Revised 17 November 2013 Page 1 of 22 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 literature 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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Cognition and Working Memory in Brain Injury and Autism
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 in order that consideration can be given to the possibility that the condition may ar
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Revised 17 November 2013
Page 1 of 22
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
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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Page 3 of 22
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
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
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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
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89 Singer, W. & Gray, C. M. Visual feature integration and the temporal correlation hypothesis.
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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.
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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.
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independent of motor involvement. Science 1997;275:1940–1943.
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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.
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