Since the 1970s, the improvement of diagnostic tools and the success of cardiac surgery have dramatically changed the natural history of complex congenital heart diseases. The number of newborns who have survived through infancy, reaching adolescence and adult age, and becoming socially integrated has increased.1,2 Consequently, nowadays determinants of late surgical results are evaluated by not only using survival as a measure, which was of major importance for surgeons and cardiologists up until the 1980s, but also by freedom from negative clinical events together with improvements in quality of life. Various guidelines,3 based on long post‐surgical follow‐up and knowledge of sequelae and complications, codify clinical evaluation of adult patients with a congenital heart defect. It is more difficult to codify the assessment of cognitive performance and quality of life.
This article reviews the mechanisms of cerebral damage in patients with congenital heart disease, the definition and measurement of quality of life, assessment of the psychological profile, and definition of cognitive functions and their measurement.
AETIOPATHOGENETIC FACTORS OF POTENTIAL CEREBRAL INJURY
The aetiological factors that modify the integrity of the brain can be related to the following: congenital heart defect, duration of haemodynamic and haematologic effects of the disease, hypoxic–ischaemic insult secondary to hypothermic cardiopulmonary bypass, and cardiac arrest during surgery.4
In patients with chromosomal abnormalities, particularly trisomy 21 and deletion on chromosome 22q11 (Di George syndrome), the neurodevelopmental outcome seems to be related more to genetic influence than to the associated cardiac defect.
Congenital heart disease characterised by hypoxaemia and cyanosis with polycythemia and microcytosis are at risk of cerebral accident, particularly during blue spells (cyanosis) or when blood viscosity is increased. Severe metabolic acidosis secondary to hypoxaemia strengthens the negative effects of ischaemia on glial and cerebral vascular cells due to the action of free radicals on membrane lipids and proteins.
Early surgery during the neonatal period or in the first trimester of life prevents cerebral complications, particularly in patients with transposition of the great arteries, avoiding hypoxia and persistent metabolic acidosis and forestalling blue spells in patients with tetralogy of Fallot. No unusual risk of cerebral injury is present in acyanotic congenital heart disease in the absence of severe cardiac dysfunction.
Surgical correction of the majority of congenital heart disease involves those methods which protect cerebral structures, such as cardiopulmonary bypass and deep hypothermia. Both these methods may have cerebral side effects caused by the risk of microembolism during bypass, an uncertain optimal temperature to obtain a safe cardiac arrest period, and the activation of a variety of inflammatory pathways.5,6 Risk factors for poor cerebral outcome after hypothermic cardiac arrest include: prolonged cardiac arrest, particularly in younger patients (more than 45–50 minutes), rapid cooling (< 20 minutes), severe hypothermia, hyperglycaemia before arrest and during reperfusion, alpha‐stat during cardiopulmonary bypass, severe cyanosis and blood hyperviscosity before surgery, low cardiac output in the early postoperative period, and alteration of cerebral blood flow secondary to deficiency of the autoregulatory process. Perioperative clinical and electroencephalographic (EEG) seizure and increased time to first EEG activity were associated with an increased risk of impaired cognitive functions.7
QUALITY OF LIFE AND HEALTH RELATED QUALITY OF LIFE
The concept of quality of life is broad and multidimensional. The temporal dimension of its assessment is very important because quality of life is not a stable and defined condition but one that changes. Because health is an important determinant of quality of life, a specific expression has been introduced—health related quality of life—which is suitable for applying to patients with congenital heart disease, for whom surgical correction prolongs survival but does not provide normality. Many of these patients need a programmed clinical follow‐up.8
In 1994 the World Health Organization revised the definition of quality of life in terms of “individuals' perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns”. According to this definition subjective parameters were introduced with limitation of their assessment because of peculiarity, no comparability, unpredictability, and individuality. Finally, no less important are the symbolic and cultural aspects. All cultures have allegoric representations of the heart with innumerable metaphors. It is well known that the influence of congenital heart disease on the parental relationship, with negative overprotective behaviour, is not related to the severity of the cardiac defect. In the past, attention was particularly paid to the family, level of education, employment and financial circumstances, and the quality of medical care received. More recently concepts of self‐perception and interaction between the disease and individual values and expectations, according to symbolic and cultural aspects of the environment (where the patient lives day to day and is confronted with the realities of life), were introduced.
The quality of life measurement has to follow the following criteria:
good validity and psychometric fidelity
reliable rules of manual correction, scoring, and interpretation selection
good comprehension of all components of the quality of life, clinical functioning, and the specific needs of the patient and his or her family.
The short form 36 (SF‐36)9 satisfies these criteria; it has an acceptable internal consistency and re‐test reliability. SF‐36 was worded to evaluate some prominent conceptions about health quality of life independently of age, pathology, and treatment. SF‐36 includes one multi‐item scale that assesses eight health concepts: physical activity, status and physical health, physical pain, general health, vitality, social activities, role and emotional status, mental health and health condition changes.
PSYCHOLOGICAL ASSESSMENT
Clinical experience and the literature both show how the psychological history of these patients is intensely conditioned not by the severity of their cardiac disease but by the type of medical care received in infancy (multiple operations, repeated hospital admissions).10 More important is how parents and relatives integrate the medical care and education with the psychological needs of their children.
The history of the patient, psychological problems, and their quality of life characterise some critical moments (table 1) that may have important negative consequences for the psychological evolution of the patient and his or her quality of life. Furthermore, during these “critical moments” patients can experience problems (for example, difficulties obeying their parents, taking their medication, or attending periodical follow‐ups) which are not medical problems related to their disease.
Table 1 Description of critical moments in the four steps of life.
• Infancy | Cardiac surgery/frequent hospital admission can cause interruption and/or modification of the relationship between child and parents |
Onset of preschool, physical activity limitations | |
• Childhood | Onset of school, learning deficits |
• Adolescence | Adolescence crisis |
Corporeal image and sexuality | |
• Adult age | Pregnancy |
Employment |
Infancy
Is the relationship between a mother and her infant with congenital heart disease at risk because of early hospitalisation and cardiac surgery? Is the quality of the mother–infant relationship related to the severity of the cardiac defect?
Clinical data have shown that fetal diagnosis of congenital heart disease and the post‐natal experience can negatively influence the type of attachment between the mother and her infant.11 The severity of the illness does not have a direct effect on the quality of the infant–mother relationship, but a “securely attached infant” showed more subsequent improvement in health than “insecurely attached” peers showed.
This is the reason why it is important during the period of hospitalisation to limit the time the infant is separated from the parents to the surgical event only; to protect the infant from pain during all phases of care; and if necessary to give psychological support to the parents. During the psychological assessment of the parents, attention has to be paid to their mental health, and to their intellectual, relation, and social capacities. Furthermore, it is important to analyse their understanding of the disease, its prognosis, and the possibility of treatment.
In newborns, psychological development can be evaluated by specific scales which measure delays in development and attachment.
In babies psychological development can be evaluated by specific psychodiagnostic instruments that measure intellectual, emotional, social, and relational capacities. Moreover, the psychologist can assess the presence of psychological abnormalities according to the International classification of diseases, 10th revision (ICD‐10) or the Diagnostic and statistical manual, 4th revision (DSM‐IV) and/or the CFTM (Clasification Francaise des Troubles Mentaux de l'Enfant e de l'Adolescent).
Childhood
It is interesting to observe through evidence provided by clinical experience and from the literature that most psychological problems emerge during childhood and adolescence, while they seem to attenuate or disappear once adulthood is reached. The major problems emerge during the period of schooling. The child may show difficulties because of repeated absences resulting from frequent hospitalisations and because he or she has some limitations in sharing physical activities with classmates. It becomes necessary to give clear indications about the physical activities of the child. If there are contraindications to certain sporting activities it might be useful to consider the experience of some specialised centres that propose alternative experiences, with the instruction of corporeal techniques that facilitate psychosomatic integration of the child.12
If a child shows learning problems it is important to evaluate him or her using an appropriate cognitive assessment test.
Adolescence
During adolescence, requests for medical counselling usually increase. Parents have difficulty controlling the relationship with their children, who often consider the parents responsible for their handicap. The onset of sexual maturity and the difficulty accepting the physical aspects of their condition, in particular the scarring on the chest caused by the cardiac operations, exacerbate the discomfort. Moreover, these patients do not accept the limitations related to their physical status.13
Psychotherapeutic support, preceding the psychological clinical interview, must be focused on individual sessions with the patient and, when necessary, with the family nucleus.
Adulthood
Patients may experience difficulties finding a satisfying job, first because of a low educational level, and also because an employer may be wary of giving a job to a person with potential physical disabilities. In these situations social workers play an important role in assisting patients and advising them of their legal position.
In women, pregnancy continues to be a risk following surgical correction of complex congenital heart disease. There is the risk that the patient's own clinical status will deteriorate, and also the risk that the cardiac defect will occur in their offspring. So genetic counselling is recommended, and also fetal echocardiography. Psycho‐prophylactic support can be useful, particularly in the last trimester of pregnancy, to attenuate anxiety over the possibility the patient might die during the delivery; this can be achieved by means of autogenic training and by preparing for the birth with breathing exercises.
A series of instruments can be used for the psychological assessment: clinical interview with the parents of the infant with congenital heart disease; observation of the infant; observation of the child; clinical interview with the adolescent with congenital heart disease; psycho‐diagnostic tests for infant age, childhood age, adolescence, and adult age.
Psychological assessment is based on a 45 minute semi‐structured interview and administration of the Minnesota multiphasic personality inventory (MMPI‐2). During the interview, psychological, social and economic areas are investigated through questions about family status, educational level, and work.
The MMPI‐214,15 is an effective and reliable test constructed in order to evaluate the most significant structural characteristics of personality. It comprises a self‐administered questionnaire to which the subject must respond “true” or “false” to a series of 567 statements about his or her personal experiences, physical conditions, habits, and attitude. It suggests an exhaustive clinical picture of the patient by means of a series of numerical variables. It has a high discriminative power to discern between normal and pathological traits of personality. It is one of the most diffuse and validated tests of personality, and its high degree of accuracy is widely accepted.
The subject must be at least 18 years of age. The administration time for the test is about 90 minutes. The test is composed of three scales of validity (L–lie, F–infrequency, K–correction), 10 base clinical scales (Hs–hypochondriasis, D–depression, Hy–hysteria, Pd–psychopathic deviate, Mf–masculinity–femininity, Pa–paranoia, Pt–psychasthenia, Sc–schizophrenia, Ma–hypomania, Si–social introversion), and 15 clinical content scales (ANX–anxiety, FRS–fears, OBS–obsessiveness, DEP–depression, HEA–health concerns, BIZ–bizarre mentation, ANG–anger, CYN–cynicism, ASP–antisocial practices, TPA–type A, LSE–low self‐esteem, SOD–social discomfort, FAM–family problems, WRK–work interference, TRT–negative treatment indicators). For psychological diagnostic purposes the entire profile is determined from both the 10 base scales and the 15 subject scales in order to achieve maximum discriminating power. The scales of the test are standardised according to a normal distribution (T scores); scores above the 65th centile are considered clinically significant.
NEUROPSYCHOLOGICAL ASSESSMENT
What is neuropsychological assessment?
Neuropsychological assessment originated in the late 19th and early 20th centuries to evaluate the mental capacities of patients with brain disease (particularly aphasics). The primary purpose of neuropsychological assessment is to draw inferences about the structural and functional characteristics of a person's brain by evaluating an individual's cognitive functions. Cognitive functions are detected by studying behaviour in defined stimulus–response situations. Neuropsychological assessment is based on tests—namely, elicitation of a specific behavioural response to specific stimuli under controlled conditions. The use of a standard test battery allows the study of behavioural characteristics that are not accessible to clinical observation; however, it is important to stress that a cognitive evaluation is more than merely administration of a test list. A comprehensive neuropsychological assessment is an evaluation of cognition, mood, personality, and behaviour. Such an evaluation usually includes a formal interview, review of medical and/or educational/vocational records, interview of significant others (as necessary), and standardised neuropsychological testing. A comprehensive assessment covers a range of cognitive domains including intelligence, learning, memory, attention, receptive and expressive language, visuospatial ability, sensory processing, motor ability, reasoning, and higher order executive functions.16
Sometimes the psychologist personally gives the test, but other times a technician who has been thoroughly trained in administration of the measures may do it. In either case, the psychologist is responsible for interpreting the data obtained.
Why should cognitive functions be evaluated in the congenital heart disease patient?
The scope of neuropsychological assessment has expanded enormously in recent decades to encompass areas beyond clinical neurology. It plays an indispensable role in detecting cerebral dysfunction in clinical situations in which there is no clear anatomical evidence of alterations to the brain. For example, such situations include evaluating the effects of environmental and industrial toxins, the cognitive changes associated with alcoholism, chronic obstructive pulmonary diseases, the behavioural sequelae of carotid endarterectomy and cardiac surgery, as well as monitoring the outcome of pharmacological treatments.
Until now, the neuropsychological consequences of various dimensions of cardiovascular diseases have generally been examined in isolation. Furthermore, studies have shown that although the vast majority of children with congenital heart disease have normal outcomes, as a group they generally show high rates of neurodevelopmental problems.17 These problems include mild deficits in cognition, attention, and neuromotor functions. The aetiology of cognitive deficits in congenital heart disease patients is probably multifactorial and includes preoperative, operative, and postoperative factors. The preoperative factors include congenital brain abnormalities, genetic syndromes, hypoperfusion, acidosis, and cyanotic episodes; operative factors consist of circulatory arrest and cardiopulmonary bypass; postoperative factors take into account low cardiac output and embolic events.
Which are the most frequent cognitive deficits observed in patients with congenital heart disease?
Most of the studies on the cognitive development of children with cardiopathy have distinguished between cyanotic and non‐cyanotic conditions. Many studies report cognitive deficits in children with congenital heart disease and a positive correlation between the level of cognitive ability and the cardiopathic clinical severity. Children younger than 3 years of age with cyanotic cardiopathy showed deficits in gross motor, adaptive, social, and fine motor areas (Gesell developmental schedules), with the lowest score reported for gross motor abilities.18 A delay in motor development has been found, despite a normal language development.
Children older than three years reported normal values of intellectual parameters, measured by the IQ index, with mildly reduced scores only in the cyanotic population. The IQ of the cyanotic patients was significantly lower than that of acyanotic patients for both the Stanford‐Binet and the Wechsler adult intelligence scale, the two IQ tests used most often. The IQ measures are not sufficient to investigate the cognitive domain. In a previous study19 a more exhaustive neuropsychological investigation revealed an impairment of cognitive abilities such as executive functions and calculation. The term “executive function” is a complex construct that can be broadly defined as higher order cognitive abilities that allow for strategic planning, cognitive flexibility, self regulation, and goal direct behaviour requiring the coordination of several sub‐processes. Executive functions are those involved in complex cognitions, such as solving novel problems, modifying behaviour in the light of new information, generating strategies, or sequencing complex actions. Neuropsychological evidence suggests that executive processes are intimately connected with the intact function of the frontal and pre‐frontal cortices.20 Usually, patients with damage to the prefrontal cortex can show impaired judgment, organisation, planning and decision making, as well as behavioural disinhibition and impaired intellectual abilities. In a neuropsychological evaluation setting, patients are impaired on tests such as set shifting (for example, the Wisconsin card sorting test (fig 1)), planning (for example, the Tower of London test (fig 2)), and various fluency tasks (for example, the verbal fluency test). The Wisconsin card sorting test21,22 was devised to measure abilities to identify abstract categories and to shift cognitive set. The test requires the subject to sort a series of cards according to selected dimensions, which are changed from time to time during the course of examination. The subject must formulate a hypothesis about the correct sorting principle and be capable of changing the hypothesis when the feedback from the examiner indicates that it is incorrect. The Tower of London test23 is a specific task to investigate executive functions and planning ability. This test is a problem solving task which requires subjects to rearrange three coloured rings (in accordance with some very simple rules) from their initial position on three upright sticks to a new set of predetermined positions. Subjects are instructed to try to achieve the goal arrangement in as few moves as possible. In the Phonemic verbal fluency test subjects are required to say words beginning with a particular letter of the alphabet for a specific time (usually one minute for each letter). Although it is a test to measure the lexical access, phonemic fluency places higher demands on frontally mediated strategic search processes.
Frontal lobe impairments all point to a breakdown of coordination processes. Patients are relatively unimpaired in a test focusing on a particular function, but when a number of different functions must be coordinated in the evaluation setting or in real life, deficits are observed. The calculation deficits found in patients with congenital heart disease might be caused by a deficit in prefrontal and fontal lobe functioning. A recent brain imaging study24 showed that in approximate calculation tasks, bilateral intraparietal, precentral, dorsolateral, and superior prefrontal regions were involved, while the left inferior prefrontal cortex and the bilateral angular regions were more activated during exact calculation tasks.
Executive dysfunctions and calculation deficits might be directly related to academic performance. These patients may have difficulty in setting a goal (that is, understanding what the assignment or question one is being asked to achieve), planning a course to achieve it, (that is, remembering the procedure appropriate to the task), holding the plan in working memory while executing it, sequencing the steps in the plan, initiating taking those steps and shifting between them, monitoring progress for both pace and quality, regulating attention and emotional responses to challenges that arise, making flexible changes in the plan as needed, and evaluating the outcome for use of the plan in a subsequent similar activity.
Measurement of cognitive outcome and QoL in congenital heart disease: key points
Improvement of diagnostic tools and success of cardiac surgery has increased dramatically the survival of patients with congenital heart disease
Potential cerebral injury from hypoxaemia, cyanosis, hypothermic cardiac bypass, and cardiac arrest can occur during surgery
Quality of life is a multidimensional concept in whom health is an important determinant
Quality of life can be obtained by well validated instruments that can be easily administered (short form 36)
Psychological history seems not to be influenced by the severity of the cardiac defect but by the duration of hospitalisation and by the quality of the attachment with the mother during infancy
Limitation of physical activity and difficulty in accepting the physical aspects of their condition, particularly during adolescence, and difficulty in finding a satisfactory job, are other psychological stressors for patients with congenital heart disease
IQ is an insufficient index of cognitive assessment, which needs a complete investigation of all cognitive domains such as language, learning, memory, psychomotor speed, attention, concentration, calculation, and executive function
Deficits of cognitive functions can be related to cerebral injury secondary to the cardiac defect and surgery
Measurements of quality of life and cognitive outcome need to be repeated during follow‐up, with particular attention to the critical moments of life
FINAL CONSIDERATIONS
A patient with a congenital heart disease usually has an unusual development, as a result of physical, psychological, and cognitive findings characteristic of the cardiac defect, and the impact that the disease has on the family setting, particularly the parents. In the last 20 years interest in patients with congenital heart disease has progressively increased, because of improvements in diagnostic and therapeutic standards resulting in the prolonging of life. But survival is not always synonymous with improved quality of life; despite positive medical results, physical, psychological and cognitive problems are present in this population and can be a limitation to therapeutic success. It is desirable that evaluation of these parameters by means of validated instruments performed by specialised operators is included in the programmed clinical follow‐up of these patients. The value of a unique assessment is relative; over time patients may adapt to their physical status and denial is a common behaviour to normalise functioning. However, during the “crisis periods” in adolescence and adult life, when the challenges of everyday life (sexuality, job, pregnancy) are being encountered, many psychological problems can emerge which affect the quality of life. The cognitive assessment cannot be limited to the IQ index, which in the majority of cases is normal; a complete evaluation of all the domains, such as learning, memory, psychomotor speed, attention, concentration, reasoning, calculation and executive function, is required. The deficit of some cognitive functions would support the presence of an organic pathological substrate secondary to the cardiac defect and/or surgery, which can be made worse by psychosocial conditions. Knowledge of these aspects is important in order to implement adequate prevention and support measures, particularly during the “crisis periods”, with consequent improvement in the quality of life of these patients.
Footnotes
In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article
References
- 1.Daliento L, Mazzotti E, Mongillo E.et al Life expectancy and quality of life in adult patients with congenital heart disease. Italian Heart Journal 20023339–347.This is a review on the clinical history of operated and unoperated grown up congenital heart disease (GUCH) patients, with particularly attention being paid to complications, sequelae, and risk. [PubMed] [Google Scholar]
- 2.Wren C, O'Sullivan J J. Survival with congenital heart disease and need for follow‐up in adult life. Heart 200185438–443. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Deanfield J, Thaulow E, Warnes C.et al Management of grown‐up congenital heart disease task force of the ESC. Eur Heart J 2003241035–1084.This report was the result of the task force of the European Society of Cardiology group on the management of adult patients with congenital heart disease, particularly after surgical correction. [DOI] [PubMed] [Google Scholar]
- 4.Hickey P R. Neurologic sequelae associated with deep hypothermic circulatory arrest. Ann Thorac Surg 19986565–70.This study suggests strategies to prevent neurological damage during cardiac surgery when cardiac arrest is utilised. [DOI] [PubMed] [Google Scholar]
- 5.Bellinger D, Wypij D, Kuban K C.et al Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low‐flow cardiopulmonary bypass. Circulation 1999100526–532. [DOI] [PubMed] [Google Scholar]
- 6.Bellinger D, Wypij D, du Plessis A J.et al Developmental and neurologic effects of alpha‐stat versus pH‐stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 2001121374–383. [DOI] [PubMed] [Google Scholar]
- 7.Stecker M M, Cheung A T, Pochettino A.et al Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials. Ann Thorac Surg 20017114–21. [DOI] [PubMed] [Google Scholar]
- 8.Fallowfield L.The quality of life: the missing measurement in health care. London: Souvenir Press, 1990
- 9.Ware J E, Sherbourne C D. The MOS 36‐item short form health survey (SF 36). Conceptual framework and item selection. Med Care 199230473–483. [PubMed] [Google Scholar]
- 10.Testone J E, Terrier N. Post‐traumatic stress disorder following medical illness and treatment. Clin Psychol Rev 200323409–448. [DOI] [PubMed] [Google Scholar]
- 11.Maunder R G, Hunter J J. Attachment and psychosomatic medicine: developmental contributions to stress and disease. Psychosom Med 200163556–567.The object of this study was to evaluate the evidence linking attachment insecurity to illness. Attachment theory describes lifelong patterns of response to threat that are learned in the interaction between an infant and his or her primary caregiver. Despite its biopsychosocial domain, attachment theory has only recently been applied to psychosomatic medicine. [DOI] [PubMed] [Google Scholar]
- 12.Moons P, Barrea C, De Wolf D.et al Changes in perceived health of children with congenital heart disease after attending a special sports camp.Pediatr Cardiol 2005261–6.This study shows how a group of children with congenital heart disease improved their self‐esteem and self‐perception after attending a special sports camp. [DOI] [PubMed] [Google Scholar]
- 13.Green A. Outcomes of congenital heart disease: a review. Pediatric Nursing 200430280–284.In this study the authors report a series of physical and behavioural abnormalities in adolescents and young adults with congenital heart disease. In these patients anxiety and depression are described. [PubMed] [Google Scholar]
- 14.Butcher J N, Rouse S V. Clinical personality assessment. Annu Rev Psychol 199647385–401. [DOI] [PubMed] [Google Scholar]
- 15.Butcher J N, Williams C L.Essentials of MMPI‐2 and MMPI—an interpretation. Minneapolis: University of Minnesota Press, 1992
- 16.Lezak M D.Neuropsychological assessment. New York: Oxford University Press, 1995This is a very important book in clinical neuropsychology. The text provides detailed discussion of assessment techniques as well as the conceptual framework, clinical issues, and neuroscience foundation.
- 17.Mahle W. Neurologic and cognitive outcomes in children with congenital heart disease. Current Opinion in Pediatrics 200113482–486. [DOI] [PubMed] [Google Scholar]
- 18.Linde L M, Dunn O J, Schireson R.et al Growth in children with congenital heart disease. J Pediatr 196770413–419. [DOI] [PubMed] [Google Scholar]
- 19.Daliento L, Mapelli D, Russo G.et al Health related quality of life in adults with repaired tetralogy of Fallot: psychosocial and cognitive outcomes. Heart 200591213–218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Royall D R, Lauterbach E C, Cummings J L.et al Executive control function. J Neuropsychiatry Clin Neurosci 200214377–405.This report reviews the state of literature and opportunities for research related to “executive control function”. Executive control function impairment has been associated with lesions to the frontal cortex and its basal ganglia–thalamic connection. [DOI] [PubMed] [Google Scholar]
- 21.Milner B. Some effects of frontal lobectomy in man. In: Warren JM, Akert K, eds. The frontal granular cortex and behavior. New York: McGraw Hill, 1964
- 22.Milner B. Effects of different brain lesions on card sorting. Arch Neurol 1963990–100. [Google Scholar]
- 23.Shallice T. Specific impairments on planning. Phil Trans R Soc Lond 1982298199–209. [DOI] [PubMed] [Google Scholar]
- 24.Stanescu‐Cosson R, Pinel P, van de Moortele P F.et al Understanding dissociations in dyscalculia. A brain imaging study of the impact of number size on the cerebral networks for exact and approximate calculation. Brain 20001232240–2245. [DOI] [PubMed] [Google Scholar]