzan 23 using 'mind maps' whereby the child can

be encouraged to use diagrams as cues to help prompt the memory process. This

technique can also be used to enhance both short-term and working memory. It can show

how new learning can be attached to older more established and more intact areas of

memory and therefore the child can be shown on which ‘hooks’ to hang the new

information.

Cortical visual processing begins in the primary visual area located in the occipital lobe

(the rear-most part of the cortex). This area receives visual information from the visual

thalamus, processes it, and then distributes its outputs to a variety of other cortical regions.

Although the cortical visual system is enormously complex,24 the neural pathways

responsible for two aspects of visual processing are fairly well understood. These involve the

20 Borod, J. C. Interhemispheric and intrahemispheric control of emotion. Journal of Consulting

and Clinical Psychology 60, 339-48; 1992.

21 Appleton, R. & Baldwin, T. Management of Brain Injured Children. 2nd Ed. OUP,2006.

22 Tromp, E. & Mulder, T. Neuropsychological slowness of information processing after a

traumatic head injury. Journal of Clinical and Experimental Neuropsychology 13, 821-30; 1991.

23 Buzan, T. Use Your Head. London: BBC Publications.; 1974.

24 Van Essen, DC. Functional organization of primate visual cortex. In Cerebral cortex, A. Peters

and E. G. Jones, eds. (New York: Plenum), pp.259-328; 1985.


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determination of ‘what’ a stimulus is and ‘where’ it is located. 25, 26 The ‘what’ pathway

involves a processing stream that travels from the primary visual cortex to the temporal lobe

and the ‘where’ pathway goes from the primary cortex to the parietal lobe.

The parietal and frontal regions in question are anatomically interconnected — the parietal

area sends axons to the prefrontal region and the prefrontal region sends axons back to

the parietal area. These findings suggest that the parietal lobe visual area works with the

lateral prefrontal cortex to maintain information about the spatial location of visual stimuli in

working memory. Similarly, Robert Desimone found evidence for reciprocal interactions be-

tween the visual areas of the temporal lobe (the ‘what’ pathway) and the lateral prefrontal

cortex in studies involving the recognition of whether a particular object had been seen

recently 27. The maintenance of visual information in working memory thus appears to

depend crucially on interactions between the lateral prefrontal region and specialized

areas of the visual cortex.

Goldman-Rakic and colleagues recorded from cells in the parietal lobe ‘where’ pathway

during short-term memory tests requiring the temporary remembering of the spatial location

of visual stimuli. They found that cells there, like cells in the lateral prefrontal cortex, were

active, suggesting that they were keeping track of the location, during the delay.

(Goldman-Rakic, 1987, idem)

Studies, especially by Wilson and associates28, have raised questions about the role of the

prefrontal cortex as a general purpose working memory processor. For example, they have

found that different parts of the lateral prefrontal cortex participate in working memory

when animals have to determine ‘what’ a visual stimulus is as opposed to ‘where’ it is

located, suggesting that different parts of the prefrontal cortex are specialized for different

kinds of working memory tasks. While these findings show that parts of the prefrontal cortex

participate uniquely in different short-term memory tasks, they do not rule out the existence

of a general-purpose workspace and a set of executive functions that coordinate the

activity of the specialized systems, especially since the tasks studied do not tax the

capacity of working memory in a way that would reveal a limited capacity system.

The pathway from the specialized visual areas tells the prefrontal cortex ‘what’ is out there

and ‘where’ it is located (bottom-up processing). The prefrontal cortex, by way of

pathways back to the visual areas, primes the visual system to attend to those objects and

spatial locations that are being processed in working memory (top-down processing).

These kinds of top-down influences on sensory processing are believed to be important

aspects of the executive control functions of working memory.

25 Ungerleider, LG; & Mishkin, M. Two cortical visual systems. In Analysis of visual behavior, D. J.

Ingle, M. A. Goodale, and R. J. W. Mansfield, eds. (Cambridge: MIT Press), pp. 549-86; 1982.

26 Ungerleider, LG; & Haxby, J. What and where; in the human brain. Current Opinion in

Neurobiology 4, 157-65; 1994.

27 Desimone, R; Miller, EK; Chelazzi, L; & Lueschow, A. Multiple memory systems in the visual

cortex. In The cognitive neurosciences, M. S. Gazzaniga, ed. (Cambridge: MIT Press), pp. 475-

86; 1995.

28 Wilson, FAW; Scalaidhe, SP; & Goldman-Rakic, PS. Dissociation of object and spatial

processing domains in primate prefrontal cortex. Science 260, 1955-58; 1993.


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Relation of the "What" and "Where" Visual Pathways to Working Memory.

Visual information, received by the visual cortex, is distributed to cortical areas that perform specialized visual processing functions. Two well-studied specialized functions are those involved in object recognition (mediated by the ‘what’ pathway) and object location (mediated by the ‘where’ pathway). These specialized visual pathways provide inputs to the prefrontal cortex (PFC), which plays a crucial role in working memory. The specialized systems also receive inputs back from the PFC, allowing the information content of working memory to influence further processing of incoming information. Leftward-going arrows represent bottom-up processing and rightward-going ones top-down processing.

Other studies that have taxed the system, like imaging studies in humans, suggest that

neurons in the lateral prefrontal cortex are part of a general-purpose working memory

network. At the same time, it is possible, given Goldman-Rakic's findings that the general-

purpose aspects of working memory are not localized to a single place in the lateral

prefrontal cortex but instead are distributed over the region. That this may occur is

suggested by the fact that some cells in the specialized areas of the lateral pre-frontal

cortex participate in multiple working memory tasks.29

Working-memory accounts of prefrontal function are favoured for a number of reasons30:

First, they are parsimonious, in that working-memory theories contain only the individual

processing components needed to perform the task without needing a central executive

(such as the SAS) to coordinate these components (and to serve as the locus of damage

when explaining patient behaviour).

Second, they have proven capable of explaining a wider range of seemingly disparate

impairments than other non-executive theories. 31

Third, they are supported by a wealth of evidence from monkey neurophysiology and, in-

creasingly, from neuro-imaging studies in humans.

Fourth, they suggest a way of resolving what is perhaps the central problem of the neuro-

29 Petrides, M. Frontal lobes and behaviour. Current Opinion in Neurobiology 4, 207-11; 1994.

30 Kimberg, DY; D’Esposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological

Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology.

McGraw-Hill, New York, 1997.

31 Kimberg DY & Farah MJ. A unified account of cognitive impairments following frontal lobe

damage: The role of working memory in complex, organized behavior. J Exp Psychol Gen

122:411-428, 1993.


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psychology of the frontal lobe function — the paradox of dissociable impairments with an

unintuitive compelling ‘family resemblance’.

If we assume that working memory is compartmentalized in the prefrontal cortex according

to what is being represented in memory (for which evidence exists), then performance in

different tasks can be impaired or spared depending on which types of working memory

have been damaged. Nevertheless, according to working-memory accounts, there is an

underlying commonality among the tasks sensitive to prefrontal damage namely, those

that have dependence on working memory. (Kimburg, et al , 1997, Idem)

There is also evidence that the general-purpose functions of working memory involve areas

other than the lateral prefrontal cortex. For example, imaging studies in humans have

shown that another area of the frontal lobe, the anterior cingulate cortex, is also activated

by working memory and related cognitive tasks. (D’Esposito, et al, 1995, Idem) & 32, 33

Like the lateral pre-frontal cortex, the anterior cingulate region receives inputs from the

various specialized sensory buffers, and the anterior cingulate and the lateral pre-frontal

cortex are anatomically interconnected. (Fuster, 1989, Idem) & 34. Moreover, both regions

are part of what has been called the frontal lobe attentional network, a cognitive system

involved in selective attention, mental resource allocation, decision-making processes, and

voluntary movement control. 35 It is tempting to think of the general-purpose aspects of

working memory as involving neurons in the lateral prefrontal and anterior cingulate regions

working together.

One other area of the prefrontal cortex, the orbital region, located on the underneath side

of the frontal lobe, has emerged as important as well. Damage to this region in animals

interferes with short-term memory about reward information, about what is good and bad

at the moment 36, and cells in this region are sensitive to whether a stimulus has just led to a

reward or punishment 37, 38, 39. Humans with orbital frontal damage become oblivious to

social and emotional cues and some exhibit sociopathic behaviour. 40 This area receives

inputs from sensory processing systems (including their temporary buffers) and is also

intimately connected with the amygdala and the anterior cingulate region. The orbital

cortex provides a link through which emotional processing by the amygdala might be

32 Corbetta, M; Miezin, FM; Dobmeyer, S; Shulman, GL; & Petersen, SE. Selective and divided

attention during visual discriminations of shape, color, and speed: Functional anatomy by

positron emission tomography. Journal of Neuroscience 11, 2383-2402; 1991.

33 Posner, M; & Petersen, S. The attention system of the human brain. Annual Review of

Neuroscience 13, 25-42; 1990.

34 Goldman-Rakic, PS. Topography of cognition: Parallel distributed networks in primate

association cortex. Annual Review of Neuroscience 11, 137-56; 1988.

35 Posner, M. Attention as a cognitive and neural system. Current Directions in Psychological

Science 1, 11-14; 1992.

36 Gaffan, D; Murray, EA; & Fabre-Thorpe, M. Interaction of the amygdala with the frontal lobe

in reward memory. European Journal of Neuroscience 5, 968-75; 1993.

37 Thorpe, SJ; Rolls, ET; & Maddison, S. The orbitofrontal cortex: Neuronal activity in the behaving

monkey. Experimental Brain Research 49, 93-115; 1983 .

38 Rolls, ET. Neurophysiology and functions of the primate amygdala. In The amygdala:

Neurobiological aspects of emotion, memory, and mental dysfunction, J. P. Aggleton, ed.

(New York: Wiley-Liss), pp. 143-65; 1992.

39 Ono, T & Nishijo, H. Neurophysiological basis of the KliiverBucy syndrome: Responses of

monkey amygdaloid neurons to biologically significant objects. In The amygdala:

Neurobiological aspects of emotion, memo,); and mental dysfunction, J. P. Aggleton, ed.

(New York: Wiley-Liss), pp. 167-90; 1992.

40 Damasio, A. Descartes error: Emotion, reason, and the human brain. New York:

Grosset/Putnam; 1994.


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related in working memory to information being processed in sensory or other regions of the

neocortex.

LeDoux writes that the involvement of specialized short-term buffers in the sensory systems

and a general-purpose working memory mechanism in the prefrontal cortex is a very

complicated system. 41 The prefrontal cortex itself seems to have regions that are

specialized, at least to some degree, for specific kinds of working memory functions. Such

findings, however, do not discredit the notion that the prefrontal cortex is involved in the

general-purpose or executive aspects of working memory since only some cells in these

areas play specialized roles. Interactions between the general-purpose cells in different

areas may coordinate the overall activity of working memory. It is thus possible that the

executive functions of the prefrontal cortex might be mediated by cells that are distributed

across the different prefrontal subsystems rather than by cells that are collected together in

one region. (LeDoux, 1998, idem)

What are Buffers? A critical component of Baddeley’s working memory model is

the existence of verbal mid-spatial storage buffers42. The cognitive concept of a buffer

translated into neural terms would propose that temporary retention of task-relevant

information requires transfer of that information to a part of the brain that is dedicated to

the storage of information. Presumably, such buffers are analogous to a computer’s RAM,

which serves as a cache for information transferred from the hard drive that is processed by

a CPU. Consistent with this interpretation of a working memory ‘buffer’, many descriptions

of cognitive models of working memory refer to the information being ‘in’ or ‘out’ of

working memory.

Relation of Specialized Short-Term Buffers,

Long-Term Explicit Memory and Working Memory.

Stimuli processed in different specialized systems (such as sensory, spatial, or language systems) can be held simultaneously in short-term buffers. The various short-term buffers provide potential inputs to working memory, which can deal most effectively with only one of the buffers at a time. Working memory integrates information received from short-term buffers with long-term memo-ries that are also activated.

LeDoux suggests that this involvement of specialized short-term buffers in the sensory

systems and a general-purpose working memory mechanism in the prefrontal cortex is a

very complicated system. The prefrontal cortex itself seems to have regions that are

41 LeDoux, J. The Emotional Brain. Weidenfeld & Nicholson, 1998 ISBN 0297841084.

42 Baddeley, A. Working Memory. New York, NY: Oxford University Press; 1986.


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specialized, at least to some degree, for specific kinds of working memory functions. Such

findings, however, do not discredit the notion that the prefrontal cortex is involved in the

general-purpose or executive aspects of working memory since only some cells in these

areas play specialized roles. Interactions between the general-purpose cells in different

areas may coordinate the overall activity of working memory. It is thus possible that the

executive functions of the prefrontal cortex might be mediated by cells that are distributed

across the different prefrontal subsystems rather than by cells that are collected together in

one region. (LeDoux, 1998, idem)

In a review of working memory, Repovs & Baddeley43 state that, “the function of the

articulatory rehearsal process is to retrieve and rearticulate the contents held in this

phonological store and in this way to refresh the memory trace”. 44 Further, while speech

input enters the phonological store automatically, information from other modalities enters

the phonological store only through recoding into phonological form, a process performed

by “articulatory rehearsal”. Later, the authors refer to, “focal shifts of attention to

memorized locations that provide a rehearsal-like function of maintaining information

active in spatial working memory”. Thus, one question that neuro-scientific data can

address regarding how the brain implements working memory processes is whether such

buffers or storage sites exist in distinct parts of the brain to support the active maintenance

of task-relevant information.

A cognitive model of working memory, has been put forth by Cowan, 45, 46 it proposes that

the ‘contents of working memory’ are not maintained within dedicated storage buffers, but

rather are simply the subset of information that is within the focus of attention at a given

time. He describes an embedded-processes model where working memory comes from

hierarchically arranged faculties comprising long-term memory, the subset of working long-

term memory that is currently activated and the subset of activated memory that is the

focus of attention. These ideas are similar to that put forth by Anderson 47 who referred to

working memory as those representations currently at a high level of activation. Thus, task-

relevant representations are not in working memory, but they do have levels of activation

that can be higher or lower. After use, for example, representations may be temporarily

more active or ‘primed’. In this formulation, working memory does not have a size, or

maximum number of items, as a structural feature. Instead, performance on working

memory tasks is determined by the level of activation of relevant representations, and the

discriminability of activation levels between relevant and irrelevant representations. 48

Again, in neural terms, Cowan’s or Anderson’s cognitive model of working memory would

predict that information that is represented throughout the brain is not transferred to an

independent buffer or storage site, but rather that temporary retention of task-relevant

information is mediated by the activation of the neural structures that represent the

information being maintained or stored (for a further discussion of these and related ideas,

43 Repovs, G.& Baddeley, A. The multi-component model of working memory: explorations in

experimental cognitive psychology. Neuroscience 139, 5-2; 2006.

44 The phonological loop (or "articulatory loop") as a whole deals with sound or phonological

information. It consists of two parts: a short-term phonological store with auditory memory

traces that are subject to rapid decay and an articulatory rehearsal component (sometimes

called the articulatory loop) that can revive the memory traces.

45 Cowan, N. Evolving conceptions of memory storage, selective attention, and their mutual

constraints within the human information processing system. Psycho I. Bull. 104, 163-171; 1988.

46 Cowan, N. An embedded-process model of working memory. In Models of working memory:

mechanisms of active maintenance and executive control (eds A. Miyake & P. Shah), pp. 62-

101. Cambridge, UK: Cambridge University Press; 1999.

47 Anderson, J. R. The architecture of cognition. Cambridge, MA: Harvard University Press; 1983.

48 Kimberg, D. Y., D'Esposito, M. & Farah, M. J. Cognitive functions in the prefrontal cortex-

working memory and executive control. Curro Dir. Psychol. Sci. 6, 185-192; 1997.


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see Ruchkin, et al 49. In other words, the temporary retention of a face, for example, would

require activation of cortical areas that are involved in the perceptual processing of faces.

From a neuroscience perspective, it is counter-intuitive that all temporarily stored

information during goal-directed behaviour requires specialized dedicated buffers. Clearly,

there could not be a sufficient number of independent buffers to accommodate the

infinite types of information that need to be actively maintained to accommodate all

potential or intended actions.

For instance, in a system with only two buffers, such as verbal and visuo-spatial, how would

the retention of odours or tactile sensations, which cannot always be recoded into verbal

or visuo-spatial representations, be accomplished? An additional episodic buffer has been

proposed to be a store capable of multi-dimensional coding that allows the binding of

information to create an integrated episode50 . However, even with the addition of this

buffer, Baddeley’s working memory model cannot accommodate storage of all possible

types of information processed by the human brain (it is important to note, however, that

this was not probably the original intent of his model).

Alternatively, in Cowan’s proposal, which does not rely on the concept of specialized

dedicated storage buffers, active maintenance or storage of task-relevant representations

could be implemented with a neural system where memory storage occurs in the very

same brain circuitry that supports the perceptual representation of information. Such a

neural system presumably would be more flexible and efficient than one that transfers

information back and forth between dedicated storage buffers. Obviously, there is still work

to be done to test these competing hypotheses.

Cognition and Working Memory

The influence of memory on perception is an example of what cognitive scientists

sometimes call top-down processing, which contrasts with the build-up of perceptions from

sensory processing, known as bottom-up processing.

Working memory, in short, sits at the crossroads of bottom-up and top-down processing

systems and makes high-level thinking and reasoning possible. Stephen Kosslyn, a leading

cognitive scientist, puts it this way:

Working memory ... corresponds to the activated information in long-term memories, the

information in short-term memories, and the decision processes that manage which

information is activated in the long-term memories and retained in the short-term memories

.... This kind of working memory system is necessary for a wide range of tasks, such as

performing mental arithmetic, reading, problem solving and . . . reasoning in general. All of

these tasks require not only some form of temporary storage, but also interplay between

information that is stored temporarily and a larger body of stored knowledge51.

Studies conducted in the 1930s by C.F. Jacobsen provide the foundation for our

understanding of this problem52. He trained monkeys using something called the delayed

response task. The monkey sat in a chair and watched the experimenter put a raisin under

one of two objects that were side by side. A curtain was then lowered for a certain amount

49 Ruchkin, D. S., Grafman, J., Cameron, K. & Berndt, R. S. Working memory retention systems: a

state of activated long-term memory. Behav. Brain Sci. 26, 709-728, discussion 728-777; 2003.

50 Baddeley, A. The episodic buffer: a new component of working memory? Trends Cogn. Sci. 4,

417—423; 2000

51 Kosslyn, SM., and Koenig, O. Wet mind: The new cognitive neuroscience; New York:

Macmillan; 1992.

52 Jacobsen, CE; & Nissen, HW. Studies of cerebral function in primates: IV. The effects of frontal

lobe lesions on the delayed alternation habit in monkeys. Journal of Comparative and

Physiological Psychology 23, 101-12; 1937.


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of time (the delay) and then the monkey was allowed to choose. In order to get the raisin,

the monkey had to remember not which object the raisin was under but whether the raisin

was under the left or the right object.

Correct performance, in other words, required that the monkey holds in its mind the spatial

location of the raisin during the delay period (during which the playing field was hidden

from view). At very short delays (a few seconds), normal monkeys did quite well, and

performance got predictably worse as the delay increased (from seconds to minutes).

However, monkeys with damage to the prefrontal cortex performed poorly, even at the

short delays. On the basis of this and research that followed, the prefrontal cortex has

come to be thought of as playing a role in temporary memory processes, processes that

we now refer to as working memory.

Previously attention has been drawn to the role of the medial prefrontal cortex in the

extinction of emotional memory. In contrast, it is the lateral prefrontal cortex that has most

often been implicated in working memory. The lateral prefrontal cortex is believed to exist

only in primates and is considerably larger in humans than in other primates53. It is not

surprising that one of the most sophisticated cognitive functions of the brain should involve

this region.

In recent years, the role of the lateral prefrontal cortex in working memory has been studied

extensively by the laboratories of Joaquin Fuster at UCLA and Pat Goldman-Rakic at

Yale54,55,56,57 . Both researchers have recorded the electrical activity of lateral prefrontal

neurons while monkeys performed delayed response tasks and other tests requiring short-

term storage. They have shown that cells in this region become particularly active during

the delay periods. It is likely that these cells are actively involved in holding on to the

information during the delay.

The Prefrontal Cortex and Working Memory

There is now a critical mass of studies that find lateral Prefrontal Cortex (PFC) activity in

humans during delay tasks. 58 For example, in a functional magnetic resonance imaging

(fMRI) study using an oculomotor delay task identical to that used in monkey studies, it was

observed that not only the frontal cortex activity during the retention interval but also the

magnitude of the activity, correlated positively with the accuracy of the memory-guided

saccade that followed later.

This relationship suggests that the fidelity of the actively maintained location is reflected in

the delay-period activity59. Thus, the existence of persistent neural activity during blank

53 Preuss, TM. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered.

Journal of Cognitive Neuroscience 7, 1-24; 1995.

54 Fuster, JM. The prefrontal cortex. New York: Raven; 1989).

55 Goldman-Rakic, PS. Circuitry of primate prefrontal cortex and regulation of behavior by

representational memory. In Handbook of physiology. Section 1: The nervous system. Vol. 5:

Higher Functions of the Brain, F. Plum, ed. (Bethesda, MD: American Physiological Society, pp.

373-417; 1987.

56 Goldman-Rakic, PS. Working memory and the mind. In Mind and brain: Readings from

Scientific American magazine, W. H. Freeman, ed. (New York: Freeman), pp. 66-77; 1993.

57 Wilson, FAW; Scalaidhe, SP; & Goldman-Rakic, PS. Dissociation of object and spatial

processing domains in primate prefrontal cortex. Science 260, 1955-58; 1993.

58 Curtis, C. E. & D'Esposito, M. Persistent activity in the prefrontal cortex during working memory.

Trends. Cogn. Sci. 7,415—423; 2003.

59 Curtis, C. E., Rao, V. Y. & D'Esposito, M. Maintenance of spatial and motor codes during

oculomotor delayed response tasks. J. Neurosci. 24, 3944-3952; 2004.


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memory intervals of delay tasks is a powerful empirical finding, which lends strong support

for the hypothesis that such activity represents a neural mechanism for the active

maintenance or storage of task-relevant representations.

The necessity of the PFC for the active maintenance of task-relevant representations has

been demonstrated by studies that have found impaired performance on delay tasks in

monkeys with selective lesions of the lateral PFC 60,61 .

However, monkey physiology studies recording from other brain areas and human fMRI

studies of working memory have also found that the PFC is not the only region that is active

during the temporary retention of task-relevant information. For example different brain

regions are involved during the performance of the oculomotor delayed response task.

Specifically, different brain regions were active depending on whether the task required

the temporary maintenance of retrospective (e.g. past sensory events) or prospective (e.g.

representations of anticipated action and preparatory set) codes.

This study demonstrated not only that many different brain regions exhibit persistent neural

activity during active maintenance of task-relevant information, but also that a unique

network of brain regions are recruited depending on the type of information being actively

maintained. The fMRI data also support the notion that even within the domain of spatial

information, separable neural mechanisms are engaged for the active maintenance of

‘motor’ plans versus ‘spatial’ codes. Moreover, given that the task only required the

oculomotor system, it is probable that distinct neural circuitry will be recruited when the

motor act involves other modalities, such as speech or limb output. 62

Thus, this is the first piece of evidence that the concept of specialized buffers (for, say,

verbal versus spatial information) may not map adequately onto neural architecture.

Rather, the findings appear more consistent with a system in which active maintenance

involves the recruitment of the same circuitry that represents the information itself, with

different circuits for different types of spatial information (e.g. visual versus oculomotor).

Similar findings exist when the ‘visual’ component of working memory is investigated with

neuro-scientific methods. For example, in another fMRI study63 , the participants were

asked to learn a series of faces, houses and face-house associations and they were

scanned while performing a delayed match-to-sample (DMS) and delayed paired -

associate (DPA) task with these stimuli.

Results showed that delay-period activity within category-selective inferior temporal sub-

regions reflected the type of information that was being actively maintained — the fusiform

gyrus showed enhanced activity when participants maintained previously shown faces on

DMS trials, and when subjects recalled faces in response to a house cue on DPA trials.

Likewise, the para-hippocampal gyrus showed enhanced activity when participants

maintained previously shown houses on DMS trials and when they recalled houses in

response to a face cue on DPA trials.

60 Bauer, R. H. & Fuster, J. M. Delayed-matching and delayed-response deficit from cooling

dorsolateral prefrontal cortex in monkeys. Q. J. Exp. Psychol. B 90, 293-302; 1976.

61 Funahashi, S., Bruce, C. J. & Goldman-Rakic, P. S. Dorsolateral prefrontal lesions and

oculomotor delayed-response performance: evidence for mnemonic "scotomas". J. Neurosci.

13, 1479-1497; 1993.

62 Hickok, G., Buchsbaum, B., Humphries, C. & Muftuler, T. Auditory-motor interaction revealed

by fMRI: speech, music, and working memory in area Spt. J. Cogn. Neurosci. 15, 673-682;

2003.

63 Ranganath, C., Cohen, M. X., Dam, C. & D'Esposito, M. Inferior temporal, prefrontal, and

hippocampal contributions to visual working memory maintenance and associative memory

retrieval. J. Neurosci. 24, 3917-3925; 2004.


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These fMRI findings are consistent with several monkey neuro-physiological studies which

have also shown that temporal lobe neurons exhibit persistent stimulus-selective activity in

tasks requiring the active maintenance of visual object information across short delays 64, 65, 66. Again, like spatial and motor codes, active maintenance of visual stimuli is mediated by

the activation of cortical regions that also support processing of that information,

perceptual in this case.

Work on neuro-scientific studies of verbal working memory, which has been most

extensively studied by behavioural methods; (Vallar & Shallice, provide a similar view

regarding the neural mechanisms underlying working memory 67 ). Consistently,

performance on tasks that tap the ‘phonological loop’, as conceptualized by Baddeley,

engage a set of brain regions that are thought to be involved in phonological processing.

For example, using functional neuro-imaging techniques during verbal working memory

tasks, the left inferior parietal lobe, posterior inferior frontal gyrus (Broca’s area), premotor

cortex and the cerebellum are typically activated. 68, 69

Schematic of Baddeley's Model

64 Miyashita, Y. & Chang, H. S. Neuronal correlate of pictorial short-term memory in the primate

temporal cortex. Nature 331,68-70; 1988.

65 Miller, E. K., Li, L. & Desimone, R. Activity of neurons in anterior inferior temporal cortex during a

short-term memory task. J. Neurosci. 13, 1460-1478; 1993.

66 Nakamura, K. & Kubota, K. Mnemonic firing of neurons in the monkey temporal pole during a

visual recognition memory task. J. Neurophysiol. 74, 162-178; 1995.

67 Vallar, G. & Shallice, T. Neuropsychological impairments of short-term memory. Cambridge,

UK: Cambridge University Press; 1990.

68 Paulesu, E., Frith, C. D. & Frackowiak, R. S. The neural correlates of the verbal component of

working memory. Nature 362,342-345; 1993

69 Awh, E., Jonides, J., Smith, E. E., Schumacher, E. H., Koeppe, R. A. & Katz, S. Dissociation of

storage and rehearsal in verbal working memory: evidence from PET. Psycho I. Sci. 7, 25-3;

1996.


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Sketch of proposed circuitry supporting phonological loop

(After Edmund Blair Bolles)

However, is this network of brain regions also responsible for the active maintenance of

non-phonological language representations (e.g. lexical-semantic).70 For visual word

recognition, a functionally specialized processing stream is thought to exist within inferior

temporal cortex, representing visual words at increasingly higher levels of abstraction along

a posterior-to-anterior axis 71.

Intracranial electrophysiological recordings, for example, (Nobre et al 72 ) show that

posterior inferior temporal cortex differentiates letter strings from non-linguistic complex

visual objects. Brain activity in more anterior inferior temporal cortical regions, in contrast,

distinguishes words from non-words and is affected by the semantic context of words,

indicating that anterior inferior temporal cortex holds more elaborate linguistic

representations (see also Marslen-Wilson & Tyler 73 and Patterson 74).

To demonstrate that there is distinct neural circuitry supporting the active maintenance of

non-phonological language representations, D’Esposito 75 explored the role of language

70 Lexical semantics is the study of how and what the words of a language denote. Words may

either be taken to denote things in the world or concepts, depending on the

particular approach to lexical semantics.

71 Cohen, L. & Dehaene, S. Specialization within the ventral stream: the case for the visual word

form area. Neuroimage 22,466—476; 2004.

72 Nobre, A. C., Allison, T. & McCarthy, G. Word recognition in the human inferior temporal lobe.

Nature 372, 260-263; 1994.

73 Marslen- Wilson, W D. & Tyler, L. K. Morphology, language and the brain: the decompositional

substrate for language comprehension. Phil. Trans. R. Soc. B 362, 823-836; 2007.

74 Patterson, K. The reign of typicality in semantic memory. Phil. Trans. R. Soc. B 362, 813-821;

2007.

75 D'Esposito, M. From cognitive to neural models of working memory. Phil. Trans. R. Soc. B. 29

May 2007; vol. 362 no. 1481 761-772


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regions within the left infero-tempora1 cortex (ITC) that are involved in visual word

recognition and word-related semantics. Using tMRI, he first localized a visual ‘word form’

area within inferior temporal cortex area and then demonstrated that this area was

involved in the active maintenance of visually presented words during a delay task 76.

Specifically, he found that this area was recruited more for the active maintenance of

words than pseudo-words (i.e. orthographically legal and pronounceable non-words).

Maintenance of pseudo-words should not elicit strong sustained activation in such brain

regions, as no stored representations pre-exist for these items. These results suggest that

verbal working memory may be conceptualized as involving sustained activation of all

relevant pre-existing cortical language (phonological, lexical or semantic) representations.

Gazzaley et al, have used a delay task to directly study the neural mechanisms

underlying top-down modulation by investigating the processes involved when

participants were required to enhance relevant and suppress irrelevant information.77

During each trial, participants observed sequences of two faces and two natural

scenes presented in a randomized order.

The tasks differed in the instructions informing the participants how to process the

stimuli:

(i) remember faces and ignore scenes,

(ii) remember scenes and ignore faces, or

(iii) passively view faces and scenes without attempting to remember them.

In each task, the period in which the cue stimuli were presented was balanced for

bottom-up visual information, thus allowing us to probe the influence of goal-directed

behaviour on neural activity (top-down modulation). In the two memory tasks, the

encoding of the task-relevant stimuli requires selective attention and thus permits the

dissociation of physiological measures of enhancement and suppression relative to the

passive baseline.

There appears to be at least two types of top-down signal, one that serves to enhance

task-relevant information and another that serves to suppress task-relevant information.

It is well documented that the nervous system uses interleaved inhibitory and excitatory

mechanisms throughout the neuro-axis (e.g. spinal reflexes, cerebellar outputs and

basal ganglia movement control networks). Thus, it may not be surprising that

enhancement and suppression mechanisms may exist to control cognition.78,79 By

generating contrast via both enhancements and suppressions of activity magnitude

and processing speed, top- down signals bias the likelihood of successful

representation of relevant information in a competitive system.

Though it has been proposed that the PFC provides a major source of the types of top-

down signals that Gazzaley has described, this hypothesis largely originates from suggestive

76 Fiebach, C. J., Rissman, J. & D'Esposito, M. Modulation of infero-temporal cortex activation

during verbal working memory maintenance. Neuron 51, 251-261; 2006.

77 Gazzaley, A, Cooney, 1. W, McEvoy, K., Knight, R. T. & D'Esposito, M. Top-down enhancement

and suppression of the magnitude and speed of neural activity. J. Cogn. Neurosci. 17, 507-

517. 2005 (doi: 10.1162/0898929053279522)

78 Knight, R. T., Staines, W R., Swick, D. & Chao, L. L. Prefrontal cortex regulates inhibition and

excitation in distributed neural networks. Acta. Psycho!. (Amst) 101, 159-178; 1999.

79 Shimamura, A. P. The role of the prefrontal cortex in dynamic filtering. Psychobiology 28, 207-

218; 2000.


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findings rather than direct empirical evidence. However, a few studies lend direct causal

support to this hypothesis. See Also 80 .

Clearly, there are other areas of multimodal cortex such as posterior parietal cortex, and

the hippocampus, that can also be the source of top-down signals. For example, the

hippocampus has been proposed to be specialized for ‘rapid learning of arbitrary

information which can be recalled in the service of controlled processing’. 81 Moreover,

input from brainstem neuro-modulatory systems probably plays a critical role in modulating

goal-directed behaviour. 82 For example, the dopaminergic system probably plays a

critical role in cognitive control processes. 83 Specifically, it is proposed that phasic bursts of

dopaminergic neurons may be critical for updating currently activated task-relevant

representations whereas tonic dopaminergic activity serves to stabilize such

representations. 84 Empirical studies in animals and man have provided support for a role

of dopamine in working memory. 85, 86

If working memory maintenance processes reflect the prolonged activation of the same

brain regions that support online processing, evidence for cortical activity in the absence of

stimuli should be evident not only in association cortex but also within primary cortical

regions. This indeed is the case as such effects have been observed in primary olfactory 87,

visual 88, 89 and auditory cortex 90, 91. Thus, the neuro-scientific data presented here is

consistent with most, if not all, neural populations being able to retain information that can

be accessed and kept active over several seconds, via persistent neural activity in the

service of goal-directed behaviour.

80 Vuilleumier, P. & Driver, J. Modulation of visual processing by attention and emotion: windows

on causal interactions between human brain regions. Phil. Trans. R. Soc. B 362, 837-855; 2007.)

81 O'Reilly, R.C., Braver, T. S. & Cohen, J. D. A biologically based computational model of

working memory. In Models of working memory: mechanisms of active maintenance and

executive control (eds Miyakw, A. & Shah, P.). Cambridge, UK: Cambridge University Press.

1999.

82 Robbins, T. W. Shifting and stopping: fronto-striatal substrates, neurochemical modulation

andclinical implications. Phil. Trans. R. Soc. B 362, 917-932; 2007. (doi: 10.1098/ rstb.2007.2097)

83 Cools, R. & Robbins, T. W. Chemistry of the adaptive mind. Phil. Trans. R. Soc. A 362, 2871-

2888.(doi:1 O. 1098/rsta.2004.1468) 2004.

84 Durstewitz, D., Seamans, I. K. & Sejnowski, T. I. Dopamine-mediated stabilization of delay-

period activity in a network model of prefrontal cortex. J. Neurophysiol. 83, 1733-1750: 2000.

85 Sawaguchi, T . The effects of dopamine and its antagonists on directional delay-

periodactivity of prefrontal neurons in monkeys during an oculomotor delayed-response task.

Neurosci. Res. 41, 115-128; 2001. (doi: 1O.1016/S0168-0102(01)00270-X)

86 Gibbs, S. E. & D'Esposito, M. A functional MRI study of the effects of bromocriptine, adopamine

receptor agonist, on component processes of working memory. Psychopharmacology (Berlin) 180, 644-

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87 Zelano, c., Bensafi, M., Porter, J., Mainland, J., Johnson, B., Bremner, E., Telles, C., Khan, R. &

Sobel, N. Attentional modulation in human primary olfactory cortex. Nat. Neurosci. 8, 114-120;

2005.

88 Klein, I., Paradis, A. L., Poline, J. B., Kosslyn, S. M. & Le Bihan, D. Transient activity in the human

calcarine cortex during visual-mental imagery: an event-related fMRI study. J. Cogn.

Neurosci. 12(Suppl. 2), 15-23; 2000.

89 Singer, W. & Gray, C. M. Visual feature integration and the temporal correlation hypothesis.

Annu. Rev. Neurosci. 18,555-586; 1995.

90 Calvert, G. A., Bullmore, E. T., Brammer, M. J., Campbell, R., Williams, S. C., McGuire, :P. K.,

Woodruff, P. W, Iversen, S. D. & David, A. S. Activation of auditory cortex during silent

lipreading. Science 276, 593-596; 1997.

91 Kraemer, D. J., Macrae, C. N., Green, A. E. & Kelley, W M. Musical imagery: sound of silence

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Cerebellar Function in Autism & Brain Injury and the

Role of the Cerebellum in Cognition and Affect

The coexistence of both cerebral and cerebellar maldevelopment may explain why the impairments in higher cognitive functions in autism are pervasive and persistent across the

life span. A postnatal period of extreme maldevelopment of these two major brain

structures will almost certainly be manifest in aberrant behavioural expression, and it is

during this early period (typically 12 to 24 months) that parents most often first express

concern about their child’s development. 92 During this developmental period, the human

brain undergoes rapid synaptogenesis, expansion of dendritic and axon arbors, and

selection of which neuronal elements to keep or eliminate. 93, 94, 95, 96 In the normally

developing brain, shaping of neural architecture and connectivity is theorised to be

significantly influenced or directed by functional neural activity driven by learning and

experience. 97, 98 In the autistic brain, however, researchers speculate that growth and

elaboration of neural architecture and connectivity occurs prematurely and without being

guided by functional experiences and adaptive learning; that is, in early life the autistic

brain exhibits premature growth without guidance. 99

In addition, the cerebellum and certain cerebral regions may perform analogous, possibly

complementary, functions. For instance, in the normal brain, cerebellar cortex is activated

by tasks that commonly activate frontal cortex, such as tasks involving working memory,

attention, or semantic association. 100, 101, 102 Adults with cerebellar lesions show impaired

performance on similar frontal lobe tasks, including tests of source memory and executive

functions (e.g., shifting attention, cognitive planning, and working memory). 103, 104 So, the

92 Cox A, Charman T, Baron-Cohen S, et al. Autism spectrum disorders at 20 and 42 months of

age: stability of clinical and ADI-R diagnosis. J Child Psychol Psychiatry 1999;5:719–732.

93 Schade JP, van Groenigen WB. Structural organization of the human cerebral cortex.

I.Maturation of the middle frontal gyrus. Acta Anat 1961;47:72–111.

94 Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human

cerebralcortex. J Comp Neurol 1997; 387:167–178.

95 Quartz SR, Sejnowski TJ. The neural basis of cognitive development: a constructivist

manifesto. Behav Brain Sci 1998;20: 537–596.

96 Courchesne E, Chisum H, Townsend J. Neural activity-dependent brain changes

indevelopment: implications for psychopathology. Dev Psychopathol 1994;6:697–722.

97 Quartz SR, Sejnowski TJ. The neural basis of cognitive development: a constructivist

manifesto. Behav Brain Sci 1998;20: 537–596.

98 Courchesne E, Chisum H, Townsend J. Neural activitydependent brain changes

indevelopment: implications for psychopathology. Dev Psychopathol 1994;6:697–722.

99 Cohen, L. & Dehaene, S. Specialization within the ventral stream: the case for the visual word

form area. Neuroimage 22,466—476; 2004.

100 Allen G, Buxton RB, Wong EC, Courchesne E. Attentional activation of the cerebellum

independent of motor involvement. Science 1997;275:1940–1943.

101 Desmond JE, Gabrieli JD, Wagner AD, Ginier BL, Glover GH. Lobular patterns of

cerebellar activation in verbal working memory and finger-tapping tasks as revealed by

functional MRI. J Neurosci 1997; 17:9675–9685.

102 Raichle ME, Fiez JA, Videen TO et al . Practice-related changes in human brain

functionalanatomy during nonmotor learning. Cereb Cortex 1994; 4:8–26.

103 Akshoomoff NA. Intramodality shifting attention in children with damage to the cerebellum.

JCogn Neurosci 1994; 6:388– 399.

104 Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain

1998;121:561–579.


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presence of both cerebral and cerebellar defects from the earliest stages of cognitive

development would likely result in severe and persistent functional deficits.

A child with impaired verbal working memory may have difficulty following instructions and

be seen as disobedient. A child who has difficulty placing information into longer-term

memory may forget previous conversations with peers and so appear to be uninterested,

possibly resulting in social rejection or social withdrawal. A child with prospective memory

problems may be seen as trying to avoid situations. Children's memory difficulties can be a

significant source of stress for their families. 105

Schmahmann and Sherman (1998) studied 20 adult patients with disease confined to the

cerebellum, evaluating the nature and severity of the changes in neurological and mental

function. They found behavioural changes to be clinically prominent in patients with lesions

involving the posterior lobe of the cerebellum and the vermis. The changes were

characterized by the following:

• impairment of executive functions such as planning,

• set-shifting,

• verbal fluency,

• abstract reasoning and working memory;

• difficulties with spatial cognition including visuo-spatial organization and memory;

• personality change with blunting of affect or disinhibited and inappropriate

behaviour;

• and language deficits including agrammatism and dysprosodia.

The investigators named this newly defined clinical entity the “cerebellar cognitive

affective syndrome”. They suggested the constellation of deficits is indicative of disruption

of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal,

superior temporal and limbic cortices with the cerebellum. 106

Scott et al. examined the role of the cerebellum in the developing cognitive profiles of

children with cerebellar tumours and observed an association between greater damage to

right cerebellar structures and a plateauing in verbal and/or literacy skills. In contrast,

greater damage to left cerebellar structures was associated with delayed or impaired

nonverbal/spatial skills. Long-term cognitive development of the children studied

tentatively supported a role for the cerebellum in learning/development. The authors

suggested that lateralized cerebellar damage may selectively impair the development of

cognitive functions subserved by the contra-lateral cerebral hemisphere. 107

From a study by Mottaghy et al., anatomical data suggested crossed reciprocal

connections between the cerebellum and higher order cortical association areas. In a

right-handed volunteer, the investigators found an activation of the left fronto-parietal

cortex and in the right cerebellar hemisphere; while in the left-handed volunteer the

activation was seen in the right fronto-parieto-temporal cortex and the left

cerebellar hemisphere. These initial results demonstrate that cerebellar activation is contra-

lateral to the activation of the frontal cortex even under conditions of different language

105 Rivara, J. B., Fay, G., Jaffe, K., Polissar, N., Shurtleff, H., & Martin, K. Predictors of family

functioning one year following traumatic brain injury in children. Archives of Physical

Medicine and Rehabilitation. 73, 899-910; 1992.

106 Schmahmann, JD & Sherman, JC. The cerebellar cognitive affective syndrome.Brain 121:561-

579; 1998.

107 Scott RB; Stoodley; CJ, Anslow P; Paul C; Stein JF; Sugden EM & Mitchell CD. Lateralized

cognitive deficits in children following cerebellar lesions. Developmental Medicine and

ChildNeurology. 43(10):685-691; 2001.


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dominance. They provide evidence for the hypothesis of a lateralized organization of the

cerebellum crossed to the cerebral hemispheres in supporting higher cognitive function. 108

These findings are entirely congruent with the findings of Chugani et al. indicating

impairment of dentato-thalamo-cortical pathways, primarily from the right dentate to left

cerebral hemisphere, in young autistic boys. 109

Baddeley’s original advance (Idem, 1986) was to move us from the concept of short-term

memory that accounted only for the storage of representations, to the concept of working

memory as a multi-component system that allows for both storage and processing of

temporarily active representations. Likewise, Logie 110 considered working memory as a

‘mental workspace’ that cannot only hold but is also able to manipulate activated

representations.

If working memory is defined as simultaneous storage and processing, then these tasks

would probably be considered to assess short-term memory rather than working memory.

Thus, it is probably fair to say that the concept of working memory as a non-unitary system

that allows for both storage and processing has gained popular acceptance. However,

less progress has been made regarding the neural mechanisms underlying the ‘processing’

component of working memory as compared with the ‘storage’ component 111 (although

see Petrides112)

Curtis et al , (2004, idem) also propose that any population of neurons within primary

or unimodal association cortex can exhibit persistent neuronal activity, which serves to

actively maintain the representations coded by those neuronal populations. Areas of

multimodal cortex, such as PFC and parietal cortex, which are in a position to integrate

representations through connectivity to unimodal association cortex, are also critically

involved in the active maintenance of task-relevant information (see also Burgess et al 113;

Stuss & Alexander. 114

Miller & Cohen 115 have proposed that in addition to the recent sensory information,

integrated representations of task contingencies and even abstract rules (e.g. if this

object — then this later response) are also maintained in the PFC. This is similar to what

Fuster 116 has long emphasized, namely that the PFC is critically responsible for temporal

integration and the mediation of events that are separated in time but contingent on one

108 Mottaghy FM; Shah NJ; Krause BJ; Schmidt D; Halsband U; Jancke L & Muller-Gartner HW.

Neuronal correlates of encoding and retrieval in episodic memory during a paired-word

association learning task: a functional magnetic resonance imaging study. Experimental

Brain Research 128:332-342; 1999

109 Chugani DC; Musik O; Rothermal R; Behen M; Chakraborty P; Mangner T; da Silva EA &

Chugoni HT. Altered serotonin synthesis in the dentat-othalamo-cortical pathway in autistic

boys. Annals of Neurology. 42:666-669; 1997

110 Logie, R. H. Visuo-spatial working memory. Hove, UK: Erlbaum; 1995.

111 D’Esposito, M. From Cognitive to neural models of working memory. In Driver, J; Haggard, P; &

Shallice, T. Mental Processes in the Human Brain. OUP, New York; 2007.

112 Petrides, M. Frontal lobes and working memory: evidence from investigations of the effects of

cortical excisions in nonhuman primates. In Handbook of Neuropsychology, vol. 9 (eds F.

Boller & J. Grafman), pp. 59-84. Amsterdam, The Netherlands: Elsevier Science B.Y; 1994.

113 Burgess, P. W, Gilbert, S. J. & Dumontheil, I. Function and localization within rostral prefrontal

cortex (area 10). Phil. Trans. R. Soc. 8 362,887-899; 2007.

114 Stuss, D. T. & Alexander, M. P. Is there a dysexecutive syndrome? Phil. Trans. R. Soc. B 362, 901-

915; 2007.

115 Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev.4,

Neurosci. 167-202; 2001.

116 Fuster, J. The prefrontal cortex: anatomy, physiology, and neuropsychology of the frontal

lobes. New York, NY: Raven Press; 1997.


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another. In this way, the PFC may exert ‘control’ in that the information it represents can

bias the posterior unimodal association cortex in order to keep neural representations of

behaviourally relevant sensory information activated when they are no longer present in

the external environment. 117, 118, 119, 120

In a real world example, when a person is looking at a crowd of people, the visual scene

presented to the retina may include a myriad of angles, shapes, people and objects.

However, if that person is a police officer looking for an armed robber escaping through the

crowd, some mechanism of suppressing irrelevant visual information while enhancing task-

relevant information is necessary for an efficient and effective search. Thus, neural activity

throughout the brain that is generated by input from the outside world may be differentially

enhanced or suppressed, presumably from top-down signals emanating from integrative

brain regions such as PFC, based on the context of the situation. So, in this formulation, the

processing component of working memory is that the control of actively maintained

representations within primary and unimodal association cortex stems from the

representational power of multimodal association cortex, such as the PFC, parietal cortex

and/or hippocampus.

If the PFC, for example, stores the rules and goals, then the activation of such PFC

representations will be necessary when behaviour must be guided by internal states

or intentions. As Miller & Cohen 121 elegantly state, putative top-down signals originating in

PFC may permit ‘the active maintenance of patterns of activity that represent goals and

the means to achieve them. They provide bias signals throughout much of the rest of the

brain, affecting visual processes and other sensory modalities, as well as systems responsible

for response execution, memory retrieval, emotional evaluation, etc. The aggregate effect

of these bias signals is to guide the flow of neural activity along pathways that establish the

proper mappings between inputs, internal states and outputs needed to perform a given

task’.

Computational models of this type of system have created a PFC module that consists of

‘rule’ units whose activation leads to the production of a response other than the one most

strongly associated with a given input. 122 Thus, this module is not responsible for carrying

out input/output mappings needed for performance. Rather it influences the activity of

other units whose responsibility is making the needed mappings’. 123 Thus, there is no need

to propose the existence of a homunculus (e.g. central executive) in the brain that can

perform a wide range of cognitive operations which are necessary for the task at hand.

The overall goal of cognitive neuroscience as a discipline is to determine the biological

basis of the mind. As an interdisciplinary discipline that has evolved from both

neuroscience and psychology, cognitive neuroscientists consume data derived from each

of these disciplines in their attempt to advance cognitive theory as well as determine how

117 Fuster, J. M. Cortical dynamics of memory. Int. J. Psychophysiol. 35, 155-164; 2000.

118 Ranganath, C., Cohen, M. X., Dam, C. & D'Esposito, M. Inferior temporal, prefrontal, and

hippocampal contributions to visual working memory maintenance and associative memory

retrieval. J. Neurosci. 24, 3917-3925; 2004.

119 Miller, B. T. & D'Esposito, M. Searching for "the top" in top-down control. Neuron 48,535-

538;2005.

120 Postle, B. R. Delay-period activity in the prefrontal cortex: one function is sensory gating.

J.Cogn. Neurosci. 17, 1679-1690; 2005.

121 Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev.

Neurosci. 4,167-202; 2001.

122 O'Reilly, R. C., Noelle, D. C., Braver, T. S. & Cohen, J. D. Prefrontal cortex and dynamic

categorization tasks: representational organization and neuro-modulatory control. Cereb.

Cortex 12, 246-257; 2002.

123 Cohen, J. D., Dunbar, K. & McClelland, J. L. On the control of automatic processes: a parallel

distributed processing account of the Stroop effect. Psychol. Rev. 97, 332-36; 1990.


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the brain implements cognitive function. Advances made in understanding the cognitive

and neural basis of working memory provide examples of this synergy. D’Esposito suggests

that future studies must continue to consider both cognitive and neural data. Research

thus far suggests that working memory can be viewed as neither a unitary nor a dedicated

system. A network of brain regions, including the PFC, is critical for the active maintenance

of internal representations that are necessary for goal-directed behaviour. Thus, working

memory is not localized to a single brain region but probably is an emergent property of the

functional interactions between the PFC and the rest of the brain.

The contribution of the lateral prefrontal cortex to working memory is still being explored.

However, considerable evidence suggests that the lateral prefrontal cortex is involved in

the executive or general-purpose aspects of working memory. For example, damage to

this region in humans interferes with working memory regardless of the kind of stimulus in-

formation involved. (Fuster, 1989, Idem) &124

Further, brain imaging studies in humans have shown that a variety of different kinds of

working memory tasks result in the activation of the lateral prefrontal cortex.125, 126, 127, 128 In

one study, for example, subjects were required to perform a verbal and a visual task either

one at a time or at the same time. 129 The results showed that the lateral prefrontal cortex

was activated when the two tasks were performed together, thus taxing the executive

functions of working memory, but not when the tasks were performed separately.

The lateral prefrontal cortex is ideally suited to perform these general purpose working

memory functions. It has connections with the various sensory systems (like the visual and

auditory systems) and other neocortical systems that perform specialized temporary

storage functions (like spatial and verbal storage) and is also connected with the

hippocampus and other cortical areas involved in long-term memory (Fuster, idem, 1989;

Goldman-Rakic, 1987, idem)&130,131. In addition, it has connections with areas of the cortex

involved in movement control, allowing decisions made by the executive to be turned into

voluntarily performed actions (Fuster, 1989, idem; Goldman-Rakic, 1978, idem). Recent

studies have begun to show how the lateral prefrontal cortex interacts with some of these

areas. However, the best-understood are the interactions with temporary storage buffers in

the visual cortex.

SUMMARY & CONCLUSIONS — In normal individuals there is not a conscious

understanding from moment to moment of how our brains are dealing with the constant

flow of information. We only know such things as a lack of comprehension and a failure of

124 Petrides, M. Frontal lobes and behaviour. Current Opinion in Neurobiology 4, 207-11; 1994.

125 Petrides, M; Alivsatos, B; Meyer, E; & Evans, AC. Functional activation of the human frontal

cortex during the performance of verbal working memory tasks. Proceedings of the National

Academy of Sciences USA 90, 878-82; 1993.

126 Jonides, J; Smith, EE; Keoppe, RA; Awh, E; Minosbima, S; & Mintun, M.A. Spatial working

memory in humans as revealed by PET. Nature 363, 623-25; 1993.

127 Grasby, PM; Firth, CD; Friston, KJ; Bench, C; Frackowiak, RSJ; & Dolan, RJ. Functional mapping

of brain areas implicated in auditory-verbal memory function. Brain 116, 1-20; 1993.

128 Swartz, BE; Halgren, E; Fuster, JM; Simpkins, E; Gee, M; & Mandelkern, M. Cortical metabolic

activation in humans during a visual memory task. Cerebral Cortex 5,205-14; 1995.

129 D'Esposito, M; Detre, J; Alsop, D; Shin, R; Atlas, S; & Grossman, M. The neural basis of the

central executive system of working memory. Nature 378,279-81; 1995.

130 Reep, R. Relationship between prefrontal and limbic cortex: A comparative anatomical

review. Brain, Behavior and Evolution 25, 5-80; 1984.

131 Uylings, HBM; & van Eden, CG. Qualitative and quantitative comparison of the prefrontal

cortex in rat and in primates, including humans. Progress in Brain Research 85, 31-62; 1990.


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memory; these events occur in what we consider to be a brain that is working normally. If

our brains do not work as well today as they did say a year ago, then we have the ability to

compare the two phases of our life. Those who have received early brain damage have to

cope with a disabled brain without any knowledge of what the situation would be if it

hadn’t been damaged.

Research thus far suggests that working memory can be viewed as neither a unitary nor a

dedicated system. A network of brain regions, including the PFC, is critical for the active

maintenance of internal representations that are necessary for goal-directed behaviour.

Thus, working memory is not localized to a single brain region but probably is an emergent

property of the functional interactions between the PFC and the rest of the brain.

It is important that this ongoing study of working memory includes work on the problems

that accrue from early brain injury and autism so that we can better understand the

difficulties of those affected in these respects. This, of necessity, needs there to be a better

acceptance that autism and autistic spectrum disorder are in effect brought about by

partially disabled brains. More importantly, that the disablement starts at an age that

precedes much neurological development. It is important for each individual so affected

that they are recognised primarily as a brain-injured person and that any possible aberrant

behaviour arises from the abnormal development of their brain. This needs to be given

appropriate consideration and steps are taken to give particular help and support to both

the child and to its parents.

Autism has been accepted for a long time now as a neurological condition and not a

psychiatric one. However, that is not always accepted and the common adjunct to that,

should it happen, is that psychotropic drugs are imposed and these can make the situation

much worse by dint of the affect that they will have on a brain and its already abnormal

pathways. Any psychotropic medication will most likely not have had any clinical trials on

patients with early brain damage and therefore they will be administered on a suck-it-and-

see basis. Just as important will be the fact that there can be little feedback from the

patient on their experiences of the medication and adverse effects are then more easily

misconstrued or discounted.

Cognition and Working Memory in Brain Injury and Autism

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