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Dysexecutive Syndrome Case Study

Abstract

Although frontal dysexecutive disorders are frequently considered to be due to working memory deficit, this has not been systematically examined and very little evidence is available for impairment of working memory in frontal damage. The objective of this study was to examine the components of working memory, their anatomy and the relations with executive functions in patients with stroke involving the frontal or posterior cortex. The study population consisted of 29 patients (frontal: n = 17; posterior: n = 12) and 29 matched controls. Phonological loop (letter and word spans, phonological store; rehearsal process), visuospatial sketchpad (visuospatial span) and the central executive (working memory span, dual task and updating process) were examined. The group comparison analysis showed impairment in the frontal group of: (i) verbal spans (P < 0.03); (ii) with a deficit of the rehearsal process (P = 0.006); (iii) visuospatial span (P = 0.04); (iv) working memory span (P = 0.001) that disappeared after controlling for verbal span and (v) running memory (P = 0.05) unrelated to updating conditions. The clinical anatomical correlation study showed that impairment of the central executive depended on frontal and posterior lesion. Cognitive dysexecutive disorders were observed in 11/20 patients with central executive deficit and an inverse dissociation was observed in two patients. Receiver operating characteristic curve analysis indicated that cognitive dysexecutive disorders had the highest ability to discriminate frontal lesions (area under curve = 0.844, 95% confidence interval: 0.74–0.95; P = 0.0001; central executive impairment: area under curve = 0.732, 95% confidence interval: 0.57–0.82; P = 0.006). This study reveals that frontal lesions induce mild impairment of short-term memory associated with a deficit of the rehearsal process supporting the role of the frontal lobe in this process; the central executive depends on lesions in the frontal lobe and posterior regions accounting for its low frequency and the negative results of group studies. Finally, the frontal dysexecutive syndrome cannot be attributed to central executive impairment, although it may contribute to some dysexecutive disorders.

brain injury, ischaemic stroke, frontal lobe, executive functions, working memory

Introduction

Disorders of executive functions are one of the most frequent cognitive deficits and are observed in many brain diseases. Following Luria’s approach (1966), the term ‘executive functions’ was coined by Lezak (1982), and was initially circumscribed to goal setting, action initiation and inhibition, planning, shifting and verification. This domain has been extended to include behavioural changes observed in frontal lesions (Baddeley and Wilson, 1988). These higher-order functions account for cognitive and behavioural control and depend mainly on frontal lobes and fronto-subcortical networks. They are assessed using conventional executive tests, such as Modified Card Sorting, Stroop, Trail Making, verbal fluency and Tower of London tests (Godefroy et al., 2010). Although an impressive number of studies have documented the frequency and variability of executive disorders, their underlying mechanisms and related anatomy remain largely undetermined, resulting in a long list of cognitive dysexecutive disorders (i.e. demonstrated on cognitive tests; Godefroy et al., 2010). A better understanding of the underlying cognitive deficits would help to clarify the dysexecutive syndrome, its assessment and its anatomy. Three main explanations for dysexecutive disorders have been proposed: a deficit of a supervisory system involved in the control of action (Norman and Shallice, 1986), a deficit of attention and sustained alertness (Posner and Petersen, 1990) and a disorder of working memory (Baddeley, 1986). On the basis of animal data (Golman-Rakic, 1987), the working memory approach has gained considerable influence (Miyake et al., 1999; Baddeley, 2000; D’Esposito, 2007). According to Baddeley (1986), working memory involves two modality-specific storage components (phonological loop and visuospatial sketchpad) and an attentional controlling system (central executive) that operates on temporary stored information and is involved in task coordination, inhibition, switching and updating (Baddeley, 1996; Miyake et al., 2000). The term ‘central executive’ was coined by Baddeley and Hitch (1974) in their initial version of the working memory model and should be differentiated from ‘executive functions’, which was subsequently proposed by Lezak (1982) to describe the processes individualized by Luria (1966). The hypothesis that executive functions depend on the intervention of the central executive is based on three lines of argument: (i) most executive tests are complex and consequently load working memory; (ii) the overlap between processes involved in conventional executive tests (i.e. Modified Card Sorting, Stroop, Trail Making, verbal fluency and Tower of London tests) and cognitive operations proposed to depend on the central executive (task coordination, inhibition, switching and updating); and (iii) the anatomical overlap as both executive functions and central executive involve the prefrontal cortex. The relationship between the central executive and frontal lobe has been mainly documented by functional imaging studies showing the prominent activation of the prefrontal cortex in conditions involving the central executive (D’Esposito et al., 1995, 2000; Colette and Van der Linden, 2002). Conversely, evidence for impairment of the central executive in frontal lesions, especially stroke, remains very limited. Frontal lesions spare digit and spatial spans (D’Esposito et al., 1999), whereas contradictory results have been reported for delayed response tasks (D’Esposito et al., 1999, 2006). Shallice and Vallar (1990) reviewed case studies assessing mechanisms of impairment of the phonological loop (storage versus rehearsal mechanism) and showed prominent impairment of storage that is usually related to a left parietal lesion. The deficit of the rehearsal mechanism is reported in rare cases, mostly in patients with a left inferior frontal lesion (Belleville et al., 1992; Waters et al., 1992; Vallar et al., 1997). Processes depending on the central executive (task coordination, switching and updating) are usually assessed using a dual task paradigm (requiring coordination of the execution of diverse sets of tasks), working memory span (requiring a simultaneous combination of online processing and information storage) and running memory task (requiring updating of relevant information and suppression of no-longer-relevant data; Pollack et al., 1959; Morris and Jones, 1990). Most studies on the central executive in focal lesions have focused on task coordination and none have systematically examined all working memory processes. Impairment of dual task due to a frontal lesion has been reported in only two studies (Cowey and Green, 1996; Leclercq et al., 2000) and only one showed that this impairment was more marked than in lesions of the posterior cortex (Cowey and Green, 1996). One (Baddeley et al., 1997) of the four negative studies (Vilkki et al., 1996, 2002; Baddeley et al., 1997; Andres and Van der Linden, 2002) showed poor performance in the subgroup of frontal patients with behavioural changes. Two studies using sequential dual tasks (Godefroy et al., 1999; Stablum et al., 2000) reported more marked response slowing in patients with frontal lesions, but this impairment was not related to other deficits of controlled processes (Godefroy et al., 1999). There is, therefore, little evidence that frontal lesions impair the central executive as defined by Baddeley et al. (1997). This contrasts with impairment of the central executive reported in diffuse diseases, such as Alzheimer’s disease (Baddeley et al., 1991; Colette et al., 1999; Huntley et al., 2010), traumatic brain injury (McDowell, 1997; Azouvi et al., 2009; Barbey et al., 2011; Hillary et al., 2011) and Parkinson’s disease (Morris et al., 1988; Pillon et al., 2001; Beato et al., 2008). However, no study has examined whether working memory impairment underlies dysexecutive disorders, i.e. the emergence of dysexecutive cognitive disorders is conditioned by impairment of working memory.

The objective of this study was to examine working memory, executive function and the relationship between the two. It was performed in stroke, a disease that frequently impairs executive functions (Tatemichi et al., 1994; Sachdev et al., 2004; Godefroy et al., 2010) and which is suitable for examining associations and dissociations between deficits (Godefroy et al., 1998; Müller and Knight, 2006).

Materials and methods

Population

Consecutive patients aged 18–70 years referred to the Lille stroke centre for recent stroke (<1 month) visualized by brain imaging were considered for inclusion. Exclusion criteria were: (i) sensorimotor deficit, hemineglect or aphasia precluding cognitive assessment (Godefroy et al., 2002); (ii) illiteracy; (iii) alcoholism or severe general comorbidity; (iv) previous neurological and psychiatric diseases except for depression or anxiety; (v) recent introduction of psychoactive or anti-epileptic medication; and (vi) absence of informed consent. This study included 29 patients and 29 age and education-matched controls (Table 1). Neuroradiological analysis was performed using MRI scans according to a method providing good inter-observer reliability (Godefroy et al., 1998; Supplementary material). It determined the presence of a lesion in the 22 regions of interest on each side and white matter abnormalities (Fazekas et al., 1987). Lesion analysis (Fig. 1) indicated that 17 patients (seven females; 10 males) had a lesion restricted to the anterior region (frontal group) and 12 patients (10 females; two males) had a lesion limited to the posterior region (posterior group; Table 1). Demographic characteristics did not differ except for gender due to a higher proportion of females in the control and posterior groups. For this reason, all analyses first assessed the gender effect; as this effect was never significant, only group comparison analyses are reported. This study was approved by the institutional review board.

Figure 1

Lesion overlaps in MNI space (−15, 0, 30 and 45 mm level). Right side corresponds to right hemisphere.

Figure 1

Lesion overlaps in MNI space (−15, 0, 30 and 45 mm level). Right side corresponds to right hemisphere.

Table 1

Demographic characteristics, lesions and performance on tests assessing executive functions

Frontal group Posterior group Controls P
n17 12 29 
Age (years) 47 ± 13 43.3 ± 13 46.3 ± 13.2 0.7 
Education (years) 10 ± 2.9 9.9 ± 2.1 10.1 ± 2.9 0.9 
Stroke type: infarct/haemorrhage 12/3 9/3 – 
White matter abnormalities 0/1/2/3 12/4/1/0 10/1/0/1 – 0.4 
Frontal: left/right 9/9 0/0 – – 
    Basal/mesial/lateral 4/6/13 0/0/0 – – 
Posterior cortex: left/right 1/2 6/6 – – 
    Temporal lateral/mesial/occipital 3/0/0 6/4/3 – – 
    Parietal superior/inferior lobulus 0 /0 2/1 – – 
Deep structures: left/right 2/5 1/4 – – 
    Lenticular nucleus/caudate nucleus/thalamus 0/2/0 1/1/2 – – 
    Semiovale centre/internal capsule 5/0 4/2 – – 
Mini-mental state examination (/30) 27.7 ± 2 28.3 ± 2 28.8 ± 0.9 0.06 
Progressive matrices (/36) 29.2 ± 4.4 30.8 ± 5.2 31.8 ± 3.5 0.14 
Premorbid IQ 104 ± 16 105 ± 14 110 ± 12 0.3 
Digit span forward 5.18 ± 1.1a5.3 ± 1 6 ± 1 0.03 
Digit span backward 3.88 ± 1.1 3.83 ± 1.2 4.55 ± 1.2 0.08 
Behaviour 
    Apathy (/5) 1.24 ± 0.4a,b1 ± 0 1 ± 0 0.005 
    Distractibility (/5) 1.5 ± 0.9a,b1 ± 0 1 ± 0.1 0.01 
Fluency 
    Animals 24.4 ± 6.5a24.8 ± 12.9a36.6 ± 7.6 0.0001 
    Letter ‘P’ 13.1 ± 6.1a13.6 ± 8.9a21.5 ± 5.8 0.0001 
Modified Card Sorting Test 
    Category 4.9 ± 1.6a5.1 ± 1.6 5.9 ± 0.3 0.007 
    Perseveration 1.3 ± 1.7 1.7 ± 2.7a0.4 ± 0.7 0.04 
Tower of London 
    Problem correct 11.1 ± 1.1a11.3 ± 0.8 11.9 ± 0.4 0.006 
Trail Making test 
    Perseveration 1.53 ± 3.5 0.6 ± 0.8 0.14 ± 0.5 0.08 
Stroop 
    Interference index 3.6 ± 6.3a0.7 ± 1.2 0.1 ± 0.6 0.006 
Frontal group Posterior group Controls P
n17 12 29 
Age (years) 47 ± 13 43.3 ± 13 46.3 ± 13.2 0.7 
Education (years) 10 ± 2.9 9.9 ± 2.1 10.1 ± 2.9 0.9 
Stroke type: infarct/haemorrhage 12/3 9/3 – 
White matter abnormalities 0/1/2/3 12/4/1/0 10/1/0/1 – 0.4 
Frontal: left/right 9/9 0/0 – – 
    Basal/mesial/lateral 4/6/13 0/0/0 – – 
Posterior cortex: left/right 1/2 6/6 – – 

Subcortical ischemic vascular disease

The term subcortical ischemic vascular disease (SIVD) was proposed to characterize a clinical profile of a dysexecutive syndrome, with no (or minimal) memory impairment, commonly accompanied by psychomotor slowing, which was seen in the presence of subcortical—including white matter—injury. Subcortical vascular injury occurs through small vessel infarct, ischemia or incomplete ischemia within the cerebral white matter, basal ganglia, and brain stem, especially the prefrontal subcortical circuit and the thalamocortical circuit. Lacunes are infarcts < 15 mm in diameter in the cortical white matter or in the corona radiata, internal capsule, centrum semiovale, thalamus, basal ganglia, or pons.45

It is clear that lesions in the prefrontal subcortical circuit (including the prefrontal cortex, caudate, pallidum, and thalamus) or thalamocortical circuit may manifest as the “subcortical syndrome” as described previously. Commonly, however, the profile is accompanied by memory impairment that is more than “minimal.”53 In any case, these lesions are also associated with increased risk of stroke and dementia. Although it has been held that this profile is associated with more rapid cognitive decline even when controlling for other vascular risk factors, this view has been disputed.54

Subcortical lesions are often associated with impairments of executive function,50,55,56 which is broadly defined as the ability to sequence, plan, organize, initiate, and shift between tasks. Even so, there are several distinct frontal lobe syndromes, so that to say a given patient has executive dysfunction is not always to give a precise account of what is wrong. Each of the major three frontal syndromes has been described in people with cerebral ischemia/infarction: dorsolateral (executive function and impaired recall), orbitofrontal (behavioral and emotional changes), and anterior cingulate (abulia and akinetic mutism).57 Clinically, however, mixed syndromes are common. The importance of executive dysfunction in VCI58–62 is unclear, but it is unlikely to be unique to VCI at any stage.30,63,64 Strong support for this contention comes from a recent prospective neuropsychological/autopsy-based study.65

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy associated with mutation in the Notch 3 gene on chromosome 19.23 Clinical presentation consists of migraine with aura, mood disturbance, recurrent subcortical strokes, and progressive cognitive decline.24 Although a comparatively rare cause of VCI, it deserves special mention for two reasons. First, it is generally considered to be a model of pure VaD because generally onset occurs between the ages of 40 and 50, when comorbid AD pathology is rare. Second, the use of cholinesterase inhibitors in those with CADASIL has shown statistically significant improvement in some measures of executive function. This provides a basis for cholinergic therapy in VCI. Cholinergic mechanisms appear to play a critical role in cerebral perfusion.66 The best diagnostic criteria for CADASIL are the NINDS-AIREN criteria for subcortical ischemic VaD.67