Neuro-Ophthalmology & Neuro-Otology
Aug. 22, 2022
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The term "executive function" broadly refers to the voluntary regulation of subsidiary cognitive functions, including memory, language, and movements that require skill. Executive function includes filtering attention, goal-directed behavior, scheduling and prioritizing planned actions, anticipation of the consequences of one's actions, and mental flexibility. The analysis of executive functions represents one of the most important research areas in contemporary neuroscience. Historically, executive function has been associated mainly with frontal lobe activity. Executive disorders have been documented in a diversity of conditions. Executive deficits early in dementia predict other behavioral disturbances, functional decline, and mortality. In elders, intellectual tasks and everyday activity programs may benefit executive function abilities.
• The term “executive functions” includes problem solving, planning, inhibiting responses, strategy development and implementation, cognitive control, and working memory.
• Three major variants of the executive dysfunction syndrome can be distinguished: orbitofrontal, medial, and dorsolateral.
• Executive dysfunction has been documented in a diversity of conditions, including dementia, traumatic brain injury, white matter lesions, borderline personality disorder, substance abuse, multiple system atrophy, multiple sclerosis, schizophrenia, autism, attention deficit hyperactivity disorder, progressive supranuclear palsy, CADASIL, and Korsakoff syndrome. It also appears in the course of generally healthy aging.
• The advent of the worldwide COVID-19 pandemic in 2020 was accompanied by a large number of chronic neurologic disturbances. Among them is executive dysfunction, associated with the common complaint of "brain fog” (impaired focusing of attention). The widespread executive dysfunction that follows COVID illness portends a considerable imposition on public health care resources.
The term "executive function" is a relatively recent addition to behavioral neuroscience. The frontal lobes were observed to be selectively involved in the self-regulation of voluntary activities, such as problem solving, planning, inhibiting responses, strategy development and implementation, and working memory. Oppenheim, in the 1890s, associated personality changes with the orbital and mesial frontal lobes (143; 144). Luria distinguished three functional units in the brain: (1) arousal-motivation (limbic and reticular systems); (2) receiving, processing, and storing information (postrolandic cortical areas); and (3) programming, controlling, and verifying activity (frontal lobes) (120). Luria mentioned that this third unit has an executive role. "Executive function" as a term has been addressed by many but was coalesced by Lezak to discriminate cognitive functions from the "how" or "whether" of human behaviors (112). Lezak emphasized the fluidity of executive function and how the other cognitive and emotional functions depended on the hypothetical "executive." Baddeley grouped these behaviors into cognitive domains that included problems in planning, organizing behaviors, disinhibition, perseveration, reduced fluency, and initiation (11). Baddeley coined the term "dysexecutive syndrome." Each component of executive function has added to the array of cognitive processes, which include maintaining a problem-solving set for goal-directed behavior, interference control, flexibility, strategic planning, and the ability to anticipate and engage in goal-directed activity (47).
The definition of executive function encompasses actions fueled by conceptualizations, such as the ability to filter interference, engage in goal-directed behaviors, anticipate the consequences of one's actions, and the adaptive concept of mental flexibility (119; 120; 48; 76; 185). The concept of morality, ethical behaviors, self-awareness, and the idea of the frontal lobes as manager and programmer of the human psyche are also included.
Elliott defines executive function as complex processing requiring coordinating several subprocesses for particular goal (58). Intact frontal processes, although not synonymous with executive function, are integral to executive function. Although attempts to localize executive function to discrete frontal areas have been inconclusive, the emerging view is that executive function is mediated by dynamic and flexible networks. Neuroimaging results have implicated posterior, cortical, and subcortical regions in executive functioning (161; 153).
Phineas Gage became a metaphor for frontal lobe dysfunction, and the dysexecutive syndrome became synonymous with frontal lobe pathology. Harlow described Phineas Gage as a responsible foreman for a railroad company who suffered a tragic accident in which a tamping rod explosively rammed through his frontal lobes when he was supervising the construction of the Rutland and Burlington Railroad across Vermont (90). He was reported to have died in a drunken brawl. Initial analyses of Phineas Gage’s skull findings suggested that the injury involved both frontal lobes (44). Computer-generated 3-D reconstructions of a thin-slice computed tomography scan of the trajectory of the rod showed that the brain damage was limited to the left frontal lobe; furthermore, the ventricles and the vital intracranial vascular structures were not affected (159). It was of interest to Harlow that other cognitive functions (ie, memory, language, and sensory motor functions) remained intact, whereas personality was so greatly altered. In this instructional historical case, the “central executive” that regulates other neurologic functions was disrupted but not the basic other, foregoing neurologic functions
During the late 19th and early 20th centuries, clinical investigations documented diverse behavioral disorders in frontal disease. In 1880, Herman Oppenheim coined the term Witzelsucht, which was demonstrated by childishness and joking with "alleged" cheerfulness (143; 144). The term moria (reflecting "stupidity" and jocular attitude) was part of the change they observed. Oppenheim’s patients all had tumors involving right frontal areas, frequently invading the mesial and basal areas. Jastrowitz noted unconcern and "inappropriate cheerfulness" (102). "Frontal lobe syndrome" was conceptualized by Feuchtwanger (64). He correlated frontal pathology with behaviors that were not related to overt speech, memory, or sensorimotor deficits. He emphasized the personality changes in motivation, affective dysregulation, and the capacity to regulate and integrate other behaviors. Kurt Goldstein expanded the capacity of frontal lobe behaviors to include "the abstract attitude," initiation, mental flexibility, and gaining both the components and the gestalt of the complex environmental arena (80). Goldstein was also sensitive to the compensatory reactions of brain injured individuals coupled with premorbid personality characteristics.
Initially, it was not apparent that "frontal lobe" and "prefrontal cortex" were not synonymous with loci associated with executive dysfunction. The first 3 decades of the 20th century described precisely the structure of the prefrontal regions. Vincent was one of the first researchers to become aware that the connections to the prefrontal cortex were important to function (198). Early studies elucidated hypothalamic prefrontal connections (199), thus, beginning the research into autonomic and emotional responses of the mesial-orbital prefrontal cortex. It was here that bilateral mesial prefrontal damage that involved the supplementary motor area and the singular cortex was found to produce amotivational akinetic apraxia and motor planning deficits.
When World War II yielded focal brain deficits, frontal lobe pathology was extensively evaluated. Luria related prefrontal lobe activity with programming movement, inhibiting immediate responses as needed, abstracting, problem solving, verbal regulation of behavior, reorienting behavior according to the behavioral consequences, temporal integration of behavior, personality integrity, and consciousness (119; 120).
Currently, executive function research uses functional brain imaging techniques to pool collateral findings, look at antecedents, and use a large sample size to eliminate spurious variables; thus, brain regions that contribute to dysexecutive syndromes may prove to be more multifunctional (117). Functional imaging has demonstrated that adults and children with focal, especially frontal, right-hemispheric lesions display similar behaviors such as attentional deficits, inability to inhibit a response, and impersistence of activity (65).
The relationship between executive functions and so-called general intelligence is not well-defined yet (69). Barbey and colleagues evaluated impairments on the Wechsler Adult Intelligence Scale and Delis-Kaplan Executive Function System in 182 patients with focal brain damage in relation to voxel-based lesion-symptom mapping (14). Abnormal performance in these tests was observed following damage to a distributed network of left lateralized brain areas (frontal and parietal cortex and white matter association tracts). It has also been pointed out that some executive function tests, such as the Wisconsin Card Sorting Test and Verbal Fluency, are closely linked to fluid intelligence. Departing from the hypothesis that fluid intelligence is related to executive function, a confirmatory factor analysis on a mixed neuropsychiatric and nonclinical sample found a high correlation between fluid intelligence and executive functioning (0.91), with working memory being the most profound indicator (195). A moderate to high correlation between crystallized intelligence and executive function was also present. The authors concluded that this study clearly supported the strong association between executive function and intelligence, particularly fluid intelligence. Executive dysfunction observed in some clinical conditions such as Parkinson disease can be interpreted to reflect a decrease in fluid intelligence (162).
The frontal lobes, the generally accepted brain's chief executive, orchestrate what is most distinctly human about us. Executive function disrupts social behaviors, motivation, and concepts that originally were guided and reinforced by external events and contingencies. The frontal lobes clearly moderate personality and affect and contribute to all behaviors. Barkley asserts that executive function primes the individual for survival by allowing appropriate self-representations to regulate internal behaviors and, thus, fosters social integration and species survival (15). The prefrontal cortex has also been identified as the core site for integrating mood and cognition (135). Goal-directed tasks and effort-demanding activities are frequently impaired in frontal lobe disease. Although language phonology, lexicon, and grammar are frequently spared, the ability to correctly select and use language (ie, language pragmatics) is significantly decreased (motor transcortical aphasia or extrasylvian aphasias). Similarly, complex aspects of writing, such as planning, narrative coherence, and maintained attention are also disturbed (dysexecutive agraphia) (10).
Stuss and Levine point out that the frontal lobes, in particular the frontal poles, are involved in uniquely human capacities that include self-awareness and mental time travel (186), although research suggests that highly intelligent other organisms may be able to conceive themselves as unique individuals, as for example with self-recognition before a mirror (177). Clinical and experimental research has converged to indicate the fractionation of frontal subprocesses and the initial mapping of these subprocesses to discrete frontal regions (186). Factor analysis has also suggested that executive functions include several subcomponents (184; 124). For example, Testa and colleagues performed a factor analysis of 19 executive function tests administered to a nonclinical sample of 200 adults, and found six independent factors: prospective working memory, set-shifting and interference management, task analysis, response inhibition, strategy generation and regulation, and self-monitoring and set-maintenance (190).
Anatomically, the frontal lobes are the most evolved anterior areas of the brain. Ontogenetically, of various brain regions the frontal lobes are the last to myelinate (87). Laterally, they are anterior to the Rolandic fissure and superior to the Sylvian fissure. Medially, they extend forward from the Rolandic fissure and the corpus callosum. It is the prefrontal cortex (Brodmann areas 8, 11, 12, 24, 25, 32, 33, 46, and 47) that is thought to play a large role in neurobehavioral syndromes (120; 185). Several variants can be distinguished.
Orbitofrontal syndrome. Orbitofrontal syndrome has been associated with disinhibition, inappropriate behaviors, irritability, mood lability, tactlessness, distractibility, and loss of import to events. Affect may become extreme with moria (an excited affect) or Witzelsucht (the verbal reiteration of caustic or facetious remarks), first noted by Oppenheim (143; 144). They are unable to respond to social cues, and they are stimulus bound. Cummings noted that automatic imitation of the gestures of others may occur with large lesions (42). It was noted by Laiacona and colleagues that these patients had no difficulty with card-sorting tasks (109). Lesions of the orbitofrontal circuit may also be implicated in obsessive compulsive disorder (188; 169).
Eslinger and Damasio coined the term "acquired sociopathy" to describe dysregulation that couples both a lack of insight and remorse regarding these behaviors (59). Much of this may reflect the stimulus-bound nature of this disorder. The orbitofrontal cortex appears to be linked predominantly with limbic and basal forebrain sites. The orbital prefrontal cortex may have the ability to maintain its own level of functional arousal due to its cholinergic innervation from the basal forebrain (133).
Medial frontal lobe. The anterior cingulate is the origin of the anterior cingulate-subcortical circuit. Goldman-Rakic and Porrino identified input from Brodmann area 24 to the ventral striatum, which includes the ventromedial caudate, ventral putamen, nucleus accumbens, and olfactory tubercle (79). Damage to these circuits causes apathy or abulia (a severe form of apathy). Acute bilateral lesions in the medial frontal area can cause akinetic mutism, in which the individual is awake and has self-awareness but does not initiate behaviors (165). These patients demonstrate diminished drive. The spectrum can range to the extreme following bilateral lesions (ie, they can result in patients who can be profoundly apathetic, rarely move, may be incontinent, may eat when fed, and may speak only in monosyllables when questioned). They are not emotionally reactive, even with painful stimuli, and appear completely indifferent (43). Subcortical deficits, as seen with Parkinson disease and Huntington disease as well as thalamic lesions, may cause apathy if the anterior cingulate is affected (149; 07; 16).
Dorsolateral syndrome. Cummings indicated that the dorsolateral circuit is the most important to executive function (42). The most noted deficit is an inability to organize a behavioral response to novel or complex stimuli. Symptoms are on a continuum and reflect capacity to shift cognitive sets, engage existing strategies, and organize information to meet changing environmental demands. Dorsolateral prefrontal cortex seemingly plays a central role in global aspects of general intelligence (13). Subcortical dementias are characterized by executive dysfunction. Typically, these patients exhibit long response latencies and difficulty with semantic retrieval with preservation of recognition (29). Various researchers, including Luria, have noted preservation, stimulus-bound behavior, echopraxia, and echolalia (119). Lateralization has been noted in executive dysfunction. Following lesion to the right dorsolateral area, a transcortical motor aprosodia is expected, whereas a left-sided dorsal lesion will produce a decline in verbal fluency on word-generation tasks and extrasylvian (transcortical) motor aphasia (19). Luria noted that such patients have emotional blunting when there is bilateral involvement as well as particular difficulty with ordering and sequencing tasks and amotivation (120). Ventral and dorsal aspects of prefrontal cortex are believed to interact in the maintenance of rational and “nonrisky” decision making (123); hence, this cortical area is seemingly involved in the cognitive control of experienced decision costs (129).
Lateralization. Goldberg describes two types of cognitive control: one guiding behavior by internal cues and the other by external cues (76). Normally operating in concert, damage to the frontal lobes can result in perseveration (disinhibited repetition) due to diminished ability to switch behaviors in response to changing demands and environmental dependency as well as due to inability to generate behaviors that are guided and personal. The left prefrontal system is thought to subserve the guiding of cognitive selection by working memory and internal contingencies, whereas the right prefrontal area mediates guiding cognitive selection by external environmental contingencies.
Ardila suggested that the prefrontal lobe participates in two closely related but different executive function abilities: (1) "metacognitive executive functions" such as problem solving, planning, concept formation, strategy development and implementation, controlling attention, manipulating concepts in working memory, and the like; and (2) "emotional/motivational executive functions" such as coordinating cognition and emotion/motivation (that is, fulfilling biological needs according to some existing conditions) (08). “Metacognitive” and “emotional/motivational” executive functions may have arisen at different times during human evolution, and although primates and hominids may possess (or have possessed) the second, the first is observed only in humans and is, therefore, likely a recent evolutionary development.
Nonetheless, not all executive processes are exclusively sustained by the frontal cortex (06), even though executive dysfunction that follows focal brain injury most often occurs (or is most severe) following frontal lobe injury. Lesions in nearly any part of the brain have been associated with executive dysfunction (92). Contemporary research even finds strategy operations in the occipital cortical neurons on visual tasks (187). Andres analyzed two executive processes: inhibition and dual-task management (05). He concluded that (1) executive processes involve links between different brain areas, not exclusively with the frontal cortex, (2) patients with no evidence of frontal damage may present with executive deficits, and (3) patients with frontal lesions do not always show executive deficits. Using a multivariate twin study of three components of executive functions (inhibiting responses, updating working memory, and shifting between tasks), Friedman and colleagues found that executive functions are highly correlated, suggesting a common factor that goes beyond general intelligence; these authors concluded that executive functions represent one of the most heritable psychological traits (67). In a convergent study, the structural integrity on brain MRI of a major white matter bundle, the superior longitudinal fasciculus, which links the frontal and parietal cortices, better correlated with concurrent executive function in stroke patients than did either general clinical stroke severity or lesion extent (197).
Interestingly, individual differences in neural mechanisms of executive control have been suggested (23). Breukelaar and colleagues investigated grey matter volume changes in children and young adults, including dorsal regions of the lateral prefrontal cortex and the parietal cortices, and they were under the assumption that these areas involve the cognitive control network (24). Volume decreases in the cognitive control network were associated with improved performance in executive function tasks in left lateral prefrontal cortex and bilateral parietal cortex. These authors suggested that these findings imply age-independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains.
The severity of executive dysfunction and the pattern of recovery are variable. Recovery may be related to the extent and the etiology of the damage or advanced age. In children, executive disorders may be observed several years after the brain pathology; initial evaluation may not demonstrate dysfunction.
The patient, a 43-year-old man, had a large bifrontal meningioma resected in 1991. MRI confirmed that he had a large heterogeneous extra-axial right frontal brain tumor. He did not demonstrate any obvious signs of cognitive dysfunction but was having severe headaches and personality changes, which included perseverative thinking and cognitive rigidity and inflexibility. Postsurgery, he remitted in all of these symptoms. He married several years later and, again, personality changes were noted. They were insidious but escalating. He was described by family members as having difficulty shifting from a topic and becoming obsessed with topics, ideas, and activities. It was difficult for him to shift from a given topic. He was having frequent altercations with his wife that she perceived as threatening, which led to a marital separation.
In 2001, MRI noted a recurring bifrontal meningioma in the left frontal area above the orbital roof and the lateral aspect of the frontal region. Biopsy confirmed benign meningioma. At the time of evaluation, 3 months postsurgery, he did not demonstrate significant deficits of memory or cognition as measured by the Wechsler Adult Intelligence Scale, 3rd edition, or the Wechsler Memory Scale, 3rd edition. His ability to use acquired knowledge, verbal reasoning, and comprehension of verbal information was in the high average range. Interestingly, he was in the superior range on the attentional task of digit span and letter-number sequencing, which reflected his auditory processing sequential ability, and his ability to hold memory in sensory memory for further manipulation was also in the superior range. Yet, tasks that reflected executive functions were decreased by slow processing speed and difficulty attaining novel strategies. On the category test, which measures problem solving ability, his ability to a generate hypothesis without a time frame was extremely slow. He had difficulty making constructive use of feedback initially but began to demonstrate the use of strategies to deal with novel tasks. Consistent with his performance on the Wisconsin Card Sorting Test, a task intended to identify abstract categories and the shifting of cognitive sets, he demonstrated perseverative responses that placed him in the low average range. He had difficulty relinquishing an old category but no difficulty maintaining a set. He again improved in his performance on this task as well; however, he would get up during the task and pace about the room, verbally mediating his performance. On the Stroop Test, which has a time restraint to measure the shifting of cognitive sets to conform to changing demands, he was in the impaired range, reading 67 words in 2 minutes. He demonstrated selective slowing on the conflict condition of this task. His perseveration and difficulty adopting novel strategies may reflect dorsolateral prefrontal disruption. His ability to regroup implies that various subsystems of the frontal lobe circuitry may allow for mediation and integration of tasks that are moderated by the frontal lobes.
Executive dysfunction is most often recognized following a stroke, tumor, or brain trauma. Children have little capacity for executive function prior to adolescence. Maturation changes implicate areas of prefrontal cortex that involve areas of response inhibition, maintenance of mental representations of information (working memory), and temporal organizational capacity (35). Attention deficit hyperactivity disorder is a much researched area where core deficits include impulsivity, hyperactivity, and attentional deficits (15; 110). The disorder has been interpreted as one of executive dysfunction that includes both cognitive and motor components (55; 68; 170). Executive dysfunction in attention deficit hyperactivity disorder is found at least through the late teen years both in boys and girls (176). It has also been pointed out that adolescents with conduct problems have impairments of executive function and inhibition, and that these impairments are associated with frontal dysfunction (106). Clinically significant focal frontal lobe dysfunction is associated with aggressive dyscontrol. Violent criminals present worse response inhibition compared to nonviolent offenders; this observation suggests a more significant prefrontal abnormality in violent individuals than in nonviolent offenders (191; 132). By the same token, sexual offenders report high rates of executive dysfunction (28).
Cognitive deficits in schizophrenia parallel deficits related to executive function. Following Lezak's model, the cardinal features of executive function, which include metacognition (113)—the ability to organize and direct attention in memory to goal-directed tasks—are impaired in schizophrenia (75). It has also been suggested that executive dysfunction may be locked in at an earlier stage of schizophrenia than the cognitive deficits so often associated with the illness (173). It has been further proposed that pathology of the dorsolateral prefrontal cortices could be the neural basis of dysexecutive behaviors in schizophrenia patients (105). Analogous executive dysfunction deficits have been noted in autistic individuals who are high functioning but perseverate on tasks with difficulty disengaging from the immediate contexts (99). Executive function disorders have also been reported in other psychopathological conditions. For example, Blair and colleagues found that individuals with psychopathy showed significant impairments on those neuropsychological tests sensitive to orbitofrontal cortex function (20), and Ross and associates reported a significant correlation between psychopathy and components of executive dysfunction (166). Executive defects have been found in violent criminals (89) and serial killers (09).
Subcortical stroke and vascular dementias demonstrate executive dysfunctions (108; 139), and subcortical lacunes are associated with executive dysfunction in otherwise cognitively normal elderly persons (33). The vascular dementias are often implicated in executive dysfunction such as progressive subcortical vascular encephalopathy and selective incomplete white matter infarction. Executive dysfunction significantly predicts future decline in this dementia (22). Diseases that are subcortical and also affect executive function are Huntington disease, Parkinson disease, progressive supranuclear palsy, multiple sclerosis, HIV, subcortical vascular dementia, and Wilson disease (57; 101; 125; 53). The executive deficits noted in these subcortical disorders may reflect a lack of facilitation of frontal integrity during executive tasks. It has been suggested that the various cognitive symptoms found in Parkinson disease are secondary to executive dysfunction (96) and probably due to impairments in frontostriatal circuits (206; 52). With PET, patients with Parkinson disease have reduced activation of the dorsolateral, frontal, mesial frontal, and striatal areas during cognitive tasks (07). Apathy, a cardinal feature in subcortical disorders, presents with poor self-initiation. Motivation and capacity can be present (57); thus, apathy may not reflect mood congruence. Executive dysfunction has also been reported in a case of anterior thalamic ischemia (116). Of note, ApoEe4 allele carrier status has been found to be significantly associated with executive dysfunction in Parkinson disease (168).
Stroke represents a frequent etiology of executive dysfunction, although specific manifestations can be different in different individuals. In a sample of 237 stroke patients (infarct: 57; cerebral hemorrhage: 54; ruptured aneurysm of the anterior communicating artery: 80; cerebral venous thrombosis: 46), dysexecutive syndrome was observed in 88 (55.7%) out of the 156 patients with full cognitive and behavioral data: 40 (45.5%) had combined behavioral and cognitive syndromes, 29 (33%) had a behavioral disorder alone, and 19 (21.6%) had a cognitive syndrome alone (167).
Executive dysfunction has been documented in a diversity of conditions, including small vessel disease (137), traumatic brain injury (even in children) (74; 66; 91; 41; 73), Parkinson disease (31), white matter lesions (194), moyamoya disease (30; 61), myotonic dystrophy type 2 (155), borderline personality disorder (51; 88), substance abuse (17; 95; 63; 121; 180), multiple system atrophy (27), multiple sclerosis (171; 36), autism (97; 70), contact-sport athletes (such as football players) (175), late life anxiety and depression (204; 160), progressive supranuclear palsy (134; 71), temporal lobe epilepsy (02), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (148), extra X chromosome (47,XXY and 47,XXX) syndrome (196), amyotrophic lateral sclerosis (50), and Korsakoff syndrome (25; 146). Patients with mild cognitive impairment also present a high prevalence of executive dysfunction symptoms (21; 164; 38). Executive functions are highly sensitive to diverse abnormal conditions, and even less effective executive function has been documented after a single night's sleep deprivation (142).
The novel COVID-19 (SARS-CoV-2) worldwide viral pandemic that began in 2020 has been accompanied by diverse chronic symptoms, despite recovery from the contagious phase of the illness. About 57% of persons may have such “long COVID” illness (189). The illness is associated with new-onset global cortical atrophy (Douad et al in press). This finding implies a serious, widespread neurologic disorder whose long-term effects are not yet understood. Furthermore, many instances of acute executive dysfunction have been reported to follow COVID illness (94; 158; 18; 82; 85; 93; 103; 145; 100; Douad et al in press), which commonly co-occurs with the complaint of “brain fog” or impairment with focusing attention.
Aging can affect one's ability to recall temporal ordering of events in both healthy and demented individuals. It is important to differentiate normal aging decrement from frontal dementia. This evaluation includes executive function. Gunning-Dixon and Raz examined the neuroanatomical substrates of age-related differences in working memory and perseverative behavior in a sample of healthy adults (50 to 81 years old) (86). Regional brain volumes and the volume of white matter hyperintensities were measured on magnetic resonance images. The analyses indicated that the volume of the prefrontal cortex and the volume of white matter hyperintensities in the prefrontal region are independently associated with age-related increases in perseverative errors on the Wisconsin Card Sorting Test.
So-called mild cognitive impairment is characterized as a transitional state when decreased performance on selected cognitive domains is observed (156; 114), frequently predicting a dementia. Different subtypes of mild cognitive impairment have been distinguished, including a dysexecutive mild cognitive impairment subtype characterized by relatively specific deficits in executive functions. Huey and colleagues selected 1167 ethnically diverse elders with clinical and cognitive testing for an average of 4.5 years (SD = 0.8 year). Four different subgroups of patients with mild cognitive impairment were separated: single-domain amnestic and dysexecutive mild cognitive impairment, and multiple-domain mild cognitive impairment with and without executive dysfunction. It was found that dysexecutive mild cognitive impairment was less associated with Alzheimer disease and more associated with stroke than amnestic mild cognitive impairment (98).
Small vessel disease, Binswanger disease, and frontotemporal dementia have a particular affinity for the prefrontal circuitry. Frontotemporal dementia is characterized by atrophy of the frontotemporal cortices, microvacuolation, gliosis, and synaptic and neuronal loss with the presence of Pick bodies (181). Alzheimer disease, primarily a neurodegeneration of the cortex, begins in limbic and hippocampal structures and spares (as a rule) the sensory and motor cortex. In later stages, the prefrontal and frontal cortices become involved; however, executive dysfunction may be an early feature of some patients with Alzheimer disease (130). The structural correlate to certain dimensions of executive dysfunction in patients with Alzheimer disease has been suggested to relate to changes in the deep frontal white matter (179). In patients with both Alzheimer disease and mild cognitive impairment a significant association between hippocampal atrophy and executive dysfunction has been demonstrated (141).
When comparing the neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease, both the patients with Alzheimer disease and semantic dementia are significantly impaired relative to the frontotemporal dementia group on verbal memory, whereas only the Alzheimer disease group is impaired on visual memory. Patients with frontotemporal dementia perform significantly worse on backward digit span and make significantly more executive errors than Alzheimer disease and semantic dementia patients. Patients with semantic dementia are more impaired than patients with Alzheimer disease and frontotemporal dementia on confrontation naming (107). It has been reported that performance on executive function tests presents an accelerated decline 2 to 3 years before the diagnosis of Alzheimer disease (84). By the same token, executive defects early in the dementia process represent a predictor of subsequent behavior disturbances (193), further functional decline, and mortality (104). A consistent association between activities of daily living in Alzheimer disease and executive functions has been reported (126), and a behavioral or dysexecutive variant of Alzheimer disease has been reported (147).
Graham and colleagues analyzed the distinctive cognitive profiles in Alzheimer disease and subcortical vascular dementia (83). They concluded that both patient groups have impairments in all cognitive domains. The Alzheimer patients, however, are more impaired than those with vascular dementia on episodic memory, whereas the patients with vascular dementia were more impaired on semantic memory, executive and attentional function, general attention, and visuospatial and perceptual skills. Interestingly, it has been documented that executive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia (72).
The disruptions that occur are both structural and chemical. Disruption of these cortical-subcortical circuits interrupts functions of the intact brain. Lesions of the dorsolateral circuit are associated with metacognition deficits, lesions of the orbitofrontal-subcortical circuit are associated with disinhibition, and lesions of the anterior cingulate circuit are associated with apathy and abulia. Each circuit is modulated by both an indirect and direct pathway to the thalamus. The direct effect of the circuit is to disinhibit the thalamus; the indirect pathway inhibits the thalamus. The indirect pathway includes the subthalamic nucleus. Although each circuit shares anatomical open afferent and efferent connections to allow communication between the circuits, neurotransmitter functions vary (39). The neurochemistry of frontal lobe integrity is core circuits that form functional neural loops to connect frontal to cortical regions. These loops reverberate from the basal ganglia, thalamus, and back to the frontal cortex. The core neurotransmitters are glutamate, an excitatory neurotransmitter, and gamma-aminobutyric acid, the major inhibitory neurotransmitter in the brain (62).
Alexander and colleagues described cumulative firings that will inhibit or disinhibit activity of the frontal-subcortical loop (04). These parallel systems allow mediation of subcircuits to selectively modulated signals that pass through the basal ganglia to the frontal cortex (62). Parent and colleagues also identified acetylcholine as contributing to frontal-subcortical signaling in the striatum (151). It is thought to play a role in more than half of the muscarinic receptors of the dorsolateral prefrontal cortex. Cholinomimetic drugs facilitate glutamate transmission in corticocortical and corticostriatal pathways. Dopamine appears to play a role in reciprocal regulation of frontal subcortical pathways.
Saxena and colleagues review structural and functional neuroimaging research that indicates hyperactivity in orbitofrontal-subcortical circuits, which may involve dysregulation in striatopallidal pathways (169). The involvement of orbitofrontal-subcortical pathways on functional imaging reinforces the comment by Mega and Cummings that frontal-subcortical circuits form one of the principal organizational networks of the brain and are central to brain-behavior relationships (131). Noteworthy, it has been observed that the prefrontal cortex white matter is particularly sensitive to aging.
Subcortical dysregulation of frontal systems reflects the direct connections between the frontal and striatal circuits. It is thought that subcortical difficulties can be secondary to executive function impairment. Cognitive studies using neuropsychological measures have implicated executive dysfunction in Parkinson disease (149). PET studies confirm reduced activation of dorsolateral frontal, mesial frontal, and striatal regions in patients with Parkinson disease during cognitive tasks (07).
The incidence of executive dysfunction has been little examined. In a French study, about one third of the middle-aged sample was shown to have executive dysfunction, despite their lack of cognitive complaint (174). This disturbance was associated with obesity. Similarly, in a study of adults who were hospitalized for acute disability and specifically without an identified brain disease, executive dysfunction was prevalent compared to average test scores in the general population (203). These observations imply that executive dysfunction is widespread in persons with general medical disease.
Impaired arousal can be confused with impaired action initiation, an aspect of executive function. When initiation (or spontaneous voluntary activity) is selectively impaired, other cognitive functions may be intact, for example, reciting well-learned material only on request, such as the alphabet or the months in their normal order. In contrast, impaired arousal will similarly limit all cognitive functions, executive and other. Impaired arousal can be judged when a patient does not obey commands while appearing to be drowsy. Further detail on the select interference with spontaneous voluntary activity in neurologic disease is discussed in the article in automatic-voluntary dissociation.
Disturbance of Theory of Mind resembles executive dysfunction. Theory of Mind refers to the ability to infer the mental functions of another person without direct knowledge, for example, by watching another person’s change in gaze or facial gestures. Theory of Mind is vital to healthy social interaction and relies on abstraction, an executive function. Consequently, executive dysfunction can undermine Theory of Mind. Nonetheless, Theory of Mind operations can be dissociated from formal executive assessments (01), which suggests that Theory of Mind as a general function is distinct from executive function.
Aging ordinarily involves executive deficits, including planning, alternating responses, controlling attention, and decision making. The extent of the aging effect is, however, different for various executive tasks and seems to be mediated by education (163). Lin and colleagues used seven executive function tests in two groups of healthy elders, with one group age 60 to 70 years and the other over 70 years. A significant difference was found between the two groups in attention, planning, and total score. Regression analyses, however, indicated that age accounted for just little variance, whereas education level accounted for a large part of varying initiation, switching and flexibility, and updating components of executive function (115). Gomez-Perez and Ostrosky-Solis observed that whereas tests related to memory are sensitive to aging, those related to executive function are mostly sensitive to education (81). Etienne and colleagues, using the 3-component model of executive functions proposed by Miyake and colleagues (inhibition of irrelevant information, updating of information in working memory, and mental shifting between tasks), found that inhibition and updating were impaired in older subjects, whereas flexibility was not (136; 60).
Executive dysfunction is usually observed in dementia, especially in frontotemporal dementia and traumatic brain injury. Some executive dysfunction is common even in early Alzheimer disease, but the specific pattern of impairment varies (183). It has been suggested that in mild cognitive impairment, two different subgroups can be separated: amnesic and dysexecutive. In the last one, significantly lower scores in executive function tests, increased behavioral symptoms, and left prefrontal cortex atrophy on magnetic resonance imaging are found (150). It has been reported that impaired subcortical connectivity is associated with significant network disruption in traumatic brain injury and that this disruption is related to the executive dysfunction found in these patients (49).
Depressed patients may present impairments in executive function, including problems with planning, initiating, and completing goal-directed activities (45). Some memory dysfunctions (in particular, lack of responsive to cues) are associated with executive dysfunction (154). Executive function fully develops during adolescence; in minors, an inability to successfully perform in executive function tasks is observed.
Comorbid non-neurologic diseases may affect executive control, a research area that is little explored. Glaucoma (excessive intraocular pressure associated with retinal damage) can impede visual executive test scores (111).
It is difficult to separate intellectual function from executive function. Dysexecutive syndrome can disrupt self-regulating, stimulus control, and purposeful rational thought, thus affecting test performance. Many of the "executive tasks" attempt to tap into the individual’s ability to formulate strategies, to separate essential from nonessential, and adapt to conditions that become novel. It has been emphasized that there is no single measure of executive function; rather, different tests represent different executive components and, as such, more than one measure should be used in a comprehensive assessment (12). Administering several tests of executive function to assess particular aspects of the executive function is recommended (77). Some standardized assessment test batteries are currently available, such as the Delis-Kaplan Executive Function System (46), the Behavioural Assessment of the Dysexecutive Syndrome (201), the Frontal Assessment Battery (56), and the Executive and Social Cognition Battery (192). However, it has been pointed out that the Frontal Assessment Battery is not sensitive to executive dysfunction, except for the verbal fluency subtest (37).
A limitation toward assessing executive function in brain-diseased populations is the common complexity of instructions for executive tests. Consequently, it is generally difficult to assess the executive abilities of persons with impaired auditory comprehension as a result of aphasia (200).
Tests frequently used include the Wisconsin Card Sorting Test and the category test, which test the dual task performance and the ability to shift cognitive sets. Observing the individual engage in tasks that are ambiguous and frustrating may reflect problems associated with real-life behaviors. Perseverations and the inability to shift from one stimulus to another as well as problems of working memory with inattention and failure to maintain set may appear during these tests (118).
Other tests, such as part B of the Trail Making Test and the Stroop Color Word Test, demonstrate slowing of responses as well as difficulty with set-shifting and maintaining attention to task (vigilance). During memory tasks that demonstrate proactive interference, one may observe preservations from previous items or interference with new information on tasks. The paced auditory serial attention task involves working memory, cognitive flexibility, and attentional vigilance to task. This task requires both the ability to inhibit responses and maintain an attentional set. The ability to inhibit distractions and engage in complex processing speed is an integral component of these tasks (113). Picture arrangement, matrix reasoning, and number-letter sequencing can, at least partially, be regarded as executive function tests.
Other executive function tests include similarities (eg, "How are a car and a bus alike?" A concrete answer may be that both have wheels, whereas an abstract answer may be that they are vehicles), proverb interpretation (eg, what does it mean "Rome was not built in one day?” A concrete answer may be that the construction of Rome took a long time, whereas an abstract answer may be that any endeavor takes time), and Luria's opposite reactions tests (eg, if the examiner presents a finger, then the patient is requested to present a fist; and if the examiner presents a fist, then the patient must switch to a finger response). In verbal fluency tests, two different conditions can be used: (1) semantic (eg, to list animals in 1 minute), and (2) phonological (to find words beginning with a particular letter). Normal performance in the first condition is about 18, whereas the second is about 12; age and education significantly affect performance. Clock drawing is another such simple test, assessing if one pays attention to whether the numerals are evenly arrayed about the circle and occur without perseverations. So-called "mental control" tasks (eg, to say the months of the year backwards) are sensitive to executive dysfunction. Spelling backwards has been shown to be sensitive to dementia in English speakers (138).
Goldberg and Podell address the ecological validity of current tests for executive dysfunction (78). Most neuropsychological tests provide an external structure for the task. Adaptive processes include priorities and internally guiding the individual toward goals and objectives. The authors indicate that tasks are needed that require the subject to make selections based on his or her preferences rather than on stimulus characteristics or constraints. The tasks must remain ambiguous and the choice of responses left up to the subject. Manchester and colleagues emphasize the importance of reliable behavioral observations in addition to the formal testing (122). Currently, several questionnaires are available such as the Dysexecutive Questionnaire Revised (DEX-R) (178). Some ecological measures of executive functions have been also proposed (128; 205).
Specific therapy for executive dysfunction is not well developed. Patients with difficulty with initiation, impulsivity, or lack of self-regulation demonstrate better response to environmental cues and external reinforcement of appropriate behaviors. Cognitive retraining can utilize compensatory devices, cues for self-instruction, and metacognitive strategies (127). Schweizer and coworkers used a cognitive rehabilitation technique, Goal Management Training, in a patient with persistent executive dysfunction with modest improvement in sustained attention, planning, and organization that improved in everyday life activities (172). The Short-Term Executive Plus (STEP) cognitive rehabilitation program has demonstrated to be useful in improving self-reported executive dysfunction in patients with traumatic head injury (32). Manipulation and modification of environmental conditions as well as behavior management have also been used in patients with executive disorders (140). Positive effects of cognitive training on the ability to set and accomplish realistic goals; to plan, initiate, and maintain real-life activities; and to resume previous social and working roles have been reported (182).
Intellectual tasks and everyday activity programs have proven beneficial in increasing executive function abilities. In a pioneer study, 149 older sedentary adults were trained to help elementary school children with reading achievement, library support, and classroom behavior for 15 hours weekly during an academic year. Participants presented some improvements in executive functions and memory when compared with matched controls. Participants with impaired baseline scores improved about 44% in executive functions and 51% in memory (34). Some authors have successfully used multidisciplinary rehabilitation programs to improve executive functions in patients with acquired brain injury and executive dysfunction (157).
Computerized training to boost the speed of decision-making on visual tasks can carry over to improving select executive function assessments (Stroop test, Trail Making Test B) in elderly individuals (202). It is not yet clear whether such training can extend to improving self-care. In a related trial, training in piano playing bested computer training on improving perception on executive test assessments in elderly participants, though retention of improvements was not examined (26).
Preliminary findings suggest that exercise can enhance executive functions in the elderly (152).
Pharmacological approaches that alter neurotransmitter function can have beneficial results. The dopamine system in the prefrontal cortex is more sensitive to mild reductions in its precursor tyramine. Dopamine neurons fire and turn over dopamine rapidly. Selectively depleting dorsolateral prefrontal dopamine can produce deficits as severe as total ablation, and dopamine antagonists impair performance of working memory functions believed to be related to dorsolateral prefrontal involvement. Noradrenergic agonists and dopamine agonists as well as atypical antipsychotics (ie, risperidone) increase dopamine in the frontal cortex. Psychostimulants, such as methylphenidate (a sympathomimetic), cause the release of norepinephrine and elevate dopamine release. Dopamine agonists may induce improved response initiation (165). Bromocriptine has been used to improve speech initiation in aphasia. Albert and colleagues attempted to restore speech fluency in a patient with long-standing transcortical motor aphasia by treating his symptoms of hesitancy and impaired initiation of speech with bromocriptine (03). During therapy, his language performance improved substantially due to reduced latency of response, decreased paraphasias, and increased naming ability. After cessation of drug therapy, his language returned to baseline. Unfortunately, treatment response to bromocriptine is highly variable.
Coull and colleagues have investigated the use of alpha-2 antagonists (idazoxan) on cognitive function in frontal lobe dementias (40). The results supported the role of the alpha-2 adrenoreceptor in both executive function and, most likely, as an attentional modulator that may mediate executive function indirectly.
Victor W Mark MD
Dr. Mark of the University of Alabama at Birmingham has no relevant financial relationships to disclose.See Profile
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