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Alan Challoner MA (Phil) MChS

There has been little scientific research into the way in which the DPT whole-cell vaccine
brings about the damage to the brain. However, there has been some work done on this in
an effort to try and discover how it might be possible. 1,2

The nature of the brain damage so caused does not follow a pattern that is evident from
case to case due to the sporadic nature of the precipitating event, the age of onset and the
varying characteristics of individual brains. This causes a great deal of difficulty for those who
are called upon to care for affected individuals and often it is found that their brain damage
is ignored because it is too complicated for people to understand; even by the professionals.
Currently there are no FDA approved pharmacotherapies for the treatment of traumatic
brain injury and it must be recognized that almost all forms of treatment for TBI are geared
towards the minimization of secondary injury, as it is assumed that primary injury is irreversible.
3 ,4

Plantier et al confirm this objective approach. They found that following a meta-analysis of
cases, there is insufficient evidence to standardize drug treatments for these disorders. They
add that there is no evidence of efficacy for neuroleptics. Their comment is that prescription
should only be based on emergency situations for a crisis (loxapine) but not for long-term use
for which there is expert consensus. 5

In traumatic brain injury the brain may be injured in a specific location or the injury may be
diffused to many different parts of the brain. It is this indefinite nature of brain injury that
makes treatment unique for each individual patient. In the past twenty years, a great deal
has been learned about brain function, and we learn more every day. We can make
guesses about the nature of the problems an individual may have from knowing the location
of a lesion. Diagnostic procedures such as CT scans and MRI's can also provide information
about a brain injury. Rehabilitation specialists can also learn about an injury by observing the
day to day activities of the patient.

Following very early acquired brain injury, it is much more tempting and less intellectually
challenging to believe that the person just lacks intelligence and therefore giving credence
to a view that they should be included in the Learning Disability Service provision. 6 This
egregious error has serious consequences for those who are truly brain damaged. Dealing
with the brain damaged individual, calls up much more serious scientific knowledge and 1
understanding of neuropsychology. By subverting assessments into a lower classification of

1 Challoner, A.
2 Challoner, A.
3 Kulbe, J R; Hill, R L; Singh, I N; Wang, J & Hall, ED. Synaptic mitochondria sustain more
damage than non-synaptic mitochondria following traumatic brain injury and are protected
by cyclosporine A. Journal of Neurotrauma. September 2016; doi:10.1089/neu.2016.4628
4 Janich, K; Ha S N; Patel, M; Saman Shabani, S; Montoure, A & Ninh Doan, N. Management of
Adult Traumatic Brain Injury: A Review. Trauma Treat 2016, 5:3. DOI: 10.4172/2167-1222.1000320
5 Plantier, D. & Luaut J. Drugs for behavior disorders after traumatic brain injury. Ann Phys
Rehabil Med. 2016 Feb;59(1):42-57. doi: 10.1016/
6 Cornwell, KL. People registered disabled with learning difficulties tend to fall through the net.
BMJ. 2004 Oct 16; 329(7471): 917. doi: 10.1136/bmj.329.7471.917-a PMCID: PMC523160

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need there is a pseudo-legitimate encouragement for the use of lesser skills in both
assessment and quality of care. Neurologic diseases can have a major impact on functional
capacity and they require individual management considerations depending upon the
extent of impairment. This relates to the ASD as well as traumatic neurologic disease. 7
Especial attention also needs to be given to dental care as examinations can be difficult for
various reasons. 8

Intellectual disability has traditionally been an exclusion criterion in research studies. At one
time, clinical lore believed that children with intellectual disability did not have behavioural
problems and that any inappropriate behaviour displayed was secondary to their mental
handicap. Research in children with intellectual disabilities is hindered as most studies do not
use standardised diagnostic interviews or criteria, and they are excluded from virtually all
treatment studies. This has ethical implications as little is known about diagnosis in and
treatment of these children, and they are often undiagnosed and untreated. This is now
being remedied and the work of Harding, Emerson & Baine is welcomed. 9

In the case of injury from DPT whole cell vaccination, it was a long established belief in
medical circles that this didnt happen and even today there is still some residual doubt that
does not help to establish a considerate care plan. However, the potential dangers of the
DPT vaccination in that form were brought to the attention of readers of the BMJ in 1958
when it was suggested that any infant who responds badly to the first incidence of
vaccination by DPT should not have any further doses in the series. 10 Further inequalities
need to be prevented, and attempts are required to promote high quality research into this
disadvantaged group. 11

Contemporary research indicates that juvenile traumatic brain injury evolves into a chronic
brain disorder and this process starts almost immediately after the injury. Atraumatic brain
injury (aTBI) refers to physical trauma to the brain that arises from non-physical means such as
toxins passing the blood/brain barrier and these lead to cognitive and other dysfunctions.
ATBI is particularly serious in infants and young children, often leading to long-term functional
impairments. Although clinical research is useful for quantifying and observing the effects of
these injuries, few studies have empirically assessed the long-term effects of juvenile TBI (jTBI)
on behaviour and histology. 12

Age of onset is a very important aspect of outcome. Until fairly recently, the impact of early
brain insult [EBI] has been considered to be less significant than for later brain injuries,
consistent with the notion that the young brain is more flexible and able to reorganize in the
context of brain insult. However, Anderson et al have reviewed childhood head trauma

through a range of ages from pre-natal to after age ten years. This study aimed to evaluate
7 Patil, A; Tamgond, S; Sandhyarani B; Shigli, A; Sharmila Patil, S & Bharati, SG. An Update on
Dental Outlook for Autism. Autism Open Access 2016, 6:3;
8 Robbins, MR. Neurologic Diseases in Special Care Patients. Dental Clinics of North America;
Vol. 60, Issue 3, July 2016; pp707-735
9 Harding, C. Health care and risk of early death for people with learning disabilities.
Developmental Medicine & Child Neurology, 2017. doi: 10.1111/dmcn.13376.
10 Berg JM. Neurological complications of pertussis immunization. British Medical Journal 2:24-27;
11 Ahuja, AS. Emotional needs of children with intellectual disabilities are unidentified. BMJ. 2004
Oct 16; 329(7471): 917. doi: 10.1136/bmj.329.7471.917 PMCID: PMC523128
12 Kamper JE, Pop V, Fukuda AM, Ajao DO, Hartman RE, Badaut J. Juvenile traumatic brain injury
evolves into a chronic brain disorder: Behavioral and histological changes over 6 months. Exp
Neurol. 2013 Dec;250:8-19. doi: 10.1016/j.expneurol.2013.09.016.

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this notion by comparing cognitive and behavioural outcomes for children sustaining EBI at
different times from gestation to late childhood. 13

Magnetic resonance imaging and histological data reveals that the effects of jTBI are
evolving for up to 6 months post-injury, with reduced cortical thickness, decreased corpus
callosum area and CA1 neuronal cell death in jTBI animals distant to the impact site. These
findings suggest that this model of jTBI produces long-term impairments comparable to those
reported clinically. Although some deficits are stable over time, the variable nature of other
deficits (e.g., memory) suggest that the effects of a single jTBI produce a chronic brain
disorder with long-term complications. (Kamper et al ibid, 2013)

Groups were similar with respect to injury and demographic factors. Children were assessed
for intelligence, academic ability, everyday executive function (see below) and behaviour.
Results showed that children with EBI were at increased risk for impairment in all domains
assessed. Furthermore, children sustaining EBI before age 2 years recorded global and
significant cognitive deficits, while children with later EBI performed closer to normal
expectations, suggesting a linear association between age at insult and outcome. In
contrast, for behaviour, children with EBI from 7 to 9 years performed worse than those with
EBI from 3 to 6 years, and more like those with younger insults, suggesting that not all
functions share the same pattern of vulnerability with respect to age at insult.

In infantile encephalitis that is caused by vaccine damage the brain is affected sporadically
and it is likely that every child so affected will have a different pattern of damage. The frontal
lobes of the brain are reported to be from 25% to 40% of the volume of the whole brain. It is
possible then that the damage may affect these areas in many if not most of those cases.
There is little if any evidence that the hindbrain 14 (old brain) is damaged and this is probably
confirmed when it is seen that what are considered to be hard wired elements of human
brain neurology continue to be available to those who have vaccine-damaged brains.

As the two frontal lobes offer differing aspects of brain functioning it is important to discover
what the outcomes might be for those infants who have encephalitic damage to one or the
other. In a broad examination of the outcome of the effects of damage to the left or right
frontal lobes, there is evidence that damage that is concentrated in the left lobe might lead
to symptoms similar to ADHD and damage to the right lobe might lead to symptoms of ASD.
Another issue that needs to be considered is how the administration of antipsychotic
medications can adversely affect brain functioning and indeed cause further damage. (See
also page 35)

Fortunately there is extensive evidence of the very different functions of the two hemispheres,
predominantly from observing people with brain injuries such as strokes. In The Master and His
Emissary, neurologist Iain McGilchrist, ventures into this contentious area to draw on
contemporary research, to reveal that the profound difference between the right and left

13 Anderson, A.; Spencer-Smith, M.; Rick Leventer R.; Lee Coleman, L.; Anderson, P.; Williams, J.;
Greenham, M. & Rani Jacobs, R. Childhood brain insult: can age at insult help us predict
outcome? Brain (2009) 132 (1): 45-56.
14 The hindbrain is the region of the brain formed by the pons, medulla oblongata (also known as
just the medulla), and the cerebellum. Together, these three structures govern our autonomic,
or 'automated' body systems, controlling everything from our heart, breathing, and sleep
patterns to our bladder function, sense of equilibrium, and fine motor control. The hindbrain
controls all the things that you want to automatically work without having to think about them.

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brain are not only in specific functions, but in their incompatible ways of experiencing the
world. 15

McGilchrists outline of the functions of the two halves of the frontal lobes

The left hemisphere is detail-oriented, prefers mechanisms to living things, and is inclined to
self-interest, while the right hemisphere has greater breadth, flexibility and generosity. The left
brain, the emissary, focuses on specific details of the experience and analyses it and returns
this detailed picture to the right half, so that in the right brain the details become integrated
to enrich the wider picture. The left brain uses language precisely, more abstractly, the right
brain understands meaning, metaphors and jokes. The left half organizes, manipulates and
controls details for a specific purpose, the right brain is responsible for empathy; relationships;
and appreciating the meaning of gestures, facial expressions and tone of voice. The right
half handles the greater part of our emotional life. The left wants consistency, it measures,
classifies and creates labels and works in abstractions; it will happily disregard inconsistent
facts or information! 16

The right half experiences time as a continuum, it responds to music, poetry, the spiritual and
moral dimensions.

Neurological bias for right-brained = ADHD (Footnote 16)

There really has been little to no research on the actual experience of being ADHD, its so
frustrating! Where are the large qualitative and quantitative studies asking ADHD adults
about their thinking, decision making, desires, values and perspectives? There are so many
writers, presenters, coaches and doctors saying so, there are websites, blogs, books, articles
that discuss these right-brained traits as being central to ADHD. It is such a shame that there is
so little funding for research available outside the ADHD is nothing more than a disability
box that is.


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There are neurological grounds for this ADHD right-brained emphasis too. Though never
mentioning ADHD, Ian McGilchrist explains that the right-brain is more neurologically tightly
connected than the left, signals travel shorter distances with less chance of signal decay.
More importantly the right brain uses nor-adrenaline, (nor-epinephrine) rather than
dopamine for communications. Research shows dopamine as the faulty neurotransmitter
at issue in ADHD, so logically you might expect the left brain to be affected, not the right?

In ADHD, with a less-dominant left brain, there is a struggle to focus on detail, lessened self-
interest, a reduced desire to organise and control but with a dominant right-brain in ADHD,
there is a greater sense of emotion, breadth, flexibility and generosity, an experience of time
as a continuum, a strong response to music, poetry and the moral dimensions.

MDL is damaged in her right brain and there is clear evidence from observations that confirm
the above and following explanations.

The Common Features of Brain Damage caused by Vaccination-induced Encephalitis

There are three elements of brain function that are commonly found to be adversely
affected following encephalitis brought about by vaccinations.

1. A failure of Executive Function


EF refers to the distinct, but related cognitive abilities which depend primarily on a network or
system comprised by the prefrontal area and its major connections.

The frontal lobe is the largest lobe in the brain, yet often it is not specifically evaluated in
routine neurologic examinations. This may in part be due to the attention to detail and to
the rigorous testing strategies that are required to probe frontal lobe functions. As successful
completion of any cognitive task considered a frontal lobe function requires multiple brain
regions both within and outside the frontal lobe. Dysfunctions of the frontal lobe can give rise
to relatively specific clinical syndromes. When a patient's history suggests frontal lobe
dysfunction, detailed neurobehavioral evaluation is necessary.

There are left and right frontal lobes and although they have multiple connections with other
brain areas. Left and right frontal lobes are differentiated. Left frontal lobe is more
specialized for language-related functions. Right frontal region is dominant in social
cognition and emotions.

Executive functions are controlled by the frontal lobes of the brain. The frontal lobes are
connected with many other brain areas and co-ordinate the activities of these other regions.
They can be thought of as the conductor of the brain's orchestra. Injury to the frontal lobes is
the most common cause of executive dysfunction. Occasionally, damage to other brain
areas which are connected to the frontal lobes can also impair executive functions.

Executive dysfunction is a term for the range of cognitive, emotional and behavioural

difficulties which often occur after injury to the frontal lobes of the brain. Impairment of

17 Miller, BL & Cummings, JL. The Human Frontal Lobes: Functions and Disorders. Guilford Press,

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executive functions is common after acquired brain injury and has a profound effect on
many aspects of everyday life.

Executive functioning is an umbrella term for many abilities including:

Planning and organization

Flexible thinking

Monitoring performance


Solving unusual problems


Learning rules

Social behaviour

Making decisions


Initiating appropriate behaviour

Inhibiting inappropriate behaviour

Controlling emotions

Concentrating and taking in information

The frontal lobes cover a large part of the front of the brain, directly behind the forehead.

The diagram below shows their location:


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The frontal lobes can be damaged by any form of acquired brain injury, such as stroke,
tumour, encephalitis and meningitis. The importance of executive functions is shown by the
difficulties caused when they don't work properly. Since the executive functions are involved
in even the most routine activities, frontal lobe injuries can lead to deficits in cognitive
(thinking) skills, personality and social behaviour.

The most common effects of executive dysfunction are summarized below:

Difficulties with initiating, organizing and carrying out activities

Loss of 'get up and go'.

Problems with thinking ahead and carrying out the sequence of steps needed to
complete a task.

This can often be mistaken for 'laziness' or a lack of motivation and energy.

Rigidity in thoughts and actions

Difficulty in evaluating the result of actions and reduced ability to change behaviour
or switch between tasks if needed.

Poor problem solving

Finding it hard to anticipate consequences.

Decreased ability to make accurate judgements or find solutions if things are going


Acting too quickly and impulsively without fully thinking through the consequences.

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Mood disturbances

Difficulty in controlling emotions which may lead to outbursts of emotion such as

anger or crying.

Rapid mood changes may occur. For example, switching from happiness to sadness
for no apparent reason.

Difficulties in social situations

Reduced ability to engage in social interactions.

Finding it hard to initiate, participate in, or pay attention to conversations.

Poor judgement in social situations, which may lead to saying or doing inappropriate

Difficulties with memory and attention

Finding it harder to concentrate.

Difficulty with learning new information.

Decreased memory for past or current events, which may lead to disorientation.

There may be different names offered for these symptoms. They are commonly referred to as
executive dysfunction but many people use the term 'dysexecutive syndrome' or simply
'frontal lobe problems'. They are sometimes referred to as a syndrome because several of the
symptoms usually occur together.

It is important to remember that not everyone with executive dysfunction experiences all of
these problems. The symptoms can range from subtle effects, which only close friends and
family members may notice, to extreme and problematic behaviour.

It is often hard for people with frontal lobe injuries to explain the difficulties they are
experiencing, often because they may be unaware that their behaviour is inappropriate.
Their behaviour may appear to be very anti-social and can be misunderstood as depression,
lack of motivation, selfishness, or aggression. Relationships with others may be negatively
affected as a result. (See Theory of Mind below)

Executive functioning problems may also have a significant emotional impact and can lead
to feelings of frustration, exhaustion, embarrassment and isolation. It is important to be aware
of the fact that these behaviours occur as a result of brain injury and are not intentional.
Specialized input from rehabilitation specialists, such as neuropsychologists and
occupational therapists, can help to compensate for the problems.

The following sections provide an overview of assessment and rehabilitation, before

providing some practical coping strategies.

Assessing executive dysfunction


The initial assessment of executive functioning after brain injury will usually be carried out by a

clinical neuropsychologist. The assessment provides detailed information about an

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individual's cognitive, emotional and behavioural deficits. The results can then assist in
planning rehabilitation strategies to manage the problems.

During an assessment, the neuropsychologist will consider the following questions:

What are the main problems for the individual and their family?

How do the problems affect functioning in everyday life?

To what extent are the executive deficits related to other problems in areas such as
language, memory and perception?

How do the person's abilities compare with others of the same age, background,
gender and with injury to a similar area of the brain?

How are the person with brain injury and their family coping?

What kind of rehabilitation should be offered?

Neuropsychological assessments involve a range of different standardised tests, which are

designed to measure different aspects of cognitive functioning. Some of these tests are in a
questionnaire, puzzle or game format, while others take place in a real-world environment. It
is very important that the tests are completed without prior knowledge or preparation in
order for them to accurately reflect an individual's abilities. For that reason, no details of
specific tests are included here.

It is important to remember that there are no passes or failures in the assessments. They simply
provide an indication of areas that need help and rehabilitation, so there is no need for
people to worry about their performance but simply to complete the tasks as best they can.

Cognitive effects of brain injury

The cognitive effects of a brain injury affect the way a person thinks, learns and remembers.
Different mental abilities are located in different parts of the brain, so a brain injury can
damage some, but not necessarily all, skills such as speed of thought, memory,
understanding, concentration, solving problems and using language.

Executive function is a set of mental skills that help you get things done. These skills are
controlled by an area of the brain called the frontal lobe.

Executive function helps you:

Manage time

Pay attention

Switch focus

Plan and organize

Remember details

Avoid saying or doing the wrong thing


Do things based on your experience

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When executive function isnt working as it should, your behaviour is less controlled. This
can affect your ability to:

Work or go to school

Do things independently

Maintain relationships

Types of Executive Function

Executive function can be divided into two groups:

Organization: Gathering information and structuring it for evaluation

Regulation: Taking stock of your surroundings and changing behaviour in response to


For example, seeing a piece of chocolate cake on a dessert cart at a restaurant may be
tempting. That's where executive function can step in. The organizational part reminds you
that the slice is likely to have hundreds of calories. Regulation tells you that eating the cake
conflicts with goals you may have, like eating less sugar or losing weight.

Problems with Executive Function

Some people are born with weak executive function. And people with ADHD, depression, or
learning disabilities often have weaknesses in it.

An injury to the front of the brain, where the frontal lobe is, can harm your ability to stay on

Children and Executive Function

Problems with executive function can run in families. You may notice them when your child
starts going to school. They can hurt the ability to start and finish schoolwork.

Warning signs that a child may be having problems with executive function include
trouble in:

Planning projects

Estimating how much time a project will take to complete

Telling stories (verbally or in writing)


Starting activities or tasks


There's no single test to identify problems with these neurological conditions. Instead, experts

rely on different tests to measure specific skills.


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Problems seen on these tests can't predict how well adults or children will do in real life.
Sometimes, watching them and trying different things are better ways to improve weak
executive function.

Treating problems with executive function early can help children outgrow it. The brain
continues to develop well into adulthood, and experiences can shape executive function as
the brain grows.

(For another in-depth analysis of EF see:


We need to borrow information Alzheimer's disease neurology and other similar conditions in
order that we can examine the outcome of atraumatic brain injury to areas that are
affected in these neurological conditions.

Frontotemporal dementia (FTD) results in tissue loss in the frontal, anterior, medial and inferior
temporal lobes including the amygdala and hippocampus; also in the insula and variably in
subcortical structures such as the caudate, putamen, thalamus and substantia nigra. Of
these regions, the frontal and anterior temporal lobes usually show the largest volume losses.

FTD is not a specific disease. It is the clinical presentation of frontotemporal lobar

degeneration, which is characterized by progressive neuronal loss predominantly involving
the frontal and/or temporal lobes, and typical loss of over 70% of spindle neurons, while other
neuron types remain intact. People with this condition may not be able to think well enough
to do normal activities, such as getting dressed or eating. They may lose their ability to solve
problems or control their emotions. Their personalities may change. They may become
agitated or see things that are not there. It should be considered that some of these
symptoms will eventually show as a result of infantile encephalitis but their brains have not
had time to develop normally and so the difference between that type of brain damage
and FTD is essentially the state of development when the condition begins to affect the


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 18,19 provided the
first detailed account of the role of working memory in prefrontal processes. He describes

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-like executive accounts of prefrontal function20, he

18 Fuster JM. The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal
Lobe. New York: Raven Press, 1980.
19 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.
20 Supervisory attentional system (SAS) 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

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writes: 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

Supervisory Attentional System According to Shallice 21,22,23 the frontal lobes

instantiate a supervisory attentional system (SAS). Although this system is not needed for
routine action, which is controlled by learned associations between stimuli in the
environment and possible action, it serves to override these associations when stimuli or goals
are novel. Thus, frontal damaged patients, in whom the SAS is damaged, are no longer able
to exert goal-directed control over their actions but simply respond to stimuli.

Mild traumatic brain injury (MTBI) is often associated with selective impairment of both
working memory and the executive functions. Research indicates that one of the
commonest deficits present in MTBI patients falls in the domain of working memory. Kumar et
al suggest that MTBI may lead to working memory deficits as the contribution of executive
processes to support the working memory is diminished following MTBI.24

Goldman-Rakic25 has proposed a working-memory account of frontal lobe function on the

basis of extensive research with non-human primates. Building on the well-established rela-
tionship between the prefrontal cortex and delayed-response tasks, she argues that the pre-
frontal cortex is responsible for maintaining information (representational memory) that is
later used to guide action. Funahashi and colleagues 26,27 have 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.

21 Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B 298:199-209, 1982.
22 Shallice T. From Neuropsychology to Mental Structure. Cambridge, England: Cambridge
University Press, 1988.
23 Shallice T. & Burgess P. Higher-order cognitive impairments and frontal lobe lesions in man, in
Levin HS, Eisenberg HM, Benton AL (eds): Frontal Lobe Function and Dysfunction. New York:
Oxford University Press, 1991.
24 Kumar S, Rao SL, Chandramouli BA, Pillai S. Reduced contribution of executive functions in
impaired working memory performance in mild traumatic brain injury patients. Clin Neurol
Neurosurg. 2013 Jan 29.
25 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.
26 Funahashi S; Bruce CJ & Goldman-Rakic PS. Mnemonic coding of visual space in the monkey's
dorsolateral prefrontal cortex. J Neurophysiol 61:331349,1989.
27 Funahashi S; Bruce CJ & Goldman-Rakic PS. Dorsolateral prefrontal lesions and oculomotor
delayedresponse performance: Evidence for mnemonic scotomas. J Neurosci 13:1479-1497,

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Neuro-imaging studies in humans28,29,30,31 suggest that similar working-memory processes are
located pre-frontally in the human brain. Goldman-Rakic (1987, idem) has suggested 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 impair-
ment could underlie the range of cognitive changes seen after prefrontal damage first found
direct support in the work of Cohen and Servan-Schreiber32.

Working-memory accounts of prefrontal function are favoured for a number of reasons 33:

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 (Cohen, 1992 idem) & 34.

Third, they are supported by a wealth of evidence from monkey neurophysiology and, in-
creasingly, from neuro-imaging studies in humans. For instance, Fougnie and Marois have
found that the hallmark of both visual attention and working memory is their severe capacity
limit. People can attentively track only about four objects in a multiple object tracking (MOT)
task and can hold only up to four objects in visual working memory (VWM). It has been
proposed that attention underlies the capacity limit of VWM.

They tested this hypothesis by determining the effect of varying the load of a MOT task
performed during the retention interval of a VWM task and comparing the resulting dual-task
costs with those observed when a VWM task was performed concurrently with another VWM
task or with a verbal working memory task. Instead of supporting the view that the capacity
limit of VWM is solely attention based, the results indicated that VWM capacity is set by the
interaction of visuospatial attentional, central amodal, and local task-specific sources of

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

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

28 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.
29 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.
30 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.
31 Jonides J; Smith E & Koeppe R, et al. Spatial working memory in humans as revealed by PET.
Nature 363:623-625, 1993.
32 Cohen JD & Servan-Schreiber D. Context, cortex, and dopamine: A connectionist approach to
behavior and biology in schizophrenia. Psychol Rev 99:4577,1992.
33 Kimberg, DY; DEsposito, 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.
34 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.
35 Fougnie, D. & Marois, R. Distinct Capacity Limits for Attention and Working Memory.
Psychological Science. 6; V17; 2006 pp 526-534.

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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, their
dependence on working memory. 36

Buffers A critical component of Baddeleys working memory model is the existence of

verbal mid-spatial storage buffers37. 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 computers 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 memories that are also activated.

36 Kimberg, DY; DEsposito, 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.
37 Baddeley, A. Working memory. New York, NY: Oxford University Press; 1986.

Page 14 of 36
For example, in a review of working memory, Repovs & Baddeley 38 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. 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, put forward by Cowan 39,40 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 hier-
archically 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 Anderson41 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 representations42 .

Again, in neural terms, Cowans or Andersons cognitive model of working memory would
predict that information that is represented throughout the brain is not transferred to an inde-
pendent 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,
see Ruchkin, et al 43. 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

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

experimental cognitive psychology. Neuroscience 139, 5-2; 2006.
39 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.
40 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.
41 Anderson, J. R. The architecture of cognition. Cambridge, MA: Harvard University Press; 1983.
42 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.
43 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.

Page 15 of 36
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? Also, 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 episode44 . However, even with the addition of this
buffer, Baddeleys 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 Cowans 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.

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 re-
quire not only some form of temporary storage, but also interplay between information that is
stored temporarily and a larger body of stored knowledge45.

How, then, does working memory work in the brain? Studies conducted in the 1930s by C.F.
Jacobsen provide the foundation for our understanding of this problem 46. 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 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.

44 Baddeley, A. The episodic buffer: a new component of working memory? Trends Cogn. Sci. 4,
417423; 2000
45 Kosslyn, SM., and Koenig, O. Wet mind: The new cognitive neuroscience; New York: Macmillan;
46 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.

Page 16 of 36
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 primates47. It is not
surprising that one of the most sophisticated cognitive functions of the brain should involve
this region.

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 Yale.48,49,50,51 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.

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. (See Curtis &
DEsposito52) 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 activity53. Thus, the existence of persistent neural activity during blank
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 54,55 .

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

47 Preuss, TM. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered.
Journal of Cognitive Neuroscience 7, 1-24; 1995.
48 Fuster, JM. The prefrontal cortex. New York: Raven; 1989).
49 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.
50 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.
51 Wilson, FAW; Scalaidhe, SP; & Goldman-Rakic, PS. Dissociation of object and spatial processing
domains in primate prefrontal cortex. Science 260, 1955-58; 1993.
52 Curtis, C. E. & D'Esposito, M. Persistent activity in the prefrontal cortex during working memory.
Trends. Cogn. Sci. 7,415423; 2003.
53 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.
54 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.
55 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.

Page 17 of 36
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 56 .

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 study57 , 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.

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 58,59,60.
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. 18

56 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.
57 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.
58 Miyashita, Y. & Chang, H. S. Neuronal correlate of pictorial short-term memory in the primate
temporal cortex. Nature 331,68-70; 1988.
59 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.
60 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.

Page 18 of 36
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 memory61 ). 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 (Brocas area), premotor cortex and the cerebellum are
typically activated62,63 .

However, is this network of brain regions also responsible for the active maintenance of non-
phonological language representations (e.g. lexical-semantic)? 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. 64

Intracranial electrophysiological recordings, for example, (Nobre et al 65 ) 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 66 and Patterson 67).

To demonstrate that there is distinct neural circuitry supporting the active maintenance of
non-phonological language representations, DEsposito 68 explored the role of language
regions within the left infero-tempora1 cortex (ITC) that are involved in visual word
recognition and word-related semantics. Using fMRI, 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. 69 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.

61 Vallar, G. & Shallice, T. Neuropsychological impairments of short-term memory. Cambridge, UK:
Cambridge University Press; 1990.
62 Paulesu, E., Frith, C. D. & Frackowiak, R. S. The neural correlates of the verbal component of
working memory. Nature 362,342-345; 1993
63 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.
64 Cohen, L. & Dehaene, S. Specialization within the ventral stream: the case for the visual word
form area. Neuroimage 22,466476; 2004.
65 Nobre, A. C., Allison, T. & McCarthy, G. Word recognition in the human inferior temporal lobe.
Nature 372, 260-263; 1994.
66 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.
67 Patterson, K. The reign of typicality in semantic memory. Phil. Trans. R. Soc. B 362, 813-821; 2007.
68 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
69 Fiebach, C. J., Rissman, J. & D'Esposito, M. Modulation of infero-temporal cortex activation dur-
ing verbal working memory maintenance. Neuron 51, 251-261; 2006.

Page 19 of 36
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 70,
visual 71,72 and auditory cortex.73,74 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.

Baddeleys 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 tempo-
rarily active representations. Likewise, Logie 75 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 76 (although see Petrides77).

DEsposito also proposes (Idem) 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 78 ; Stuss & Alexander79.

70 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;
71 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.
72 Singer, W. & Gray, C. M. Visual feature integration and the temporal correlation hypothesis.
Annu. Rev. Neurosci. 18,555-586; 1995.
73 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.
74 Kraemer, D. J., Macrae, C. N., Green, A. E. & Kelley, W M. Musical imagery: sound of silence
activates auditory cortex. Nature 434,158.; 2005.
75 Logie, R. H. Visuo-spatial working memory. Hove, UK: Erlbaum; 1995.
76 DEsposito, 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
77 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.
78 Burgess, P. W, Gilbert, S. J. & Dumontheil, I. Function and localization within rostral prefrontal
cortex (area 10). Phil. Trans. R. Soc. B 362,887-899; 2007.
79 Stuss, D. T. & Alexander, M. P. Is there a dysexecutive syndrome? Phil. Trans. R. Soc. B 362, 901-
915; 2007.

Page 20 of 36
Miller & Cohen 80 have proposed that in addition to their theory about 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 Fuster81 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 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 envi-

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. Thus, 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 & Cohen86 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

Computational models of this type of system have created a PFC module (e.g. OReilly et

al87.) that consists of rule units whose activation leads to the production of a response other

80 Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev.
Neurosci. 4, 167-202; 2001.
81 Fuster, J. The prefrontal cortex: anatomy, physiology, and neuropsychology of the frontal lobes.
New York, NY: Raven Press; 1997.
82 Fuster, J. M. Cortical dynamics of memory. Int. J. Psychophysiol. 35, 155-164; 2000.
83 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.
84 Miller, B. T. & D'Esposito, M. Searching for "the top" in top-down control. Neuron 48, 535-538;
85 Postle, B. R. Delay-period activity in the prefrontal cortex: one function is sensory gating. J.
Cogn. Neurosci. 17, 1679-1690; 2005.
86 Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev.
Neurosci. 4, 167-202; 2001.
87 O'Reilly, R. C., Noelle, D. C., Braver, T. S. & Cohen, J. D. Prefrontal cortex and dynamic categori-
zation tasks: representational organization and neuro-modulatory control. Cereb. Cortex 12,
246-257; 2002.

Page 21 of 36
than the one most strongly associated with a given input. Thus, this module is not responsible
for carrying out input-output mappings needed for performance. Rather, this module
influences the activity of other units whose responsibility is making the needed mappings
(e.g. Cohen et al88 ). 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.

DEsposito has 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 information89 . 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 move-
ment control networks). Thus, it may not be surprising that enhancement and suppression
mechanisms may exist to control cognition.90,91 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 DEsposito has described, this hypothesis largely originates from suggestive
findings rather than direct empirical evidence. However, a few studies lend direct causal
support to this hypothesis (see also Vuilleumier & Driver92 ).
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

88 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.
89 Gazzaley, A., Cooney, J. 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, 1-11.
90 Knight, R. T., Staines, W R., Swick, D. & Chao, L. L. Prefrontal cortex regulates inhibition and
excitation in distributed neural networks. Acta. Psychol. (Amst) 101, 159-178; 1999.
91 Shimamura, A. P. The role of the prefrontal cortex in dynamic filtering. Psychobiology 28, 207-
218; 2000.
92 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.

Page 22 of 36
hippocampus has been proposed to be specialized for rapid learning of arbitrary
information which can be recalled in the service of controlled processing. Moreover, input
from brainstem neuro-modulatory systems probably plays a critical role in modulating goal-
directed behaviour. For example, the dopaminergic system probably plays a critical role in
cognitive control processes. (DEsposito, idem 2007 & Stuss DT, idem 2007)

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) & 93.

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. 94,95,96,97 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 time98. 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)&99,100. 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, idem, 1989; Goldman-Rakic, 1978, idem). Several studies have shown 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.

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 complex101, the neural pathways responsible for two

93 Petrides, M. Frontal lobes and behaviour. Current Opinion in Neurobiology 4, 207-11; 1994.
94 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.
95 Jonides, J; Smith, EE; Keoppe, RA; Awh, E; Minosbima, S; & Mintun, M.A. Spatial working
memory humans as revealed by PET. Nature 363, 623-25; 1993.
96 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.
97 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.
98 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.
99 Reep, R. Relationship between prefrontal and limbic cortex: A comparative anatomical
review. Brain, Behavior and Evolution 25, 5-80; 1984.
100 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.
101 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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aspects of visual processing are fairly well understood. These involve the determination of
what a stimulus is and where it is located.102,103 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.

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)

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 between 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 recently104.
The maintenance of visual information in working memory thus appears to crucially depend
on interactions between the lateral prefrontal region and specialized areas of the visual

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 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)

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.

Studies, especially by Goldman-Rakic and associates, have raised questions about the role
of the prefrontal cortex as a general purpose working memory processor. (Wilson et al, 1993;
Idem) 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

102 Ungerleider, LG; & Mishkin, M. Two cortical visual systems. In Analysis of visual behavior, D. J.
Ingle, M. A. Goodale, and R. W. Mansfield, eds. Cambridge: MIT Press, pp. 549-86; 1982.
103 Ungerleider, LG; & Haxby, J. What and where in the human brain. Current Opinion in
Neurobiology 4, 157-65; 1994.
104 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.

Page 24 of 36
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 did not
tax the capacity of working memory in a way that would reveal a limited capacity system.

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. (Petrides, 1994, 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. (DEsposito, et al, 1995, Idem) &105,106

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


105 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.
106 Posner, M; & Petersen, S. The attention system of the human brain. Annual Review of
Neuroscience 13, 25-42; 1990.

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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) &107. 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 control108. 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 109, and cells in this region are sensitive to whether a stimulus has just led to a
reward or punishment 110,111,112. Humans with orbital frontal damage become oblivious to
social and emotional cues and some exhibit sociopathic behaviour. 113 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
related in working memory to information being processed in sensory or other regions of the
There is still much to be learned about working memory and its neural basis. It is not clear, for
example, whether both the temporary workspace and the executive functions are actually
located in the frontal cortex. It is possible that the prefrontal areas do not store anything but
instead just control the activity of other regions, allowing the activity in some areas to rise
above the threshold for consciousness and inhibiting the activity of the others. In spite of the
fact that we still have much to learn, the researchers in this area have made considerable
progress on this very tough, and very important, problem. (LeDoux, Idem, 1998

This very complicated span of neural activity is carried out in our brains without us having to
think about it consciously. However, with subjects like MDL, 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 her brain damage and

not by lack of intellect.

107 Goldman-Rakic, PS. Topography of cognition: Parallel distributed networks in primate
association cortex. Annual Review of Neuroscience 11, 137-56; 1988.
108 Posner, M. Attention as a cognitive and neural system. Current Directions in Psychological
Science 1, 11-14; 1992.
109 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.
110 Thorpe, SJ; Rolls, ET; & Maddison, S. The orbitofrontal cortex: Neuronal activity in the behaving
monkey. Experimental Brain Research 49, 93-115; 1983.
111 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.
112 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.
113 Damasio, A. Descartes error: Emotion, reason, and the human brain. New York:
Grosset/Putnam; 1994.

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From the extensive research noted above there can be no doubt that MDLs behavioural
symptoms stem to a great extent from damage to the frontal lobes. It can also be
understood just how difficult it is to predict how MDLs brain damage affects the processing of
information and to what extent the deficiencies of her working memory adds to these
problems. Consider as 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 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. MDL
has to cope with a disabled brain without any knowledge of what the situation would be if it
hadnt been damaged. Even if changes have taken place in her brain since the original
injury, she does not have the ability to know why or even to question why.


Theory of Mind and Brain Damage

Lack of a theory of mind (ToM) has important knock-on effects upon emotions. The
cerebellum is linked to the hypothalamus, amygdala, hippocampus, anterior cingulate and
prefrontal cortex. 114,115,116,117,118 They make up our limbic system the part of the brain
which creates our emotions. During development this emotional processing needs to
become socialised and that needs the brain to associate with other people's responses,
particularly as shaped by their minds. What is the point of crying if we cannot connect with a
meaning for those tears and provide or receive a comfort? Why should we seek to enjoy
doing something with another if we cannot link this with the pleasure of their responses back
to us? Infants need these connections if they are to grow emotionally.

If the prefrontal cortex is damaged by toxins there may be nociceptive discharges 119 evoked
and these are conceivably involved in the affective rather than the sensory-discriminative
responses. Monosynaptic projections from the basolateral nucleus of the amygdala to the
prefrontal cortex are known to produce long-lasting synaptic plasticity120. If the prefrontal
cortex is damaged in a way that interferes with the synaptic plasticity then there may be

resulting abnormalities in the amygdala and the hippocampus and these may mimic some
aspects of autistic spectrum disorder and thus these may be associated with loss of acquired

motor, communication, and social skills. It has also been discovered that injuries of this type

114 Heath, R., & Harper, J. Ascending projections of the cerebellar fastigial nucleus to the
hippocampus, amygdala, and other temporal lobe sites. Experimental Neurology, 45, 268-287;
115 Haines, D., May, P., & Dietrichs, E. Neuronal connections between the cerebellar nuclei and
hypothalamus in Macaca Fascicularis: Cerebello-visceral circuits. Journal of comparative
neurology, 299, 106-122; 1990.
116 Supple, W. J. Hypothalamic modulation of Purkinje cell activity in the anterior cerebellar vermis.
NeuroReport, 4, 979-982; 1993.
117 Vilensky, J. A., & Van Hoesen, G. W. Corticopontine projections from the cingulate cortex in
the rhesus monkey. Brain Research, 205, 391-395; 1981.
118 Schmahmann, J. D. The cerebellum in autism: Clinical and anatomic perspectives. In M. L.
Bauman & T. L. Kemper, (Eds.), Neurobiology of autism, pp 195-226, Baltimore, ML: John Hopkins
University Press; 1994.
119 A tissue damaging event
120 The ability of the connection, or synapse, between two neurons to change in strength in
response to either use or disuse of transmission over synaptic pathways

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may bring about cognitive abnormalities. Hippocampus-dependent spatial memory,
contextual fear memory, and social memory may also be significantly impaired. 121

A child will be socially blinded if it lacks the ability to see how its stimulation of others minds
makes return responses. People might be responding to their attempts to interest and
interact with them, but their brains would be indifferent to their returning behavioural echoes.
As a result they would be unable to use feedback to give them a sense of their presence in
the world. They will, as a result, stop seeking social responses, becoming to the outside world,
remote and unaffectionate. Thus cerebellar circuits and their links with the rest of the brain
which enable tracking are essential: it is they that give us our interface with human life, and
so let us emotionally grow up as social beings.
Denis et al studied ToM in children with traumatic brain injury (TBI) and age- and gender-
matched children with orthopaedic injuries (OI), using a new three-frame Jack and Jill
cartoon task that measured intentional thinking separate from contingent task demands. In
the key ToM trials, which required intentional thinking, Jack switched a black ball from one
hat to another of a different colour, but Jill did not witness the switch; in the otherwise
identical non-theory of mind trials, the switch was witnessed. Overall accuracy was higher in
children with OI than in those with TBI. Children with severe TBI showed a larger decline in
accuracy on ToM trials, suggesting a specific deficit in ToM among children with severe TBI.
Accuracy was significantly higher on trials following errors than on trials following correct
responses, suggesting that all groups monitored performance and responded to errors with
increased vigilance. TBI is associated with poorer intentional processing in school-age
children and adolescents relative to peers with OI; furthermore, children with TBI are
challenged specifically by intentional demands, especially when their injury is severe. 122
Bellerose et al have also studied ToM in preschool children following mild TBI. More recently
they have followed this up in order to determine whether those findings were the result of a
brain-injury-specific effect or rather a general-injury effect and to examine the long-term
evolution of ToM skills following preschool mTBI, as well as to investigate the links between
ToM abilities and general social functioning. They found that, there was a brain-injury-
specific effect that persisted in the long-term following mTBI in preschool children. 123
The hippocampus also plays another vital role in memory; it is where short-term memories are
turned into long-term memories, which are then stored elsewhere in the brain. While it was
once thought that new nerve cells only grew in embryos or young children, research has now
shown that nerve cells develop throughout adulthood. The hippocampus is one of the few
places in the brain where the new nerve cells can be generated.
The hippocampus helps humans process and retrieve two specific kinds of memories:
declarative memories and spatial relationships. Declarative memories are memories related
to facts and events. Learning how to memorize speeches or lines in a play is a good example
of declarative memories in action. Spatial relationship memories involve pathways or routes,
as when cab drivers learn routes through a city. Knowledge of brain functions has grown to

121 Moretti, P.; Levenson, JM.; Battaglia, F.; Atkinson, R.; Teague,R.; Antalffy, B.; Armstrong, D.;
Arancio, O.; Sweatt, JD. & Huda Y. Zoghbi1, HY. Learning and Memory and Synaptic Plasticity
Are Impaired in a Mouse Model of Rett Syndrome. The Journal of Neuroscience, January 4,
2006; 26(1):319327
122 Dennis M, Simic N, Gerry Taylor H, Bigler ED, Rubin K, Vannatta K, Gerhardt CA, Stancin T,
Roncadin C & Yeates KO. Theory of mind in children with traumatic brain injury. J Int
Neuropsychol Soc. 2012 Sep;18(5):908-16.
123 Bellerose J ; Bernier A ; Beaudoin C ; Gravel J & Beauchamp MH. Long-Term Brain-Injury-Specific
Effects Following Preschool Mild TBI: A Study of Theory of Mind. Neuropsychology. 2017 Jan 23.
doi: 10.1037/neu0000341. [Epub ahead of print]

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the point where researchers can now say spatial relationship memories are stored in the right
hippocampus. 124
Temporo-mesial structures are critical for the organization of long term declarative memories
during developmental age. This means that the architecture of the anatomical structures is
established very early in life. Very early lesions can cause memory deficits of different
severity and typology and are age-related. These early lesions (particularly of the
hippocampus) irreversibly compromise the capacity to acquire complex modalities of
verbal and social communication and to organize a personal and unique cognitive map.
A study by Frye et al, has found an improvement in an important core ASD symptom, verbal
communication, in non-syndromic ASD children receiving high-dose folinic acid vs placebo,
particularly in those participants who were positive for folate receptor- auto-antibodies.
Improvement in a number of secondary outcomes was observed as well, with no significant
adverse events. The effect of folinic acid is consistent with the therapeutic effect of early
behavioural interventions. 125,126, 127
Dennis et al report how children with traumatic brain injury understand ironic criticism and
empathic praise, on a task requiring them to identify speaker belief and intention for direct
conative speech acts involving literal truth, and indirect speech acts involving either ironic
criticism or empathic praise. Deficits in understanding the social, conative function of indirect
speech acts like irony and empathy have widespread and deep implications for social
function in children with traumatic brain injury. 128

Later lesions cause amnesia of different severity, with impairment of episodic memory and
preservation of semantic memory if the lesion is localized to the hippocampus, or the
impairment of both types of memory in case of hippocampus and para-hippocampus
localization. More particularly, the temporo-mesial structures are critical for the development of
long-term declaratory memories. 129

Damage to the hippocampus or to some of its connections such as the fornix produces
deficits in learning about the places of objects and about the places where responses should
be made. For example, humans with damage to the hippocampal system or fornix are
impaired in object-place memory tasks in which not only the objects seen, but where they
were seen, must be remembered. Further, neurotoxic lesions that selectively damage the
primate hippocampus impair spatial scene memory. Also, fornix lesions impair conditional

124 Ming GL & Song H. Adult Neurogenesis in the Mammalian Brain: Significant Answers and
Significant Questions. Neuron. 2011 May 26; 70(4): 687702. doi: 10.1016/j.neuron.2011.05.001

125 Frye, RE. et al Folinic acid improves verbal communication in children with autism and
language impairment: a randomized double-blind placebo-controlled trial. Molecular
Psychiatry 2016; doi: 10.1038/mp.2016.168.
126 Schreibman L. & Stahmer AC. A randomized trial comparison of the effects of verbal and
pictorial naturalistic communication strategies on spoken language for young children with
autism. J Autism Dev Disord 2014; 44: 12441251.
127 Wetherby, AM; Guthrie, W; Woods, J; Schatschneider, C; Holland, RD& Morgan L et al. Parent-
implemented social intervention for toddlers with autism: an RCT. Pediatrics 2014; 134: 1084
128 Dennis M; Simic N; Agostino A; Taylor HG; Bigler ED; Rubin K; Vannatta K; Gerhardt CA; Stancin
T & Yeates KO. Irony and empathy in children with traumatic brain injury. J Int Neuropsychol
Soc. 2013 Jan 21:1-11.
129 Riva, D; Saletti, V; & Nichelli, F. The organization of memory in temporo-mesial structures in
developmental age. In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental
Functions. John Libby, London; 2000.

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left-right discrimination learning, in which the visual appearance of an object specifies
whether a response is to be made to the left or the right. 130, 131

Evidence from Monti et al suggests that a history of head trauma is associated with memory
deficits later in life. The majority of previous research had focused on moderate-to-severe
traumatic brain injury (TBI), but evidence suggests that even a mild TBI (mTBI) can interact
with the aging process and produce reductions in memory performance. This study
examined the association of mTBI with memory and the brain by comparing young and
middle-aged adults who have had mTBI in their recent (several years ago) and remote
(several decades ago) past, respectively, with control subjects on a face-scene relational
memory paradigm while they underwent functional magnetic resonance imaging (fMRI). 132

In observations of hippocampal volumes from high-resolution structural images Monti et al

have also shown that middle-aged adults with a head injury in their remote past had
impaired memory compared to gender, age, and education matched control participants,
consistent with previous results in the study of memory, aging, and TBI. Their findings extended
previous results by demonstrating that these individuals also had smaller bilateral
hippocampi, and had reduced neural activity during memory performance in cortical
regions important for memory retrieval. These results also indicate that a history of mTBI may
be one of the many factors that negatively influence cognitive and brain health in aging.

One way of relating the impairment of spatial processing to other aspects of hippocampal
function is to note that this spatial processing involves a snapshot type of memory, in which
one whole scene must be remembered. This memory may then be a special case of
episodic memory, which involves an arbitrary association of a particular set of events which
describe a past episode.133 Further, the non-spatial tasks impaired by damage to the
hippocampal system may be impaired because they are tasks in which a memory of a
particular episode or context rather than of a general rule is involved. Further, the deficit in
paired associate learning in humans may be especially evident when this involves arbitrary
associations between words.134

The evidence provided from a historical case known as HM and many others after him made
it possible to arrive at the definition of a memory system organized into short- and long-term
components. Long-term memory is sub-divided into implicit (or procedural) and explicit (or
declarative) memory.135,136 Procedural memory is at most only partially conscious and
consists of a collection of different skills; it is expressed by means of activities, does not
respond to the criterion of true/false; progressively increases with experience, and generally
represents a predisposition to behave in a particular way on the basis of previous memories.
On the contrary, declarative memory is conscious and expressed by means of words,

130 Rolls, ET. Memory, Attention and Decision-Making. OUP; 2008.

131 Petrides, M. Deficits on conditional associative-learning tasks after frontal- and temporal-lobe
lesions in man. Neuropsychologia 23; 601-614.
132 Monti JM; Voss MW; Pence A; McAuley E; Kramer AF & Cohen NJ. History of mild traumatic
brain injury is associated with deficits in relational memory, reduced hippocampal volume, and
less neural activity later in life. Front Aging Neurosci. 2013 Aug 22;5:41 PMID 23986698.
133 Rolls, ET. The primate hippocampus and episodic memory; in, Dere, Huston & Easton (Eds)
Episodic Memory Research; Elsevier, Amsterdam, 2008.
134 Rolls, ET. Memory, Attention and Decision-Making. OUP; 2008.
135 Tulving, E. Episodic and semantic memory. In: Organization of memory, eds. E. Tulving & W.
Donaldson. New York: Academic Press, 1972.
136 Tulving, E. In: Elements of episodic memory. Oxford: Oxford University Press; 1983.

Page 30 of 36
concepts and propositions; it is also expressed by means of images and the recall of
previously encountered facts and events.

Declarative memory is further sub-divided into semantic and episodic memory. Semantic
memory represents our knowledge of the world beyond any context or temporal
parameters, is automatically expressed and lives in the present; episodic memory is based on
facts/events occurring in a precise temporal and spatial context in which the fundamental
reference point is the person remembering. Amnesia is therefore related to the long-term
declarative memory137 . Given the existence of different types of memory, it follows that they
are processed by different brain areas and based on different neuronal circuits. 138

Short-term memory is probably processed by the inferior parietal lobe (although not
everybody agrees on this point); declaratory long-term memory is processed by the
temporo-mesial structures, in particular, the hippocampus and para-hippocampal regions,
whereas procedural memory seems to be processed by the striatum and the cerebellum.

Given that different brain areas process different components of the memory system, it
follows that these components may be independently deficient depending on the
damaged area. Short-term memory deficits can therefore exist in the presence of a
perfectly functioning long-term memory, and vice versa; a deficient declaratory memory in
the presence of an intact procedural memory, and vice versa; and a deficient semantic
memory in the presence of an integral episodic memory and vice-versa139,140 .

In Mishkin and Eichenbaum's model of the anatomy of the temporo-mesial structures, the
memory is seen as being very flexible and based on representations stored in the neocortex
in a highly precise and sophisticated manner. 141,142

Systematic studies of animal temporo-mesial structures have made it possible to validate the
model in an irrefutable manner.143,144,145 A rat's hippocampus is the site of spatial memory,
but actually provides what is nothing less than a cognitive map of the entire ecological
space in which it is capable of navigating by using the procedures, moves and anticipations
of events that come from previous individual experiences. It has also been found that

primates have the possibility of taking advantage of a cognitive map of their episodic

137 Baddeley, A. The human memory (1982). Italian edn. La memoria umana. Bologna: II Mulino;
138 Gabrieli, J.D.E., Brewer, J.B., Desmond, J.E. & Glover, G.H. Separate neural bases of two
fundamental memory processes in the human medial temporal lobe. Science 276, 264-266;
139 Baddeley, A. The human memory (1982). Italian edn. La memoria umana. Bologna: II Mulino;
140 Ellis, W.A. & Young, A.W. Memory. In: Human cognitive neuropsychology. Hove, London,
Hillsdale; 1988.
141 Mishkin, M., Suzuki, W., Gadian, D.G. & Vargha-Khadem, F. Hierarchical organization of
cognitive memory. Phil. Trans. Roy. Soc. London (B) 352,1461-1467; 1997.
142 Eichenbaum, H. How does the brain organize memory? Science 277,330-332; 1997.
143 Mishkin, et al, Idem. 1997.
144 Suzuki, W.A & Amaral, D.G. Perirhinal and parahippocampal cortices orille macaque monkey:
cortical afferents. J. Compo Neurol. 350, 497-533; 1994.
145 Suzuki, W.A & Amaral, D.G. Topographic organization of the reciprocal connections between
monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J. Neurosci. 14,
1856-1877; 1994.

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Kitamura et al have shown however, that whilst the hypothalamus is a key brain structure for
learning and memory. Recall of some associative and spatial memories initially depends on
the hippocampus, but that hippocampal dependency progressively decays over time, a
process that is associated with a gradual increase of neocortex-dependency.146

It has been suggested that the quality of original memories also transforms from a precise
(i.e., detailed) form to a less precise (i.e., more schematic or generic) form with similar time
course. 147,148,149 The question arises of whether changes in the quality of the original
memories depend on the shift in brain regions on which the recall of these memories relies,
i.e., whether the hippocampus is always required for the precision of memories. This is an
important question for understanding physiological significances of the hippocampal-
cortical complementary memory systems.

In the study by Kitamura et al, they found clear indication that the association with fear,
masks the actual precision of place memory. Moreover, in contextual fear conditioning, the
experimental subjects (mice) showed the freezing responses even for unconditioned place in
recent memory test, whereas in the non-associative place recognition test mice did not
show any adaptation behaviour even for similar place in remote memory test. Therefore, the
conclusions of previous studies using contextual fear conditioning150,151,152 need to be
validated by non-associative protocols. Thus, they examined the contribution of
hippocampal function on the precision of remote place memory by non-associative place
recognition test.

Using this procedure, they found that the place memory is precisely maintained for 28 days,
which may require -CaMKII-dependent plasticity in the cortex, and that the retrieval of
remote place memory (not recent memory) does not require hippocampal function. These
results indicate that the quality of a place memory does not correlate with the brain region
on which that memory depends. Moreover, they found that the inactivation of
hippocampal function does not inhibit the precision of remote place memory. These results
indicate that the hippocampal function is not required for the precision of remote place
memory. This is consistent with a human case study in which a patient with bilateral
extensive hippocampal damage showed intact memories for places learned long ago, but
not intact recent place memory153. Eight patients with bilateral hippocampal damage were

146 Kitamura, T; Reiko Okubo-suzuki, R; Takashima, N; Murayama, A; Hino, T; Nishizono, H; Kida, S. &
Inokuchi, K. Hippocampal function is not required for the precision of remote place memory.
Molecular Brain 2012, 5:5 doi:10.1186/1756-6606-5-5
147 Nadel L, & Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal
complex. Curr Opin Neurobiol 1997, 7:217-227.
148 Moscovitch M; Nadel L; Winocur G; Gilboa A. & Rosenbaum RS. The cognitive neuroscience of
remote episodic, semantic and spatial memory. Curr Opin Neurobiol 2006, 16:179-190.
149 McKenzie S. & Eichenbaum H. Consolidation and reconsolidation: two lives of memories?
Neuron 2011, 71:224-233.
150 Winocur G; Moscovitch M. & Sekeres M. Memory consolidation or transformation: context
manipulation and hippocampal representations of memory. Nat Neurosci 2007, 10:555-557.
151 Wiltgen BJ; Zhou M; Cai Y; Balaji J; Karlsson MG; Parivash SN; Li W. & Silva AJ. The hippocampus
plays a selective role in the retrieval of detailed contextual memories. Curr Biol 2010, 20:1336-
152 Wang SH; Teixeira CM; Wheeler AL & Frankland PW. The precision of remote context memories
does not require the hippocampus. NatNeurosci 2009, 12:253-255.
153 Teng E & Squire LR. Memory for places learned long ago is intact after hippocampal damage.
Nature 1999, 400:675-677.

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able to recall their remote autobiographical memories. 154 Thus, the quality of original place
memories is not determined by brain regions on which the memory depends.

Ablation of the anterior portion of the temporal lobe + amygdala + part of the hippocampus
or excision of the temporal cortex/neocortex (excluding the amygdala and hippocampus)
or selective ablation of the amygdala and hippocampus cause learning and delayed recall
deficits respectively relating to verbal or non-verbal stimuli (the latter being generally less
severe). The underlying pathogenic mechanism could be the disconnection of the cortex
from the hippocampus: although the neocortex is still capable of storing the memories, it
cannot pass them to the hippocampus and the para-hippocampal structures, and so they
cannot be recalled as such or rearranged 155 .

These results show that the temporo-mesial structures also process long-term declarative
memory at developmental age. This not only means that the architecture of the anatomical
structures is established very early in life, but also that an early lesion affecting these
structures cannot be compensated for by the establishment of alternative pathways and,
furthermore, that the degree of impairment is age-related (i.e. it is greater in patients who are
affected at a younger age).

Very early lesions of (particularly) the hippocampus irreversibly compromise the possibility of
acquiring complex modalities of verbal and social communication, as well as the possibility
of organizing an absolutely personal cognitive map.156 Later lesions only cause amnesias of
various degrees of severity, with impairment of episodic; but the preservation of semantic
memory, if localized to the hippocampus; or the impairment of both in cases that involve
both the hippocampus and para-hippocampus.

These results not only confirm that dissociations between the various components of the
memory system are also possible at a very early developmental age, but also confirm the
structure of the circuit. The cortex/neocortex faithfully stores the information. The para-
hippocampal regions codify the information belonging to the same categories in a
contiguous manner, and are also capable of re-evoking simple connections with the
cortex/neocortex under the impulse of simple stimuli, particularly if they are contiguous and
mono modal. The hippocampus analyses different elements of various experiences and
stimuli, acquired in different spatio-temporal contexts and via a wide range of modalities
(sight, touch, smells, sounds, emotions, etc.), and is capable of relating them to each other in
a myriad of different combinations and in a totally flexible and inexhaustible manner.

Studies of the temporo-mesial structures therefore not only highlight specific

neuropsychological deficits, but also provide an extremely interesting insight into the
pathologies typical of childhood development, such as infantile autism.

Schuetze et al have shown that morphological alterations in the thalamus, striatum and
pallidum are present in those with ASD.157 Lesion studies have shown social deficits (a core

154 Bayley PJ; Hopkins RO & Squire LR. Successful recollection of remote autobiographical
memories by amnesic patients with medial temporal lobe lesions. Neuron 2003, 38:135-144.
155 Jones-Gotman, M; Zatorre, RJ; Olivier, A; Andermann, F; Cendes, F; Stauton, H; McMackin,
Dumpsy; Siegel, A.M. & Wieser, H.G. Learning and retention of words and designs following
excision from medial or lateral temporal-lobe structures. Neuropsychologia 35, 963-973; 1997.
156 Challoner, A. Abnormal Brain Structure & Autism
157 Schuetze, M.; Park, MTM; Cho, I Y; MacMaster, FP; Chakravarty, MM & Signe Bray, SL.
Morphological Alterations in the Thalamus, Striatum, and Pallidum in Autism Spectrum Disorder.
Neuropsychopharmacology (2016) 41, 26272637

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symptom in ASD) resulting from injury to areas of the orbitofrontal circuit. 158, 159 Schuetze et
al also show findings which suggest that cellular-level properties within the thalamus may
contribute to these differences in connectivity. Functionally, abnormalities in the pulvinar
may have particular relevance to well-documented differences in attention skills in ASD. 160

In the typical population, IQ has been associated with total brain volume 161 as well as
structure of cortical, white matter, and subcortical regions162,163. Grazioplene et al also
suggest that any findings of morphological differences in pallidum, putamen and thalamus
should be considered relative to intellectual functioning (idem). This is important to consider
for any structural study of ASD; while intellectual disability is not among the diagnostic criteria
for ASD, it is an extremely common comorbidity.164

Schuetze et al (idem 2016) show very important confirmations that brain injuries are possible
causes of ASD.

These studies of Executive Function, Working Memory and ToM, show not only what is a
wonderful system but also emphasizes their complexity and reminds us of just how damage
caused to even limited areas of the frontal cortex can disable so much information and lead
to the permanent disability of ASD and other conditions.

Early Brain Damage and Autism Spectrum Disorder (ASD)

Patho-physiology of Autism The patho-physiology of the clinical syndrome of autism

is controversial, with multiple different hypotheses as to the central neuro-psychologic deficit
and central nervous system localization. Regardless of differences, current theories propose
a primary deficit in higher-order cognitive abilities and localization at the neural systems level
or at multiple levels of the neuraxis. The predominant theories propose a core deficit in

158 Bechara A. Emotion, decision making and the orbitofrontal cortex. Cereb Cortex 10: 295307;

159 Hillis, AE. Inability to empathize: brain lesions that disrupt sharing and understanding anothers
emotions. Brain 137: 981997; 2014.
160 Allen, G. & Courchesne, E. Attention function and dysfunction in autism. Front Biosci 6: D105
D119; 2001.
161 McDaniel, M. Big-brained people are smarter: a metaanalysis of the relationship between in
vivo brain volume and intelligence. Intelligence 33: 337346; 2005.
162 Grazioplene, RG; Ryman, GS; Gray JR, Rustichini, A; Jung, RE; DeYoung, CG. Subcortical
intelligence: caudate volume predicts IQ in healthy adults. Hum Brain Mapp 36: 14071416;
163 Schumann, CM; Hamstra, J; Goodlin-Jones BL; Kwon, H; Reiss, AL & Amaral DG. Hippocampal
size positively correlates with verbal IQ in male children. Hippocampus 17: 486493; 2007.
164 Yeargin-Allsopp, M; Rice, C; Karapurkar, T; Doernberg, N; Boyle, C & Murphy, C. Prevalence of
autism in a US metropolitan area. JAMA 289: 4955; 2003.

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executive functions165, control of attention166, or complex information processing167.
Localizations proposed for these deficits include frontal systems, frontal cortex-parietal
cortex-neocerebellar vermis, and generalized involvement of neocortical systems,

It can be seen that damage to these areas post-natally may produce autistic-type deficits.
It is said that treatment of autism and similar disorders involves primarily an environmental
and behavioural approach, as there are no medications with demonstrated efficacy against
the primary deficits in autism.

Patients who are chronically treated with antipsychotic drugs show changes in brain
structure. There is strong support for this view from Chege et al who, using resonance
imaging findings, have found that there is increasing evidence to suggest that antipsychotic
drugs (APD) might affect brain structure directly, particularly the cerebral cortex. They used
automated analysis techniques to map the regions that show maximal impact of chronic (8
weeks) treatment with either haloperidol or olanzapine on the rat cortex. 168, 169

Academic intervention should employ a model that is the converse of the traditional learning
disability approach, with a particular emphasis on interpretative and problem-solving
deficits. (Minshew, 1997, Idem)

There has been little clinical consideration given to the possibility of early brain damage
being a possible cause of ASD. 170 However, many studies indicate that children with an
ASD diagnosis have brain pathology suggestive of ongoing neuroinflammation or
encephalitis in different regions of their brains. Evidence of neuroinflammation or encephalitis
in ASD includes: microglial and astrocytic activation, a unique and elevated pro-
inflammatory profile of cytokines, and aberrant expression of nuclear factor kappa-light-
chain-enhancer of activated B cells. A conservative estimate based on the research
suggests that at least 69% of individuals with an ASD diagnosis have microglial activation or
neuroinflammation. Encephalitis is defined as inflammation of the brain; however, children
with an ASD diagnosis are not generally assessed for a possible medical diagnosis of
encephalitis. This is unfortunate because if a child with ASD has neuroinflammation, then

165 Ozonoff S; Strayer DL & McMahon WM, et al. Executive function abilities in autism: An
information processing approach. J Child Psychol Psychiatry 35:659-685, 1994.
166 Courchesne E; Townsend JP & Akshoomoff NA, et al. A new finding: Impairment in shifting
attention in autistic and cerebellar patients, in Broman SH, Grafman J (eds): Atypical Deficits in
Developmental Disorders: Implications for Brain Function. Hillsdale, NJ: Erlbaum, 1994, pp 101-
167 Minshew NJ; Goldstein G & Siegel DJ. Profile of neuropsychologic functioning in autism: A
generalized disorder of complex information processing. J Int Neuropsychol Soc. 3, 303-316;
168 Chege,W.; Natesan, S.; Modo, M.; Cooper, JD.; Williams, SCR. & Kapur, S. Reduced Cortical
Volume and Elevated Astrocyte Density in Rats Chronically Treated with Antipsychotic Drugs
Linking Magnetic Resonance Imaging Findings to Cellular Pathology. Biol. Psych. published
online 21 October 2013 doi:10.1016/j.biopsych.2013.09.012.
169 Molina, V; Martn C; Ballesteros A; de Herrera AG & Hernndez-Tamames JA. Optimized voxel
brain morphometry association between brain volumes and the response to atypical
antipsychotics. Eur Arch Psychiatry Clin Neurosci (2011) 261:40716.10.1007/s00406-010-0182-2
[PubMed] [Cross Ref]
170 Challoner, A. Abnormal Brain Structure and Autism.

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treating the underlying brain inflammation could lead to improved outcomes. Future studies
should include treatments for neuroinflammation in ASD. 171

Critical to identifying the causal factors of autism, and key to its relevance to normal
development, is the recognition that autism is actually the extreme of a spectrum of
abnormalities. Milder phenotypes on this spectrum include Asperger syndrome 172 in which
language is relatively unimpaired, and the Broader Autism Phenotype in which
characteristic cognitive traits are present sub-clinically173. The combination of this broad
variation of phenotypes and a 6090% concordance rate in identical twins174 suggests a
large number of genetic and environmental biasing factors 175.

In addition to the central coherence paradigm, autism has been variously characterized as
a deficit of executive function 176, complex information processing 177, ToM 178, and

171 Kern,JK; Geier, DA; Lisa K. Sykes, LK & Geier, MR. Relevance of Neuroinflammation and
Encephalitis in Autism. Front. Cell. Neurosci., 19 January 2016
172 Wing, L. Aspergers syndrome: a clinical account. Psychol Med 11:115129; 1981.
173 Dawson, G.; Webb, S.; Schellenberg, GD; Dager, S; Friedman, S; Aylward, E & Richards, T.
Defining the broader phenotype of autism: genetic, brain, and behavioural perspectives. Dev
Psychopathol 14:581 611; 2002.
174 Bailey, A; Le Couteur, A; Gottesman, I; Bolton, P; Simonoff, E; Yuzda, E & Rutter, M. Autism as a
strongly genetic disorder: evidence from a British twin study. Psychol Med 25:6377; 1995
175 Muhle, R; Trentacoste, SV & Rapin I. The genetics of autism. Pediatrics 113:e472 e486; 2004.
176 Ozonoff, S; Pennington, B & Rogers, SJ. Executive function deficits in high-functioning autistic
individuals: relationship to theory of mind. J Child Psychol Psychiatry; 32:10811105; 1991.
177 Minshew, NJ; Goldstein, G & Siegel DJ. Neuropsychologic functioning in autism: profile of a
complex information processing disorder. J Int Neuropsychol Soc 3:303316; 1997.
178 Baron-Cohen S; Leslie AM. & Frith U. Does the autistic child have a theory of mind? Cognition
21:37 46; 1985.
179 Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn Sci 6:248 254; 2002.

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