Age-related differences in enhancement and suppression of neural activity underlying selective attention in matched young and old adults.

Selective attention reflects the top-down control of sensory processing that is mediated by enhancement or inhibition of neural activity. ERPs were used to investigate age-related differences in neural activity in an experiment examining selective attention to color under Attend and Ignore conditions, as well as under a Neutral condition in which color was task-irrelevant. We sought to determine whether differences in neural activity between old and young adult subjects were due to differences in age rather than executive capacity. Old subjects were matched to two groups of young subjects on the basis of neuropsychological test performance: one using age-appropriate norms and the other using test scores not adjusted for age. We found that old and young subject groups did not differ in the overall modulation of selective attention between Attend and Ignore conditions, as indexed by the size of the anterior Selection Positivity. However, in contrast to either young adult group, old subjects did not exhibit reduced neural activity under the Ignore relative to Neutral condition, but showed enhanced activity under the Attend condition. The onset and peak of the Selection Positivity occurred later for old than young subjects. In summary, older adults execute selective attention less efficiently than matched younger subjects, with slowed processing and failed suppression under Ignore. Increased enhancement under Attend may serve as a compensatory mechanism.

The plight of caring for young patients with frontotemporal dementia.

We present the case of a 39-year-old patient with frontotemporal dementia. This case depicts the complexities in the process leading to the diagnosis, treatment, and placement of young patients presenting with severe psychiatric symptoms as the first signs of an underlying neurological disease. Obstacles in the health care system and residential placement process that hinder the optimal and timely care of such difficult cases are discussed. Practical solutions are offered that center upon better awareness and education and the provision of additional resources. These interventions are likely to provide a positive return on investment for the medical system and could be used as strong levers for new health policies relevant to younger patients with neurological illness.

Frontal and parietal components of a cerebral network mediating voluntary attention to novel events.

Despite the important role that attending to novel events plays in human behavior, there is limited information about the neuroanatomical underpinnings of this vital activity. This study investigated the relative contributions of the frontal and posterior parietal lobes to the differential processing of novel and target stimuli under an experimental condition in which subjects actively directed attention to novel events. Event-related potentials were recorded from well-matched frontal patients, parietal patients, and non-brain-injured subjects who controlled their viewing duration (by button press) of line drawings that included a frequent, repetitive background stimulus, an infrequent target stimulus, and infrequent, novel visual stimuli. Subjects also responded to target stimuli by pressing a foot pedal. Damage to the frontal cortex resulted in a much greater disruption of response to novel stimuli than to designated targets. Frontal patients exhibited a widely distributed, profound reduction of the novelty P3 response and a marked diminution of the viewing duration of novel events. In contrast, damage to posterior parietal lobes was associated with a substantial reduction of both target P3 and novelty P3 amplitude; however, there was less disruption of the processing of novel than of target stimuli. We conclude that two nodes of the neuroanatomical network for responding to and processing novelty are the prefrontal and posterior parietal regions, which participate in the voluntary allocation of attention to novel events. Injury to this network is indexed by reduced novelty P3 amplitude, which is tightly associated with diminished attention to novel stimuli. The prefrontal cortex may serve as the central node in determining the allocation of attentional resources to novel events, whereas the posterior parietal lobe may provide the neural substrate for the dynamic process of updating one's internal model of the environment to take into account a novel event.

Suppression of false recognition in Alzheimer's disease and in patients with frontal lobe lesions.

Previous research has shown that patients with Alzheimer's disease show increasing levels of false recognition across five repeated study-test trials of semantic associates. The present study tested the hypotheses that (i) the increasing false recognition was partly due to the frontal lobe dysfunction of patients with Alzheimer's disease, and (ii) a failure of source monitoring was the central mechanism by which frontal lobe dysfunction led to increasing false recognition across trials. In Experiment 1, patients with frontal lobe lesions and controls were examined in the same repeated trials paradigm as that used previously in patients with Alzheimer's disease. Although controls were able to reduce their false recognition across trials, the patients with frontal lobe lesions were not, and instead showed a constant level of elevated false recognition across the study-test trials. In Experiment 2, two groups of patients with Alzheimer's disease and healthy older adult controls were studied: the first group was given a single study session followed by a recognition test, the second group was given five study sessions followed by a single recognition test. Older adults who were exposed to five study lists demonstrated lower levels of false relative to true recognition, whereas patients with Alzheimer's disease in this condition exhibited levels of false recognition elevated to that of their true recognition, even with the source memory confusion of intervening tests eliminated. The authors suggest that impairment in aspects of frontal lobe function, such as verification-inhibition mechanisms, probably contributes to the inability of patients with Alzheimer's disease to suppress their false recognition across repeated trials. Lastly, it is speculated that one way in which the frontal lobes enable normal episodic memory function is by facilitating the suppression of false recognition and other distortions of memory.

Selective cell loss in Edinger-Westphal in asymptomatic elders and Alzheimer's patients.

Exaggerated pupillary response to a low concentration of cholinergic antagonists has been suggested as an early marker for Alzheimer's Disease (AD). To examine the anatomic basis of this phenomenon, we determined possible neuropathological changes in the Edinger-Westphal (EW) nucleus, a midbrain neural center with a significant functional role in the control of pupil size. Stereologically determined neuronal numbers within the EW were counted in individuals with pathologically confirmed AD, control cases with no AD-type pathology, and subjects with AD pathology not meeting diagnostic criteria for AD. The EW of AD patients displayed a marked and striking neuronal loss when compared with controls. In contrast, the number of neurons in the somatic portion of the nucleus of the third cranial nerve (NCNIII) remained intact. The EW in brains from clinically normal individuals with evidence of early AD-type pathology also displayed a significant and selective loss of neurons. The magnitude of EW neuronal loss in the latter group was smaller than that observed in AD. These findings suggest that pupillary hypersensitivity in AD may be caused by abnormalities in the EW. Neuronal loss and pathology within the EW in a subpopulation of clinically silent controls with pathologic findings consistent with early-stage AD constitutes a possible explanation for the reported exaggerated pupil response in some normal elderly subjects.

Pathophysiology underlying diminished attention to novel events in patients with early AD.

BACKGROUND: Patients with mild to moderate AD often are apathetic and fail to attend to novel aspects of their environment. OBJECTIVE: To investigate the mechanisms underlying these changes by studying the novelty P3 response that measures shifts of attention toward novel events. METHODS: While event-related potentials were recorded, mildly impaired AD patients and matched normal controls (NC) viewed line drawings that included a repetitive background stimulus, an infrequent target stimulus, and infrequent novel stimuli. Subjects controlled how long they viewed each stimulus by pressing a button. This served as a measure of their allocation of attention. They also responded to targets by depressing a foot pedal. Patients did not differ from NC in age, education, estimated IQ, or mood but were judged by informants to be more apathetic. RESULTS: P3 amplitude to novel stimuli was significantly smaller for AD patients than NC. However, P3 amplitude to target stimuli did not differ between groups. For NC, P3 response to novel stimuli was much larger than to background stimuli. In contrast, for patients with AD, there was no difference in P3 response to novel vs background stimuli. Although NC spent more time looking at novel than background stimuli, patients with AD distributed their viewing time evenly. Remarkably, for patients with AD, the amplitude of the novelty P3 response powerfully predicted how long they would spend looking at novel stimuli (R2 = 0.52) and inversely correlated with apathy severity. CONCLUSIONS: The decreased attention to novel events exhibited by patients with AD cannot be explained by a nonspecific reduction in their attentional abilities. The novelty P3 response is markedly diminished in mild AD, at a time when the target P3 response is preserved. The disruption of the novelty P3 response predicts diminished attention to novel stimuli and is associated with the apathy exhibited by patients with AD.

Perceptual false recognition in Alzheimer's disease.

Previous research has found that patients with probable Alzheimer's disease (AD) show lower levels of false recognition of semantic associates than do healthy older adults. To investigate whether this finding is attributable to semantic impairments in patients with AD, the authors examined false recognition of perceptually related novel objects with little semantic content in patients with AD and healthy older adults. By using corrected recognition scores to control for unrelated false alarms, it was found that patients with AD showed lower levels of both true and false recognition of novel objects than did older adults. These results suggest that the previous difference in false recognition of semantic associates observed between patients with AD and older adults is not entirely attributable to semantic memory deficits in patients with AD but may also involve poorly developed gist information in these patients.

Regional magnetic resonance imaging lesion burden and cognitive function in multiple sclerosis: a longitudinal study.

OBJECTIVE: To investigate the relationship between magnetic resonance imaging regional lesion burden and cognitive performance in multiple sclerosis (MS) over a 4-year follow-up period. DESIGN: Twenty-eight patients with MS underwent magnetic resonance imaging and took the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis at baseline, 1-year, and 4-year follow-up. An automated 3-dimensional lesion detection method was used to identify MS lesions within anatomical regions on proton density T2-weighted images. The relationship between magnetic resonance imaging regional lesion volumes and the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis results was examined using regression analyses. RESULTS: At all time points, frontal lesion volume represented the greatest proportion of total lesion volume, and the percentage of white matter classified as lesion was also highest in frontal and parietal regions. On neuropsychological testing, when compared with age- and educational level-matched control subjects, patients with MS showed significant impairment on tests of sustained attention, processing speed, and verbal memory (P<.001). Performance on these measures was negatively correlated with MS lesion volume in frontal and parietal regions at baseline, 1-year, and 4-year follow-up (R = -0.55 to -0.73, P<.001). CONCLUSIONS: Multiple sclerosis lesions show a propensity for frontal and parietal white matter. Lesion burden in these areas was strongly associated with performance on tasks requiring sustained complex attention and working verbal memory. This relationship was consistent over a 4-year period, suggesting that disruption of frontoparietal subcortical networks may underlie the pattern of neuropsychological impairment seen in many patients with MS.

An electrophysiological index of stimulus unfamiliarity.

This study investigated the functional significance of the N2 response to novel stimuli. In one condition, background, target, and deviant stimuli were simple geometric figures. In a second condition, all stimulus types were unfamiliar/unusual figures. In a third condition, background and target stimuli were unusual figures and deviant stimuli were simple shapes. Unusual figures, whether they were deviant, target, or background stimuli, evoked larger N2 responses than their simple, familiar counterparts. N2 elicited by an unusual background stimulus was larger than that evoked by simple, deviant stimuli, a pattern opposite that exhibited by the subsequent P3. Deviance from immediate context had limited influence over N2 amplitude. The results suggest that novelty N2 and novelty P3 reflect the processing of different aspects of "novel" visual stimuli. The novelty P3 is particularly sensitive to deviation from immediate context. In contrast, the novelty N2 is sensitive to deviation from long-term context that renders a stimulus unfamiliar and difficult to encode.

The influence of stimulus deviance on electrophysiologic and behavioral responses to novel events.

This study investigated the role of stimulus deviance in determining electrophysiologic and behavioral responses to "novelty." Stimulus deviance was defined in terms of differences either from the immediately preceding context or from long-term experience. Subjects participated in a visual event-related potential (ERP) experiment, in which they controlled the duration of stimulus viewing with a button press, which served as a measure of exploratory behavior. Each of the three experimental conditions included a frequent repetitive background stimulus and infrequent stimuli that deviated from the background stimulus. In one condition, both background and deviant stimuli were simple, easily recognizable geometric figures. In another condition, both background and deviant stimuli were unusual/unfamiliar figures, and in a third condition, the background stimulus was a highly unusual figure, and the deviant stimuli were simple, geometric shapes. Deviant stimuli elicited larger N2-P3 amplitudes and longer viewing durations than the repetitive background stimulus, even when the deviant stimuli were simple, familiar shapes and the background stimulus was a highly unusual figure. Compared to simple, familiar deviant stimuli, unusual deviant stimuli elicited larger N2-P3 amplitudes and longer viewing times. Within subjects, the deviant stimuli that evoked the largest N2-P3 responses also elicited the longest viewing durations. We conclude that deviance from both immediate context and long-term prior experience contribute to the response to novelty, with the combination generating the largest N2-P3 amplitude and the most sustained attention. The amplitude of the N2-P3 may reflect how much "uncertainty" is evoked by a novel visual stimulus and signal the need for further exploration and cognitive processing.

When false recognition is unopposed by true recognition: gist-based memory distortion in Alzheimer's disease.

The authors examined false recognition of semantic associates in patients with probable Alzheimer's disease (AD), older adults, and young adults using a paradigm that provided rates of false recognition after single and multiple exposures to word lists. Using corrected false recognition scores to control for unrelated false alarms, the authors found that (a) the level of false recognition after a single list exposure was lower in AD patients than in controls; (b) across 5 trials, false recognition increased in AD patients, decreased in young adults, and showed a fluctuating pattern in older adults; and (c) all groups showed an increase in true recognition over the 5 trials. Analyses suggested that AD patients built up semantic gist across trials, whereas both control groups were able to use increased item-specific recollection and more conservative response criteria to suppress gist-based false alarms.

The central role of the prefrontal cortex in directing attention to novel events.

The physiological basis for the striking decrease of attention to novel events following frontal lobe injury is poorly understood. In this study, event-related potentials (ERPs) were recorded from patients with frontal lobe damage and matched subjects, who controlled the duration of viewing of background, novel and target stimuli. Frontal lobe patients did not differ from normal controls in terms of age, education, estimated IQ or mood. However, they were judged to be more apathetic as measured by self-report and informants' ratings. Patients with frontal lobe damage exhibited markedly reduced amplitude of the novelty P3 response and the duration of viewing of novel stimuli. In contrast, injury to the frontal lobes had a limited impact on P3 amplitude and behavioural responses (viewing duration and reaction time) to target stimuli. A strong correlation was found between measures of apathy and both attenuated P3 amplitude and viewing duration in response to novel but not target stimuli. Differences in amplitude of the novelty P3 response explained a large portion of the variance associated with duration of viewing of novel stimuli. After controlling for the influence of P3 amplitude, there was no association between frontal lobe injury and reduced viewing of novel stimuli. The results of this study suggest that frontal lobe damage leads to diminished visual attention to novel events through its disruption of neural processes underlying the novelty P3 response. These processes appear to regulate the allocation of attentional resources and early exploratory behaviours, and are not limited to immediate orienting responses. Damage to the frontal lobes may prevent the generation of a signal which indicates that a novel event in the environment requires additional attention due to its potential behavioural significance. The disruption of these processes is likely to contribute to the apathy observed in patients after injury to the frontal lobes.

Donepezil therapy in clinical practice: a randomized crossover study.

OBJECTIVE: To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice. DESIGN: Two-center, randomized, placebo-controlled, double-masked crossover study. SETTING: Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston. PATIENTS: Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale. INTERVENTIONS: Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks. PRIMARY OUTCOME MEASURE: Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods. RESULTS: Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each). CONCLUSION: This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

Disruption of attention to novel events after frontal lobe injury in humans.

OBJECTIVE: To investigate whether frontal lobe damage in humans disrupts the natural tendency to preferentially attend to novel visual events in the environment. METHODS: Nine patients with chronic infarctions in the dorsolateral prefrontal cortex (DLPFC) and 23 matched normal controls participated in a study in which subjects viewed repetitive background stimuli, infrequent target stimuli, and novel visual stimuli (for example, fragmented or "impossible" objects). Subjects controlled viewing duration by a button press that led to the onset of the next stimulus. They also responded to targets by pressing a foot pedal. The amount of time spent looking at the different kinds of stimuli, and the target detection accuracy and speed served as dependent variables. RESULTS: Overall, normal controls spent significantly more time than frontal lobe patients looking at novel stimuli. Analysis of responses across blocks showed that initially frontal lobe patients behaved like normal controls by directing more attention to novel than background stimuli. However, they quickly began to distribute their viewing time evenly between novel and background stimuli, a pattern that was strikingly different from normal controls. By contrast, there were no differences between frontal lobe patients and normal controls for viewing duration devoted to background and target stimuli, target detection accuracy, or reaction time to targets. Frontal lobe patients did not differ from normal controls in terms of age, education, estimated IQ, or mood, but were more apathetic as measured by self report and informants' judgments. Attenuated responses to novel stimuli significantly correlated with degree of apathy. CONCLUSIONS: This study demonstrates that DLPFC injury selectively impairs the natural tendency to seek stimulation from novel and unusual stimuli. These data provide the first quantitative behavioural demonstration that the human frontal lobes play a critical part in directing and sustaining attention to novel events. The impairment of novelty seeking behaviour may contribute to the characteristic apathy found in patients with frontal lobe injury.

Focal pathology in the Edinger-Westphal nucleus explains pupillary hypersensitivity in Alzheimer's disease.

Patients who suffer from Alzheimer's disease (AD) and a sub-population of community-dwelling elders show an exaggerated pupillary reaction to dilute tropicamide, a cholinergic antagonist. This finding may serve as an early diagnostic marker of AD. Here we report a likely pathological basis for this hypersensitive pupillary response. Our observations indicate that the Edinger-Westphal nucleus (EW), a known center for the control of pupillary function, is a selective target of Alzheimer pathology early in the course of the disease. In all AD cases examined, the EW contained plaques and tangles. In contrast, the adjacent somatic portion of the oculomotor complex was virtually spared of pathology. Early pathology in the EW is likely to initiate a cascade of events that may give rise to pupillary hypersensitivity.

Mechanisms underlying diminished novelty-seeking behavior in patients with probable Alzheimer's disease.

OBJECTIVE: To better understand apathy and disengagement in patients with Alzheimer's disease (AD), the authors investigated possible behavioral mechanisms underlying diminished novelty-seeking activity in patients with probable AD. BACKGROUND: Apathy and disengagement have been shown to be the most common behavioral changes associated with AD. METHOD: Patients and age-matched normal controls had their eye movements recorded while pairs of line drawings pitting an incongruous figure against a congruous figure were shown on a screen for 12 seconds. Characteristics of a subset of AD patients who were indifferent to novel visual stimuli as measured by exploratory eye movements were compared to those of a subset of AD patients who were attracted to novel stimuli to a degree similar to that of normal controls. RESULTS: The indifferent patients were judged by informants, who completed a personality questionnaire, to exhibit a greater degree of apathy. The two AD groups did not differ in overall dementia severity or performance on a Saccade-to-Target Task that required shifts of attention and gaze. In a separate task, the indifferent patients were able to accurately identify the more novel stimuli in 97.5% of trials. Normal control subjects exhibited a strong bias toward processing novel stimuli, directing a higher proportion of their first fixations and dwell time to the incongruous stimuli whether the analysis was run for 3, 6, or 12 seconds of viewing. Indifferent patients did not direct their initial fixation toward novel stimuli and distributed their looking time evenly between incongruous and congruous stimuli throughout all measured intervals. CONCLUSIONS: The results suggest that the indifference to novelty observed in some patients with probable AD cannot simply be attributed to global cognitive decline, more elementary attentional deficits, more rapid habituation of response to novel stimuli, or an inability to discriminate upon demand between stimuli of varying degrees of novelty. It is more likely that their behavior reflects a disruption, by AD pathology, of neural systems that modulate behavioral engagement and maintain attentional bias toward novel events in the environment.

Regulation of attention to novel stimuli by frontal lobes: an event-related potential study.

This study examined the relationship between orienting responses to novel events and subsequent exploratory behavior. The N2-P3 electrophysiologic component of the orienting response was found to be larger for novel than repetitive background stimuli. Across subjects, the amplitude of this N2-P3 response in frontal regions strongly predicted the proportional increase in the duration of viewing directed toward novel compared to background stimuli. Within subjects, larger N2-P3 amplitudes in response to novel stimuli were associated with longer viewing durations on those stimuli. These results suggest that the N2-P3 component of the orienting response reflects the activity of a neural system involving frontal networks that dynamically regulates the subsequent allocation of attentional resources to novel stimuli.

Psychiatric and behavioral problems.

In an emergency setting, many neurologic conditions present with psychiatric and behavioral symptoms. These symptoms may either be the first manifestation of the neurologic illness or a later occurrence in the progression of the disease. It is important for clinicians evaluating patients with psychiatric symptoms to identify the signs indicating associated neurologic illness and to have strategies for managing the acute, potentially dangerous, neuropsychiatric manifestations of the disease. This article addresses emergency evaluation and management of depression, anxiety, psychosis, mania, suicide attempts, neuroleptic malignant syndrome and other hypermetabolic and amnestic syndromes, somatoform disorders, aggression, and legal issues, such as capacity to accept or refuse treatment.

Deficient antisaccades in the social-emotional processing disorder.

We investigated whether adolescents and adults with the developmental social-emotional processing disorder (SEPD) exhibit deficits in visual attention, as measured by eye movements, when compared with dyslexic and normal control subjects. On the antisaccade task, subjects with SEPD made more errors than either control group and were the only group to show a decrease in performance accuracy compared with prosaccade. This deficit in inhibiting reflexive shifts of attention and gaze suggests that individuals with SEPD have dysfunction of the prefrontal component of the right hemisphere dominant network for spatially directed attention.