The effects of adjunctive topiramate on cognitive function in patients with epilepsy

PURPOSE: We investigated possible cognitive effects of topiramate (TPM) in polypharmacy on patients with intractable epilepsy. METHODS: Study 1 evaluated 22 consecutively admitted patients whose antiepileptic drugs (AEDs) on admission to the Montreal Neurological Hospital included TPM. Performance on neuropsychological tests administered on and subsequently off TPM was analyzed. Four patients also were tested before taking TPM, allowing comparisons off, then on, and then off the drug again. Measures included intellectual function, verbal and nonverbal memory, language, word and design fluency, somatosensory sensitivity, and motor skills. In Study 2, 16 patients at the Minnesota Epilepsy Group were tested first off, then on TPM with nine cognitive tasks that measured concentration, verbal fluency, language, and psychomotor speed. RESULTS: In Study 1, significant (p < or = 0.01) improvements were observed off TPM on 13 measures including verbal and nonverbal fluency and certain verbal and perceptual tasks. Notably, verbal learning and memory were unaffected; a limited effect was observed on nonverbal memory. Patients tested 3 times scored better in both tests off TPM compared with on this drug. In Study 2, declines on TPM were observed on all measures, significantly (p < or = 0.05) for tests of fluency, sustained concentration, and visual motor processing speed. CONCLUSIONS: TPM was associated with declines in fluency, attention/concentration, processing speed, language skills, and perception; working memory but not retention was affected. As the two studies used an opposite order of testing on versus off TPM, our results clearly show a performance decrement while patients are taking TPM, without respect to which condition is tested first.     

Evaluation of a remedial programme for attentional deficits following closed-head injury

Abstract

Although the frequency and implications of disorders of attention in head-injured subjects have been recognised in recent years, there have been few carefully controlled attempts to evaluate remedial interventions. The present study employed a multiple baseline across subjects design to evaluate a computer-mediated programme for the remediation of deficits in speed of information processing in 10 severely head-injured subjects, aged 17–38 years. Following a baseline period, the effectiveness of computer training alone was compared with that combined with therapist feedback and reinforcement in separate training phases, each lasting 3 weeks. The final phase involved a return to baseline conditions. Dependent measures of attention, taken across all phases, included psychometric measures of processing speed, a rating scale completed by the patient's Occupational Therapist, and a video of the patient working in therapy. Results suggested that, once spontaneous recovery and practice effect were controlled, the patients showed little response to the interventions in terms of the dependent measures used.     

Visual information processing in the lion-tailed macaque (Macaca silenus): mental rotation or rotational invariance?

Mental rotation is a widely accepted concept indicating an image-like mental representation of visual information and an analogue mode of information processing in certain visuospatial tasks. In the task of discriminating between image and mirror-image of rotated figures, human reaction times increase with the angular disparity between the figures. In animals, tests of this kind yield inconsistent results. Pigeons were found to use a time-independent rotational invariance, possibly indicating a non-analogue information processing system that evolved in response to the horizontal plane of reference birds perceive during flight. Despite similar ecological demands concerning the visual reference plane, a sea lion was found to use mental rotation in similar tasks, but its processing speed while rotating three-dimensional stimuli seemed to depend on the axis of rotation in a different way than found for humans in similar tasks. If ecological demands influence the way information processing systems evolve, hominids might have secondarily lost the ability of rotational invariance while retreating from arboreal living and evolving an upright gait in which the vertical reference plane is more important. We therefore conducted mental rotation experiments with an arboreal living primate species, the lion-tailed macaque. Performing a two-alternative matching-to-sample procedure, the animal had to decide between rotated figures representing image and mirror-image of a previously shown upright sample. Although non-rotated stimuli were recognized faster than rotated ones, the animal's mean reaction times did not clearly increase with the angle of rotation. These results are inconsistent with the mental rotation concept but also cannot be explained assuming a mere rotational invariance. Our study thus seems to support the idea of information processing systems evolving gradually in response to specific ecological demands.     

Effects of processing speed training on cognitive functions and neural systems

Processing speed (PS) is an individual cognitive ability that measures the speed with which individuals execute cognitive tasks, particularly elementary cognitive tasks. PS has been proposed to be a key cognitive component, along with working memory, and is psychologically and clinically important. Various types of speed training affect performance of untrained cognitive measures. In this article, we review studies of PS training or training involving speeded tasks and describe the methodologies along with the psychological and neuroimaging findings related to PS training. There are various types of PS (speed) training tasks. Evidence indicates that PS training can enhance performance on untrained speeded tasks. However, the extent of transfer may vary depending on the methodology. A particular type of speed training seems to affect mental health in older adults. Neuroimaging studies of speed training have shown that the effects of speed training on neural mechanisms may vary depending on the training tasks. Adaptive procedures to modulate the difficulties of training tasks based on a subject's performance by modulating the task speed can be applied to various cognitive tasks, and these procedures can perhaps be used to develop training protocols for enhancing various cognitive functions.     

The contribution of executive functions deficits to impaired episodic memory in individuals with alcoholism

Individuals with alcoholism commonly exhibit impaired performance on episodic memory tasks. However, the contribution of their impaired executive functioning to poor episodic memory remains to be clarified. Thirty-six recently detoxified and sober asymptomatic alcoholic men and 36 matched non-alcoholic participants were tested for processing speed, prepotent response inhibition, mental flexibility, coordination of dual-task and a verbal episodic memory task. Compared with non-alcoholic individuals, the alcoholic patients showed impaired executive functions combined with below normal performance on both free and delayed recall. In contrast, processing speed, cued recall and recognition were preserved. Regression analyses revealed that 47% of alcoholics' episodic memory's free recall performance was predicted by mental flexibility and that 49% of their delayed recall performance was predicted by mental flexibility, manipulation of dual-task and prepotent response inhibition. Regarding participants' executive predictors of episodic memory performance, the slopes of β coefficients were significantly different between the two groups, with alcoholics requiring more their executive system than non-alcoholics. Once detoxified, alcoholic patients showed episodic memory deficits mainly characterized by impaired effortful (executive) processes. Compared with controls, patients used effortful learning strategies, which are nonetheless less efficient.     

Evaluation of a remedial programme for attentional deficits following closed-head injury

Although the frequency and implications of disorders of attention in head-injured subjects have been recognised in recent years, there have been few carefully controlled attempts to evaluate remedial interventions. The present study employed a multiple baseline across subjects design to evaluate a computer-mediated programme for the remediation of deficits in speed of information processing in 10 severely head-injured subjects, aged 17-38 years. Following a baseline period, the effectiveness of computer training alone was compared with that combined with therapist feedback and reinforcement in separate training phases, each lasting 3 weeks. The final phase involved a return to baseline conditions. Dependent measures of attention, taken across all phases, included psychometric measures of processing speed, a rating scale completed by the patient's Occupational Therapist, and a video of the patient working in therapy. Results suggested that, once spontaneous recovery and practice effect were controlled, the patients showed little response to the interventions in terms of the dependent measures used.     

Sentence comprehension in multiple sclerosis

Introduction - Explanations of sentence processing difficulty in aphasia have implicated slowed information processing speed. We tested this hypothesis by evaluating sentence comprehension in multiple sclerosis (MS), and relating comprehension performance to measures of information processing speed. Material & methods - Twenty right-handed, high school-educated, non-demented, native English speakers with clinically definite MS and 16 age- and education-matched control subjects were examined on 3 different sentence comprehension measures that stress grammatical appreciation. Performance was related to quantitative assessments of mental information processing speed. Results - Group-wide analyses demonstrated a trend toward sentence comprehension difficulty in MS. Analyses of individual patient profiles identified a subgroup of MS patients who were consistently impaired to a significant extent across all sentence comprehension tasks. Their sentence comprehension difficulty was associated with selectively compromised mental information processing speed. Conclusion - Sentence comprehension difficulty in MS is associated with slowed information processing speed. This finding supports the claim that information processing speed contributes to sentence processing.     

EEG and cognitive performance following closed head injury

Ten closed head-injured patients and 10 matched control subjects participated in a study that examined quantitated EEG data during cognitive task performance. The head-injured patients performed significantly worse than controls on all four tasks and had significantly higher EEG amplitudes and amplitude variances. A discriminant analysis function correctly identified 0% of the subjects on the basis of the EEG data. Frequency analysis indicated that these higher amplitudes were a product of across-frequency increases in voltage. In addition, EEG data were significantly correlated with performance on one cognitive task in the head-injured group. Results suggest that, contrary to standard clinical EEG findings, identifiable EEG changes may persist for years following moderate to severe closed head injury, and these changes are related to residual cognitive deficits.     

Neural correlates in exceptional mental arithmetic—About the neural architecture of prodigious skills

Prodigies are individuals with exceptional mental abilities. How is it possible that some of these people mentally calculate exponentiations with high accuracy and speed? We examined CP, a mental calculation prodigy, and a control group of 11 normal calculators for moderate mental arithmetic tasks. CP has additionally been tested for exceptionally difficult exponentiations. We hypothesized that, if CP would activate similar brain regions as controls for both moderate and very difficult tasks, his special exceptional abilities could rather be explained by neuroplastic changes as a result of obsessive practice than by unusual mental strategies and/or neurocognitive mechanisms. For very difficult exponentiation tasks, CP showed activation patterns in brain regions adjacent to those, which were activated for moderate task calculation by both CP and control participants. We concluded, therefore, that CP's exceptional calculation performance might rather be based on neuroplastic changes substantially caused by years of daily hours of training combined with excellent working memory capabilities and not on the recruitment of additional brain mechanisms. Furthermore, but considering that only one prodigy was compared with a control group, results of the present study imply that the neural substrate, which is potentially necessary to enhance specific skills dramatically by positively motivated excessive mental training, might be present in every healthy individual.     

Minor head injury: pathophysiological or iatrogenic sequelae?

This study addresses the possibility that cognitive sequelae--albeit of a transient or minor character--can be associated with mild head injury. Twenty men (aged 16-30 years of age), whose post-traumatic amnesia did not exceed eight hours, were examined within 48 hours of their accident and again one month later. This unselected sample had no previous history of head injury. A control group of 20 men of similar socioeconomic background, was selected from medical wards (where they had been admitted for orthopaedic treatment or a minor operation). They were also retested one month after the first examination. Neuropsychological tests were selected to measure abilities often compromised after significant head injury, namely memory and attention. The experimental component consisted of the fractionation of a complex skill (paced addition) to probe for deficits at different stages of information processing: perception and input into storage; search for and retrieval of information from working memory; and paced and unpaced addition. In general, no significant difference was found between the experimental and control groups, with the possible exception of an initial decrement on two working memory tasks: probe digits and a keeping track task (where the subject has to keep in mind and update a number of variables at the same time). The keeping track paradigm, ostensibly of ecological relevance, may well be worth further exploration in memory research, and in studies of more severely head-injured patients. It is further suggested that the appropriate management and counselling of mildly head-injured patients may help to avert symptoms that are of psychological rather than pathophysiological origin.     

Cognitive dysfunction in non-demented Parkinson's disease patients: Controlled and automatic behavior

The evidence with regard to impaired automatic and controlled information processing in non-demented patients with Parkinson's disease (PD) is critically discussed. We use a comprehensive mental schema framework of executive functioning, that is the planning and regulation of behavior in complex everyday tasks (International Classification of Functioning - ICF - activity level).In this framework monitoring, inhibition, mental effort, planning, working memory and flexibility are important elements of controlled processing (supervisory attentional control) and controlled processing can only influence performance by modulating automatic processes. The striatum plays an important role in the interface between controlled and automatic processes.It is wel documented that PD patients show impairments applying and achieving automaticities. With sustained cortical control of task performance during both automatic and controlled processing, not showing the transition to striatal control, which is normal in the case of skill learning.In addition, PD patients have been shown to be limited in executive functioning. Many authors have interpreted this as evidence for impaired executive functions (ICF body level). But the question must be asked to what extent these limitations are an indirect effect of impaired automatic processing. To answer this question, studies on executive functioning are critically assessed with regard to the control they have provided for impaired automaticity.It is concluded that only for cognitive flexibility and working memory, the evidence for impairments is convincing because significant limitations have also been shown in tasks with very low automatic processing demands. Impairments in other executive functions, such as monitoring, inhibition and planning have not been convincingly shown in non-demented PD patients and are likely to be due to treatment strategies and factors such as fatigue.     

Training mobility tasks after stroke with combined mental and physical practice: a feasibility study

This study examines the potential of using mental practice (MP) to promote the learning of 2 mobility tasks in persons with stroke. Twelve patients were trained with MP to increase the loading of the affected limb while standing up from a chair and sitting down. Vertical forces were recorded using force plates under each foot and the chair. Changes in the loading of the affected limb and in task duration, immediately after 1 training session and 24 h later, served as outcomes. After training, the loading of the affected limb had increased (P < 0.001) during standing up (16.2%) and sitting down (17.9%), and the improvement remained significant 24 h later, indicating a learning effect. In contrast, the duration of the performance did not change with training. The results indicate that, in the early stage of learning with MP, changes in limb-loading strategies are a more sensitive measure of performance than is speed.     

Interference between postural control and mental task performance in patients with vestibular disorder and healthy controls

OBJECTIVES: To determine whether interference between postural control and mental task performance in patients with balance system impairment and healthy subjects is due to general capacity limitations, motor control interference, competition for spatial processing resources, or a combination of these. METHOD: Postural stability was assessed in 48 patients with vestibular disorder and 24 healthy controls while they were standing with eyes closed on (a) a stable and (b) a moving platform. Mental task performance was measured by accuracy and reaction time on mental tasks, comprising high and low load, spatial and non-spatial tasks. Interference between balancing and performing mental tasks was assessed by comparing baseline (single task) levels of sway and mental task performance with levels while concurrently balancing and carrying out mental tasks. RESULTS: As the balancing task increased in difficulty, reaction times on both low load mental tasks grew progressively longer and accuracy on both high load tasks declined in patients and controls. Postural sway was essentially unaffected by mental activity in patients and controls. CONCLUSIONS: It is unlikely that dual task interference between balancing and mental activity is due to competition for spatial processing resources, as levels of interference were similar in patients with vestibular disorder and healthy controls, and were also similar for spatial and non-spatial tasks. Moreover, the finding that accuracy declined on the high load tasks when balancing cannot be attributed to motor control interference, as no motor control processing is involved in maintaining accuracy of responses. Therefore, interference between mental activity and postural control can be attributed principally to general capacity limitations, and is hence proportional to the attentional demands of both tasks.     

Kognitive Beeinträchtigungen unter Add-on-Therapie mit Topiramat

In an open study, 37 epilepsy patients were investigated with regard to cognitive impairments in anticonvulsant add-on therapy with topiramate (TPM). In addition to a preexisting antiepileptic medication, TPM administration was started and increased by 25 mg/week. Cognitive side effects noted by the patient or doctor were assessed by a neuropsychological test battery. In 18/37 patients (49%), cognitive deficits consisting of impaired concentration, psychomotoric slowing, memory deficits, and dysphasia were observed. The adverse effects became apparent at dosages of 50-575 mg TPM/day (average 210 mg). In four patients, they were reversible after reducing the dose of TPM by 25-150 mg/day. In eight patients, the adverse effects led to withdrawal of TPM. In spite of slow titration, the present study showed a higher frequency of cognitive side effects under TPM than was previously reported. In some patients, these side effects led to substantial impairments in daily life and at work. For early recognition of cognitive impairments, neuropsychological baseline and follow-up investigations of verbal fluency, psychomotor processing speed, and verbal memory are recommended.     

Deficits in inhibitory executive functions in Klinefelter (47, XXY) syndrome

Klinefelter syndrome (47, XXY) is a sex chromosome aneuploidy associated with mild deficits in cognitive and language functions. Dysfunctions have also been reported in performance of tasks which examine executive functions. However, it is unclear whether the impaired performance is caused or accentuated by problems with semantic processing and information processing speed. In the present study we used an experimental task which is relatively insensitive to these confounding factors. We examined inhibitory executive functions in a group of XXY males compared with male (XY) and female (XX) controls, using a dichotic listening speech sound task with instructions to focus attention on either the right or the left ear stimulus. With this task, inhibitory executive functions can be assessed separately from language, processing speed, and attention orientation abilities. We found that XXY males showed a selective deficit in inhibitory executive functions compared to both control groups, whereas attentional orientation was not impaired. The present findings suggest that executive dysfunctions associated to Klinefelter syndrome can be selectively identified, and are particularly accentuated in the inhibitory sub-component. Such improved understanding of the nature of executive dysfunctions in XXY males may aid the development of specific neuropsychological rehabilitation strategies.     

Facial identity and facial emotions: speed, accuracy, and processing strategies in children and adults

As yet, nearly all studies in face and facial affect recognition typically provide only data on the accuracy of processing, invariably also in the absence of reference data on abstract information processing. In this study, accuracy and speed of abstract visuo-spatial processing, face recognition, and facial emotion recognition were investigated in normal school children (7-10 years) and adults (25+/-4 years). In the age range of 7-10 years, accuracy of facial processing hardly increased, while speed did substantially increase with age. Adults, however, were substantially more accurate and faster than children. Differences between facial and abstract information processing were related to type of processing strategy, that is, configural or holistic processing versus featural or piecemeal processing. Improvement in task performance with age is discussed in terms of an enhanced efficiency of the configural organization of facial knowledge (facial information processing tasks), together with a further increase in processing capacity (all tasks). The differential developmental course of speed and accuracy levels indicates that speed is a more sensitive measure when children get older. Moreover, it also suggests that speed of performance, in addition to accuracy, might be successfully used in the assessment of clinical deficits, as has recently been demonstrated in children with autistic disorders of social contact.     

rCBF pathology in Alzheimer's disease is associated with slow processing speed

Decreased information processing speed (mental slowing) is a known sequelae of many brain disorders, and can be assessed by continuous naming tasks. Functional imaging studies have shown that pause and articulation times in continuous speech are normally associated with different brain regions, but knowledge about such association in dementia is lacking. We therefore tested the hypothesis that perfusion deficits in Alzheimer's disease (AD) are not only associated with slower processing, but also with these speech measures. Using regional cerebral blood flow (rCBF) measurements during the performance of a continuous colour and form-naming task, we found that naming speed was substantially slower in AD patients than in controls. This slower naming was exclusively determined by an increase in mean pause time, and only to a limited extent by articulation time. The increased pause time was uniquely associated with temporo-parietal rCBF reductions of the patients, while articulation was not. By contrast, the rCBF of healthy elderly control subjects was consistently accompanied by substantially shorter articulation and pause times, although the naming measures were not statistically associated with rCBF.

These findings suggest that pause time (in contrast to articulation time) may serve as a sensitive measure in the assessment of information processing speed deficits in dementia, by virtue of its close association with brain pathology.     

fMri studies of Stroop tasks reveal unique roles of anterior and posterior brain systems in attentional selection

The brain's attentional system identifies and selects information that is task-relevant while ignoring information that is task-irrelevant. In two experiments using functional magnetic resonance imaging, we examined the effects of varying task-relevant information compared to task-irrelevant information. In the first experiment, we compared patterns of activation as attentional demands were increased for two Stroop tasks that differed in the task-relevant information, but not the task-irrelevant information: a color-word task and a spatial-word task. Distinct subdivisions of dorsolateral prefrontal cortex and the precuneus became activated for each task, indicating differential sensitivity of these regions to task-relevant information (e.g., spatial information vs. color). In the second experiment, we compared patterns of activation with increased attentional demands for two Stroop tasks that differed in task-irrelevant information, but not task-relevant information: a color-word task and color-object task. Little differentiation in activation for dorsolateral prefrontal and precuneus regions was observed, indicating a relative insensitivity of these regions to task-irrelevant information. However, we observed a differentiation in the pattern of activity for posterior regions. There were unique areas of activation in parietal regions for the color-word task and in occipitotemporal regions for the color-object task. No increase in activation was observed in regions responsible for processing the perceptual attribute of color. The results of this second experiment indicate that attentional selection in tasks such as the Stroop task, which contain multiple potential sources of relevant information (e.g., the word vs. its ink color), acts more by modulating the processing of task-irrelevant information than by modulating processing of task-relevant information.     

Divided attention and mental effort after severe traumatic brain injury

The aim of this study was to assess dual-task performance in TBI patients, under different experimental conditions, with or without explicit emphasis on one of two tasks. Results were compared with measurement of the subjective mental effort required to perform each task. Forty-three severe TBI patients at the subacute or chronic phase performed two tasks under single- and dual-task conditions: (a) random generation; (b) visual go-no go reaction time task. Three dual-task conditions were given, requiring either to consider both tasks as equally important or to focus preferentially on one of them. Patients were compared to matched controls. Subjective mental effort was rated on a visual analogic scale. TBI patients showed a disproportionate increase in reaction time in the go-no go task under the dual-task condition. However, they were just as able as controls to adapt performance to the specific instructions about the task to be emphasised. Patients reported significantly higher subjective mental effort, but the variation of mental effort according to task condition was similar to that of controls. These results suggest that the divided attention deficit of TBI patients is related to a reduction in available processing resources rather than an impairment of strategic processes responsible for attentional allocation and switching. The higher level of subjective mental effort may explain why TBI patients frequently complain of mental fatigue, although this subjective complaint seems to be relatively independent of cognitive impairment.     

Event-related potentials during arithmetic and mental rotation.

In separate studies of arithmetic and mental rotation, similar posterior negative slow waves have been found. This similarity was surprising given the difference in cognitive processing required by these tasks. Furthermore, delayed responses were employed in these studies, so that it was not possible to determine the extent to which the slow wave activity was too late to be associated with processing that was specific to performance of the tasks. This experiment was intended to clarify the task-specific and non-specific nature of the slow wave activity. Subjects performed either an arithmetic or mental rotation task at two levels of difficulty on a random, trial-to-trial basis and gave an immediate response. There were a number of late posterior negativities, each with a different timing and topography, which were sensitive to type of task and/or task difficulty. Some components were associated with early task processing that was synchronized to the stimulus while others, revealed by response-synchronized averaging, were associated with later stages of task processing. There also was post-task activity that was sensitive to the difficulty level of the prior operations. In both tasks, there was a pre-frontal positive wave that persisted over most of the pre-response epoch, evidently related to a process that was active throughout the task. There also was centro-frontal phasic negativity, with a large peak at 380 msec in mental rotation, and a smaller, longer latency peak in arithmetic, apparently related to the complexity of the stimulus. Thus we conclude that arithmetic and mental rotation each elicit task-specific slow wave activity.