Assessing cognitive functioning in ALS: A focus on frontal lobe processes.

OBJECTIVE: It is generally acknowledged that at least 50% of individuals with amyotrophic lateral sclerosis (ALS) will exhibit cognitive deficits outside of the characteristic motor neuron involvement. However, a specific cognitive profile has been difficult to ascertain due to disease-related testing barriers and limitations in the sensitivity and specificity of available assessment methods. This study assessed the level of functioning of extramotor frontal cognitive processes in ALS, and the amount of change in the functioning in these processes over time as disease progresses. METHODS: Empirical tests validated for a model of frontal lobe functioning were modified into an assessment battery appropriate for individuals with ALS in a clinical setting (the ALS-CFB, Computerised Frontal Battery). Twenty ALS participants and 36 age- and education-matched neurologically healthy controls were tested, and a sub-sample of each group (11 ALS and 20 controls) re-tested after approximately nine months. RESULTS AND CONCLUSIONS: Compared to standard neuropsychological screening tests that did not show a difference between ALS participants and healthy controls, the ALS-CFB illustrated a profile of extramotor frontal dysfunction involving energisation (preparing the neural system to respond) and executive functions, a profile that may be indicative of the nature of neurodegeneration in ALS.

No evidence of risk-taking or impulsive behaviour in a person with episodic amnesia: Implications for the role of the hippocampus in future-regarding decision-making.

Does advantageous decision-making require one to explicitly remember the outcome of a series of past decisions or to imagine future personal consequences of one's choices? Findings that amnesic people with hippocampal damage cannot form a clear preference for advantageous decks over many learning trials on the Iowa Gambling Task (IGT) have been taken to suggest that complex decision-making on the IGT depends on declarative (episodic) memory and hippocampal integrity. Alternatively, impaired IGT performance in amnesic individuals could be secondary to risk-taking and/or impulsive behaviour resulting from impaired episodic future thinking (i.e. prospection) known to accompany amnesia. We tested this possibility in the amnesic individual K.C. using the IGT and the Toronto Gambling Task (TGT), a novel task that dissociates impulsivity from risk-taking without placing demands on declarative memory. K.C. did not develop a preference for advantageous over disadvantageous decks on the IGT and, instead, showed a slight preference for short-term gains and an inability to acquire a more adaptive appreciation of longer-term losses. He also did not display impulsive or risk-taking behaviour on the TGT, despite a profound inability to imagine personal future experiences. These findings suggest that impaired decision-making on the IGT in amnesia is unlikely to reflect a predilection to act in the moment or failure to take future consequences into account. Instead, some forms of future-regarding decision-making may be dissociable, with performance on tasks relying on declarative learning or on episodic-constructive processes more likely to be impaired.

Visual rating versus volumetry to detect frontotemporal dementia.

BACKGROUND/AIMS: Automated, volumetrically defined atrophy in the left anterior cingulate (LAC) and anterior temporal regions (LAT) on MRI can be used to distinguish most patients with frontotemporal dementia (FTD) from controls. FTD and Alzheimer's disease (AD) can differ in the degree of anterior temporal atrophy. We explored whether clinicians can visually detect this atrophy pattern and whether they can use it to classify the 2 groups of dementia patients with the same accuracy. METHODS: Four neurologists rated atrophy in the LAC and LAT regions on MRI slices from 21 FTD, 21 controls, and 14 AD participants. Inter-rater reliability and diagnostic accuracy were assessed. RESULTS: All 4 raters agreed on the presence of clinically significant atrophy, and their atrophy scoring correlated with the volumes, but without translation into high inter-rater diagnostic agreement. CONCLUSIONS: Volumetric analyses are difficult to translate into routine clinical practice.

Normal-pressure hydrocephalus: is there a genetic predisposition?

BACKGROUND: Normal-pressure hydrocephalus (NPH) is characterized by gait disturbance, cognitive impairment, with or without urinary incontinence, enlarged ventricles with or without cerebral atrophy and normal cerebrospinal fluid pressure. METHODS: We report two sisters with NPH who lived together their entire lives and whose natural history might provide insights into genetic and environmental mechanisms underlying this disorder. Both patients were in their early seventies, single, had similar daily habits and hypertension. No other family members had NPH. RESULTS: They both underwent shunt placement and showed improvement documented by history and neuropsychological assessment. Both showed a delayed deterioration due to vasculopathy. Both patients were homozygous for the apolipoprotein E (ApoE) e3 allele on chromosome 19. No environmental factors that might have influenced the development of NPH were identified. CONCLUSION: Our report of two sisters with NPH may indicate the presence of genetic predisposition and further studies involving genetics and environmental factors are necessary to elucidate their role in the pathogenesis of NPH.

Impulsivity and risk-taking behavior in focal frontal lobe lesions.

Frontal lobe dysfunction may underlie excessively impulsive and risky behavior observed in a range of neurological disorders. We devised a gambling task to examine these behavior tendencies in a sample of patients who had sustained focal damage to the frontal lobes or nonfrontal cortical regions as well as in a matched sample of healthy control subjects. The main objectives of the study were: (1) to behaviorally dissociate impulsivity and risk-taking; (2) to examine potential associations between specific frontal lesion sites and impulsivity or risk-taking; (3) to investigate the influence of reinforcement and trial timing on both behaviors. Our results indicated that patients and controls were equally likely to perform impulsively. Risk-taking performance strategies, however, were related to left ventrolateral and orbital lesion sites. Moreover, risk-taking was also associated with blunted response alteration following a nonrewarded trial. Patients and control subjects showed identical responses to reward-timing manipulations consistent with formal decision-making theory. These findings suggest that ventrolateral and orbital lesions are related to the reward-based aspects of decision-making (risk-taking) rather than to simple response disinhibition (impulsivity). Reduced reaction to the negative consequences of one's actions may underlie this behavior pattern.

Regional frontal injuries cause distinct impairments in cognitive control.

BACKGROUND: Lesions of the frontal lobes may impair the capacity of patients to control otherwise intact cognitive operations in the face of ambiguous sensory input or conflicting possible responses. OBJECTIVE: To address the question of whether focal lesions in different regions of the frontal lobes produced specific impairments in cognitive control. METHODS: We evaluated 42 patients with chronic frontal lesions and 38 control subjects on a modified Stroop test that allowed measurement of reaction times and errors. Planned, stratified analyses permitted identification of discrete frontal lesions that are critical for impaired performance. RESULTS: Lesions of the left ventrolateral region produced an increased number of incorrect responses to distractors. Lesions of a large portion of the right superior medial region, including anterior cingulate, supplementary motor area (SMA), pre-SMA, and dorsolateral areas, caused a slow reaction time and a decreased number of correct responses to targets. CONCLUSION: Lesions in two distinct frontal regions impair cognitive control for a Stroop task, and the mechanisms of impairment are specific to the region of injury. This is support for a general proposal that the supervisory system is constructed of distinct subsystems.

Changes in coping style following traumatic brain injury and their relationship to productivity status.

The use of maladaptive coping strategies following traumatic brain injury (TBI) is known to be associated with increased depression and a lower productivity status. What is not known is whether coping behaviours change following TBI and if they do change whether these changes account for significant variance in outcome. Seventy-three significant others of TBI survivors were recruited at the time their friend/family member was injured and followed prospectively. They reported on their friend/family member's pre-injury and 6-month coping behaviours using the Coping with Health Injuries and Problems Scale. The use of emotional pre-occupation coping (p = .02) increased significantly and approached significance for distraction coping(p = .08). These changes in coping also accounted for significant variance (22%, p = .02) in productivity status over and above that accounted for by demographics and injury severity. Whether maladaptive coping changes can be prevented with a view to improving outcomes is a question that now needs to be explored.

Impaired concentration due to frontal lobe damage from two distinct lesion sites.

BACKGROUND: Investigations of cognitive deficits after frontal lobe damage have commonly relied on multidimensional tests and relatively coarse specification of lesion anatomy. Some form of impairment in attention is often asserted to cause the revealed deficits. OBJECTIVE: To describe a disorder of attention in patients with frontal damage using a theoretical model of the fundamental cognitive processes that underlie attention. METHODS: The ability to perform a task of concentrated responding was studied in 43 patients with well-defined chronic frontal lesions and 38 control subjects using a continuous reaction time (RT) test. Performance measures were mean RT, RT across blocks of the test, and errors. Lesion measures were coarse localization and a hot-spot analysis to detect finer grained lesion effects. RESULTS: Only patients with lesions in the right superomedial (SM) frontal regions had significantly prolonged RT consistently across the entire test. The critical lesion was in Brodmann's areas 24, 32, 9, and 46 days and in the adjacent corpus callosum. Patients with lesions in left lateral frontal (LL) regions made significantly more errors on the 20% of trials in the first block. The critical lesion was in areas 44, 45, and 47/12. CONCLUSION: Concentrating attention to respond is affected by lesions in two different frontal regions for reasons that reflect impairments in different cognitive processes. Right superomedial lesions cause an insufficient energizing of attention to respond. Left lateral lesions cause defective setting of specific stimulus-response contingencies. Constrained tests of attention can demonstrate impairments in specific cognitive operations following lesions to different regions of the frontal lobes.

MEG analysis of "theory of mind" in emotional vignettes comprehension.

OBJECTIVE: Several studies suggested that an impaired "theory of mind" might play a key role in psychiatric disorders, such as autism and schizophrenia. Medial frontal lobe lesions of the right frontal lobe were reported to impair this ability. The aim of our study was to locate areas of the brain associated with the process of "theory of mind" in normal subjects. METHODS: In order to index the activity of brain areas related to "theory of mind" reasoning in sixteen normal adults, we administered an emotional ("happy", "sad", "angry" and "neutral") vignettes comprehension task during magnetoencephalography (MEG) recordings and analyzed these data by using SAM (synthetic aperture magnetometry), SPM99 and the permutation method. Subjects were presented with eight different videotaped social situations (each emotion has two vignettes) and were asked to indicate which emotion they represented. RESULTS: Statistically significant activation in the comparison of "happy"-"sad" and "angry"-"sad" was observed in the bilateral medial prefrontal cortices in the alpha frequency band. There were no significant differences in comparisons of each type of emotional vignette to the neutral vignettes, "happy"-"angry" comparison, and male-female comparisons. There was no significant difference in other frequency bands. CONCLUSION: This result suggests that bilateral medial prefrontal cortex are involved in the comprehension of emotional states of others.

California Verbal Learning Test: performance by patients with focal frontal and non-frontal lesions.

Although frontal lobe lesions do not cause classic amnesia, they may disrupt learning and memory in a number of ways. To investigate in finer detail the regions of frontal injury that are associated with impaired learning and to define the cognitive processing deficits specific to each region that disrupt memory, we compared 33 patients with focal frontal injury with patients with non-frontal injury and with normal controls on a standard neuropsychological instrument, the California Verbal Learning Test (CVLT). Subgroups of patients with distinct lesion site profiles were compared in a number of learning measures. All of the subgroups of patients with frontal lesions (with one exception) had inefficient learning due to poor implementation of a strategy of subjective organization. Despite this organizational deficiency, the performance of patients with frontopolar lesions normalized across trials. Only the subgroups with lesions centred either on the left posterior dorsolateral frontal region or the posterior medial frontal region had overall impaired learning and recall. The left posterior dorsolateral frontal group was most significantly impaired on all measures. This recall impairment was secondary to a mild lexical-semantic deficit. A recognition memory deficit in the same group was due to an abnormal response bias. Several groups had a modest increase in perseverative recalls; the underlying mechanisms differed. Disruption of different cognitive processes associated with specific frontal regions underlies the varied patterns of memory impairment. This study has demonstrated even finer differentiations within the frontal region than previously known.

Functional reorganisation of memory after traumatic brain injury: a study with H(2)(15)0 positron emission tomography.

OBJECTIVE: To study the effects of moderate to severe traumatic brain injury (TBI) on the functional neuroanatomy supporting memory retrieval. METHODS: Subjects were six patients who had sustained a moderate to severe TBI about four years before scanning and had since made a good recovery. Eleven healthy young adults matched to the patients for age and education served as controls. An established H(2)(15)0 positron emission tomography paradigm was used to elicit brain activations in response to memory retrieval. TBI patients' patterns of brain activation were compared statistically with those of control subjects. Both group and individual case data were analysed. RESULTS: Both TBI patients and controls engaged frontal, temporal, and parietal regions known to be involved in memory retrieval, yet the TBI patients showed relative increases in frontal, anterior cingulate, and occipital activity. The hemispheric asymmetry characteristic of controls was attenuated in patients with TBI. Reduced activation was noted in the right dorsomedial thalamus. Although local aspects of this pattern were affected by the presence of focal lesions and performance differences, the overall pattern was reliable across patients and comparable to functional neuroimaging results reported for normal aging, Alzheimer's disease, and other patients with TBI. CONCLUSIONS: The TBI patients performed memory tasks using altered functional neuroanatomical networks. These changes are probably the result of diffuse axonal injury and may reflect either cortical disinhibition attributable to disconnection or compensation for inefficient mnemonic processes.

The Trail Making Test: a study in focal lesion patients.

The relationship of the Trail Making Test (TMT) to the frontal lobes was tested by comparing patients with damage to the frontal and nonfrontal regions to control participants. Although the analysis of time measurements, both raw and transformed, showed notable slowing of frontal groups, error analysis proved to be a more useful method of categorizing performance. Analysis of errors on Part B indicated that all patients who made more than 1 error had frontal lesions. Dividing the frontal damaged patients into subgroups on the basis of the number of errors yielded specificity of brain-behavior relations within the frontal lobes. Patients with damage in dorsolateral frontal areas were most impaired. Those with inferior medial damage to the frontal lobes were not significantly affected in TMT Part B performance.

Stroop performance in focal lesion patients: dissociation of processes and frontal lobe lesion location.

There were three primary objectives: to examine the usefulness of the Stroop interference effect as a measure of frontal lobe function; to investigate the possibility of distinct lesion effects for word reading or color naming; and to specifically determine the brain regions necessary for the performance of the incongruent condition. Fifty-one patients with single focal brain lesions in frontal and non-frontal regions and 26 normal control subjects (CTL) were administered the word reading, color naming and incongruent conditions of the Stroop task. Only frontal lesions produced significant impairment. Patients with posterior lesions were not significantly deficient in any condition. Damage to the left dorsolateral frontal lobe resulted in increased errors and slowness in response speed for color naming. Contrary to Perret (Neuropsychology, 1974; 12: 323-330), lesions of the left frontal lobe did not result in a selective interference deficit on the Stroop incongruent condition. Rather, bilateral superior medial frontal damage was associated with increased errors and slowness in response time for the incongruent condition. This result is interpreted as failure of maintenance of consistent activation of the intended response in the incongruent Stroop condition. The results and conclusion are compatible with the prevalent theories of both the Stroop effect and the role of the superior medial frontal regions. The role of the anterior cingulate cortex on performance of the Stroop task is likely related to task and patient context.

The frontal lobes are necessary for 'theory of mind'.

Patients with limited focal frontal and nonfrontal lesions were tested for visual perspective taking and detecting deception. Frontal lobe lesions impaired the ability to infer mental states in others, with dissociation of performance within the frontal lobes. Lesions throughout the frontal lobe, with some suggestion of a more important role for the right frontal lobe, were associated with impaired visual perspective taking. Medial frontal lesions, particularly right ventral, impaired detection of deception. The former may require cognitive processes of the lateral and superior medial frontal regions, the latter affective connections of the ventral medial frontal with amygdala and other limbic regions.

Assessment of strategic self-regulation in traumatic brain injury: its relationship to injury severity and psychosocial outcome.

Standard neuropsychological tests administered in a constrained and artificial laboratory environment are often insensitive to the real-life deficits faced by patients with traumatic brain injury (TBI). The Revised Strategy Application Test (R-SAT) creates an unstructured environment in the laboratory in which environmental cues and internal habits oppose the most efficient strategy, thus mimicking the real-life situations that are problematic for patients with TBI. In this study, R-SAT performance was related both to severity of TBI (i.e., depth of coma) sustained 2-3 years earlier and to quality of life outcome as assessed by the Sickness Impact Profile. This relationship held after accounting for variance attributable to TBI-related slowing and inattention. These findings support the validity of the R-SAT and suggest that behavioral correlates of quality of life outcome in TBI can be assessed in the laboratory with unstructured tasks.

Executive functions and the frontal lobes: a conceptual view.

Several problems in understanding executive functions and their relationships to the frontal lobes are discussed. Data are then presented from several of our studies to support the following statements: (1) the examination of patients with focal frontal lobe lesions is a necessary first step in defining the relation of executive functions to the frontal lobes; (2) there is no unitary executive function. Rather, distinct processes related to the frontal lobes can be differentiated which converge on a general concept of control functions; (3) a simple control-automatic distinction is inadequate to explain the complexity of control-automatic processes; (4) the distinction between complex and simple tasks cannot explain the differences in functions between the frontal lobes and other brain regions; and (5) the most important role of the frontal lobes may be for affective responsiveness, social and personality development, and self-awareness and unconsciousness.

Rehabilitation of executive functioning: an experimental-clinical validation of goal management training.

Two studies assessed the effects of a training procedure (Goal Management Training, GMT), derived from Duncan's theory of goal neglect, on disorganized behavior following TBI. In Study 1, patients with traumatic brain injury (TBI) were randomly assigned to brief trials of GMT or motor skills training. GMT, but not motor skills training, was associated with significant gains on everyday paper-and-pencil tasks designed to mimic tasks that are problematic for patients with goal neglect. In Study 2, GMT was applied in a postencephalitic patient seeking to improve her meal-preparation abilities. Both naturalistic observation and self-report measures revealed improved meal preparation performance following GMT. These studies provide both experimental and clinical support for the efficacy of GMT toward the treatment of executive functioning deficits that compromise independence in patients with brain damage.

Prediction of recovery of continuous memory after traumatic brain injury.

OBJECTIVE: To evaluate the ability of measures of initial severity, tests of attention, and demographic characteristics to predict recovery of continuous memory for words over a 24-hour period in patients with acute traumatic brain injury. METHODS: Recovery of continuous memory was assessed prospectively in 94 patients with nonpenetrating traumatic brain injury. A classification and regression tree analysis identified a hierarchical subset of variables that may be used as a simple guideline for predicting recovery of continuous memory. Weibull regression models evaluated and compared the predictive ability of multiple variables. RESULTS: Four groups of patients were identified based on measures of severity of injury and demographic characteristics. These four groups had recovery profiles that were more precise than could be obtained by using the Glasgow Coma Scale alone: mild, about 1 week to recovery of continuous memory; moderate, 1 to 4 weeks; severe, 2 to 6 weeks; and extremely severe, 4 to 8 weeks. Regression analysis confirmed that measures of capacity (inherent resources such as indicated by age) and compromise (general functional brain state measured neuropsychologically) improved prediction over models based only on injury severity measures, such as the Glasgow Coma Scale. CONCLUSIONS: Approaches to predicting recovery of continuous memory in the acute period after traumatic brain injury that take into account multiple measures provide a more sensitive predictive index.

Wisconsin Card Sorting Test performance in patients with focal frontal and posterior brain damage: effects of lesion location and test structure on separable cognitive processes.

Forty-six patients with single focal lesions (35 frontal, 11 nonfrontal) were administered the Wisconsin Card Sorting Test (WCST) under three conditions of test administration. The three conditions varied in the amount of external support provided via specificity of instructions. The WCST, while a multifactorial test, is specifically sensitive to the effects of frontal lobe damage if deficits in language comprehension and visual-spatial search are controlled. There is also specificity of functioning within the frontal lobes: patients with inferior medial frontal lesions, unilateral or bilateral, were not impaired on the standard measures although they had increased loss of set when informed of the sorting categories. Verbal instructions may provide a probe to improve diagnosis and prognosis, assessment of the potential efficacy of treatment, and the time frame of plasticity of specific cognitive operations.