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Background: Based on previously reported changes in muscle metabolism that could increase susceptibility to fatigue, we speculated that patients with chronic obstructive pulmonary disease (COPD) have reduced quadriceps endurance and that this will be correlated with the proportion of type I muscle fibres and with the activity of oxidative enzymes., Methods: The endurance of the quadriceps was evaluated during an isometric contraction in 29 patients with COPD (mean (SE) age 65 (1) years; forced expiratory volume in 1 second 37 (3)% predicted) and 18 healthy subjects of similar age. The electrical activity of the quadriceps was recorded during muscle contraction as an objective index of fatigue. The time at which the isometric contraction at 60% of maximal voluntary capacity could no longer be sustained was used to define time to fatigue (Tf). Needle biopsies of the quadriceps were performed in 16 subjects in both groups to evaluate possible relationships between Tf and markers of muscle oxidative metabolism (type I fibre proportion and citrate synthase activity)., Results: Tf was lower in patients with COPD than in controls (42 (3) v 80 (7) seconds; mean difference 38 seconds (95% CI 25 to 50), p<0.001). Subjects in both groups had evidence of electrical muscle fatigue at the end of the endurance test. In both groups significant correlations were found between Tf and the proportion of type I fibres and citrate synthase activity., Conclusion: Isometric endurance of the quadriceps muscle is reduced in patients with COPD and the muscle oxidative profile is significantly correlated with muscle endurance.

The ability to mentally simulate motor actions was studied in 25 patients with stroke. The duration of imagined and executed movements of the arm and leg was compared. Both executed and imagined movements took longer with the affected limbs than with the unaffected limbs. For both tasks, the duration of movements with the unaffected limbs was longer in the imagined than in the executed conditions, indicating a lack of temporal congruence on that side. Because the temporal uncoupling was found in the limbs contralateral to the intact hemisphere, we propose that this reflects a general slowing in motor imagery that is an indirect consequence of the lesion, rather than a deficit in movement representation within the unaffected hemisphere per se., (Copyright 2004 Lippincott Williams and Wilkins)

Objective: To investigate the effect of mental practice on the learning of a sequential task for the lower limb in a patient with a hemiparesis resulting from a stroke., Design: A single-case study., Setting: Research laboratory of a university-affiliated rehabilitation center., Patient: A right-handed 38-year-old man who had suffered a left hemorrhagic subcortical stroke 4 months prior., Intervention: The patient practiced a serial response time task with the lower limb in 3 distinct training phases over a period of 5 weeks: 2 weeks of physical practice, 1 week of combined physical and mental practice, and then 2 weeks of mental practice alone., Main Outcome Measures: Performance on the task measured through errors and response times. Imagery abilities measured through questionnaires., Results: The patient's average response time improved significantly during the 1st 5 days of physical practice (26%) but then failed to show further improvement during the following week of physical practice. The combination of mental and physical practice during the 3rd week yielded additional improvement (10.3%), whereas the following 2 weeks of mental practice resulted in a marginal increase in performance (2.2%)., Conclusion: The findings show that mental practice, when combined with physical practice, can improve the performance of a sequential motor skill in people who had a stroke, and suggest that mental practice could play a role in the retention of newly acquired abilities.

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.

Objective: To examine the relationship between working memory and motor improvement obtained after a single training session combining mental and physical practice., Design: Before-after trial., Setting: Laboratory of a university-affiliated research rehabilitation center., Participants: A sample of 12 patients with stroke and 14 age- and gender-matched healthy subjects., Intervention: In a single session, patients were trained with combined mental and physical practice to increase the loading on the affected leg while standing up and sitting down., Main Outcome Measures: Motor improvement as measured by the percentage change in limb loading on the affected limb after training and 24 hours later (follow-up), and the relationship between working memory and percentage motor improvement., Results: The loading on the affected leg was improved after training (P< .01) and at follow-up (P< .05), and working memory scores at follow-up correlated significantly (P< .004 to P< .007) with the level of improvement. The visuospatial domain yielded the strongest correlation (r= .83), followed by the verbal (r= .62) and kinesthetic (r= .59) domains., Conclusions: These results suggest that the outcome (improved limb loading) of mental rehearsal with motor imagery depends on the ability to maintain and manipulate information in working memory.

Patients with Parkinson's disease (PD) exhibit impairments in several cognitive functions similar to those observed in patients with prefrontal cortex (PFC) lesions. The physiological origins of these cognitive deficits are not well documented. Two mechanisms have been proposed: disruptions in corticostriatal circuits or a deficiency in frontal dopamine. We previously used functional magnetic resonance imaging (fMRI) in young healthy subjects to separate patterns of PFC and striatum activity during distinct phases of performance of the Wisconsin Card Sorting Task, a set-shifting task that reveals deficits in patients with PD. Here, the same fMRI protocol was used in PD patients and matched controls. Decreased activation was observed in the PD group compared with the matched control group in the ventrolateral PFC when receiving negative feedback and the posterior PFC when matching after negative feedback. In controls, these prefrontal regions specifically coactivated with the striatum during those stages of task performance. In contrast, greater activation was found in the PD group compared with the matched control group in prefrontal regions, such as the posterior and the dorsolateral PFC when receiving positive or negative feedback, that were not coactivated with the striatum in controls. These results suggest that both nigrostriatal dopamine depletion and intracortical dopamine deficiency may play a role in cognitive deficits in PD, depending on the involvement of the striatum in the task at hand.

NMDA receptor antagonists impair learning and memory in animal models, presumably by inhibiting long-term potentiation in the motor cortex. Human studies are limited and restricted by the paucity of safe NMDA antagonists. Here, we investigated the contribution of glutamatergic neurotransmission to the capacity of acquiring motor-adaptation learning in humans. In a double-blind design, 200 mg of amantadine (a low-affinity NMDA receptor channel blocker) or a matching placebo were given orally to groups of 14 and 13 human healthy young volunteers, respectively. Blood samples were collected 3 h after treatment to assay plasma concentrations, and the subjects were then tested using a motor-adaptation paradigm consisting of an eight-target-pointing task. To rule out drug-related generalized impairments such sedation, tests measuring motor dexterity and attention were also administered pre- and post-treatment. Comparison of the mean performance levels on the motor-adaptation task revealed that subjects in the amantadine group performed at a lower level than those in the placebo group, but this difference did not reach significance. Interestingly, however, despite plasma amantadine concentrations being relatively low, ranging from 2.09 to 4.74 microM (mean=3.3 microM), they nevertheless correlated negatively with motor learning. Furthermore, when the amantadine group was divided into low-performance and high-performance subgroups, subjects in the former subgroup displayed mean amantadine concentrations 36% higher than the latter subgroup, and performed significantly worser than the placebo group. No change in performance was found on the motor-dexterity and attention tests. Altogether, our results lend support to the hypothesis that normal NMDA receptor function is necessary for the acquisition of motor adaptation.

In this study, we used a modified version of the Tower of London (TOL) planning task, in conjunction with positron emission tomography, to examine the neural substrates mediating cognitive skill learning. Twelve healthy, right-handed participants solved a total of 90 different TOL problems. They were scanned on four occasions during the fast learning stage as well as in a condition designed to control for internally guided movements. Practice of the TOL task resulted in a significant decrease in planning, execution, and total time taken to solve the problems. Consistent with the results of previous studies, early performance of the TOL task was associated with increased blood flow activity in the dorsolateral prefrontal, orbitofrontal, and parietal cortices on the left, as well as in the caudate nucleus, cerebellum, and premotor cortex, bilaterally. Interestingly, however, activity in the left caudate nucleus was maintained from the beginning to the end of the learning process, suggesting that this structure plays a role in this type of cognitive skill learning. In addition, correlational analyses revealed that improved performance on the TOL task was associated with a significant decrease of activity in the medial orbitofrontal and frontopolar cortices over the course of learning, areas thought to be involved in decision making, guessing, and monitoring of feedback information. In sum, the results lend further support to the idea that the learning of cognitive skills requiring planning and working memory capacities is mediated through a fronto-striatal network.

The task-oriented approach incorporating treadmill walking for retraining gait early after stroke has contributed to promote locomotor recovery. To augment practice, training strategies such as mental practice and training in virtual environments are proposed. While the former offers more practice with less physical exertion, the latter allows safe practice in a variety of challenging environments. Work is under way to assess whether these new strategies can further enhance locomotor recovery.

The goal of the present study was to examine, via positron emission tomography, the functional changes associated with the learning of a sequence of foot movements through mental practice with motor imagery (MI). Following intensive MI training over several days, which led to a modest but significant improvement in performance, healthy subjects showed an increase in activity restricted to the medial aspect of the orbitofrontal cortex (OFC), and a decrease in the cerebellum. These main results are largely consistent with those found in a previous study of sequence learning performed in our laboratory after physical practice of the same task [NeuroImage 16 (2002) 142]. Further analyses showed a positive correlation between the blood flow increase in the OFC and the percentage of improvement on the foot sequence task. Moreover, the increased involvement of the medial OFC revealed a modality specific anatomo-functional organization, as imagination of the sequential task after MI practice activated a more posterior region than its execution. These results demonstrate that learning a sequential motor task through motor imagery practice produces cerebral functional changes similar to those observed after physical practice of the same task. Moreover, the findings are in accord with the hypothesis that mental practice with MI, at least initially, improves performance by acting on the preparation and anticipation of movements rather than on execution per se.

Positron emission tomography (PET) was used to study the involvement of supraspinal structures in human locomotion. Six right-handed adults were scanned in four conditions while imagining locomotor-related tasks in the first person perspective: Standing (S), Initiating gait (IG), Walking (W) and Walking with obstacles (WO). When these conditions were compared to a rest (control) condition to identify the neural structures involved in the imagination of locomotor-related tasks, the results revealed a common pattern of activations, which included the dorsal premotor cortex and precuneus bilaterally, the left dorsolateral prefrontal cortex, the left inferior parietal lobule, and the right posterior cingulate cortex. Additional areas involving the pre-supplementary motor area (pre-SMA), the precentral gyrus, were activated during conditions that required the imagery of locomotor movements. Further subtractions between the different locomotor conditions were then carried out to determine the cerebral regions associated with the simulation of increasingly complex locomotor functions. These analyses revealed increases in rCBF activity in the left cuneus and left caudate when the W condition was compared to the IG condition, suggesting that the basal ganglia plays a role in locomotor movements that are automatic in nature. Finally, subtraction of the W from the WO condition yielded increases in activity in the precuneus bilaterally, the left SMA, the right parietal inferior cortex and the left parahippocampal gyrus. Altogether, the present findings suggest that higher brain centers become progressively engaged when demands of locomotor tasks require increasing cognitive and sensory information processing., (Copyright 2003 Wiley-Liss, Inc.)

This review paper focuses on studies in healthy human subjects that examined the functional neuroanatomy and cerebral plasticity associated with the learning, consolidation and retention phases of motor skilled behaviors using modern brain imaging techniques. Evidence in support of a recent model proposed by Doyon and Ungerleider [Functional Anatomy of Motor Skill Learning. In: Squire LR, Schacter DL, editors. Neuropsychology of Memory. New York: Guilford Press, 2002.] is also discussed. The latter suggests that experience-dependent changes in the brain depend not only on the stage of learning, but also on whether subjects are required to learn a new sequence of movements (motor sequence learning) or learn to adapt to environmental perturbations (motor adaptation). This model proposes that the cortico-striatal and cortico-cerebellar systems contribute differentially to motor sequence learning and motor adaptation, respectively, and that this is most apparent during the slow learning phase (i.e. automatization) when subjects achieve asymptotic performance, as well as during reactivation of the new skilled behavior in the retention phase.

The search for the neural substrates mediating the incremental acquisition of skilled motor behaviors has been the focus of a large body of animal and human studies in the past decade. Much less is known, however, with regard to the dynamic neural changes that occur in the motor system during the different phases of learning. In this paper, we review recent findings, mainly from our own work using fMRI, which suggest that: (i) the learning of sequential finger movements produces a slowly evolving reorganization within primary motor cortex (M1) over the course of weeks and (ii) this change in M1 follows more dynamic, rapid changes in the cerebellum, striatum, and other motor-related cortical areas over the course of days. We also briefly review neurophysiological and psychophysical evidence for the consolidation of motor skills, and we propose a working hypothesis of its underlying neural substrate in motor sequence learning., (Copyright 2002 Elsevier Science (USA))

The aim of the present positron emission tomography study was to measure the dynamic changes in cerebral activity before and after practice of an explicitly known sequence of foot movements when executed physically and to compare them to those elicited during motor imagery of the same movements. Nine healthy volunteers were scanned while performing both types of movement at an early phase of learning and after a 1-h training period of a sequence of dorsiflexions and plantarflexions with the left foot. These experimental conditions were compared directly, as well as to a perceptual control condition. Changes in regional cerebral blood flow associated with physical execution of the sequence early in the learning process were observed bilaterally in the dorsal premotor cortex and cerebellum, as well as in the left inferior parietal lobule. After training, however, most of these brain regions were no longer significantly activated, suggesting that they are critical for establishing the cognitive strategies and motor routines involved in executing sequential foot movements. By contrast, after practice, an increased level of activity was seen bilaterally in the medial orbitofrontal cortex and striatum, as well as in the left rostral portion of the anterior cingulate and a different region of the inferior parietal lobule, suggesting that these structures play an important role in the development of a long lasting representation of the sequence. Finally, as predicted, a similar pattern of dynamic changes was observed in both phases of learning during the motor imagery conditions. This last finding suggests that the cerebral plasticity occurring during the incremental acquisition of a motor sequence executed physically is reflected by the covert production of this skilled behavior using motor imagery., (2002 Elsevier Science (USA).)

We used positron emission tomography to examine learning and retention of timed motor sequences. Subjects were scanned during learning (LRN) and baseline (ISO) on 3 d: day 1, after 5 d of practice (day 5) and after a 4 week delay (recall). Blood flow was compared across days of learning and between the LRN and ISO conditions. Overall, significant changes in activity were seen across days for the LRN condition, but not the ISO baseline. Day 1 results revealed extensive activation in the cerebellar cortex, particularly lobules III/IV and VI. Day 5 results showed increased activity in the basal ganglia (BG) and frontal lobe, with no significant cerebellar activity. At recall, significantly greater activity was seen in M1, premotor, and parietal cortex. Blood flow in the cerebellum decreased significantly between day 1 and recall. These results reveal a dynamic network of motor structures that are differentially active during different phases of learning and delayed recall. For the first time our findings show that recall of motor sequences in humans is mediated by a predominantly cortical network. Based on these results, we suggest that during early learning cerebellar mechanisms are involved in adjusting movement kinematics according to sensory input to produce accurate motor output. Thereafter, the cerebellar mechanisms required for early learning are no longer called into play. During late learning, the BG may be involved in automatization. At delayed recall, movement parameters appear to be encoded in a distributed representation mediated by M1, premotor, and parietal cortex.

Studies in experimental animals and humans have stressed the role of the cerebellum in motor skill learning. Yet, the relative importance of the cerebellar cortex and deep nuclei, as well as the nature of the dynamic functional changes occurring between these and other motor-related structures during learning, remains in dispute. Using functional magnetic resonance imaging and a motor sequence learning paradigm in humans, we found evidence of an experience-dependent shift of activation from the cerebellar cortex to the dentate nucleus during early learning, and from a cerebellar-cortical to a striatal-cortical network with extended practice. The results indicate that intrinsic modulation within the cerebellum, in concert with activation of motor-related cortical regions, serves to set up a procedurally acquired sequence of movements that is then maintained elsewhere in the brain.

The aim of this pilot study was to examine the role of the striatum and cerebellum in the adaptation to a novel movement within a sequence of practiced movements using a motor learning paradigm. The performance of patients in the early or advanced stages of Parkinson's disease (PD) and of patients with damage to the cerebellum (CE) was compared, respectively to a group of aged and young matched controls on an adapted version of the Mirror-Tracing Test. In this task, subjects were required to trace a series of complex figures in two conditions: (1) a Practiced condition, in which the figures were composed of the juxtaposition of three simple designs that were extensively practiced before; and (2) a Mixed condition in which triads were created by replacing the last simple figure of the triads in the Practiced condition by a new simple figure that had never been traced individually before. Results showed that all clinical groups were slower than controls at tracing the Practiced triads. Most interestingly, however, only patients in the advanced stages of PD showed increased completion time to trace the triads in the Mixed condition. This suggests that a bilateral striatal dysfunction affects the ability to adapt to a novel motion within a sequence of practiced movements. Although exploratory, these results support a functional dissociation between the striatum and cerebellum in acquiring visuomotor skilled behaviors.

For many patients with damage to the central nervous system (CNS), execution of motor tasks is very difficult, sometimes impossible, even after early participation in an active rehabilitation program. Several investigators have recently proposed that mental practice could be used by these patients as a therapeutic tool to improve their performance of motor functions, yet very little empirical work addresses this issue directly. This article discusses the rationale for investigating mental practice as a means of promoting motor recovery in patients with a neurologic disorder. We first present evidence supporting the existence of a similarity between executed and imagined actions using data from psychophysical, neurophysiologic, and brain imaging studies. This parallel is then extended to the repetition of movements during physical and mental practice of a motor skill. Finally, a new model is proposed to emphasize the key role of motor imagery as an essential process of mental practice, and also to stimulate additional research on this type of training in the rehabilitation of patients with motor impairments of cerebral origin.

We have developed a genetic method to determine the active orientation of dimeric transmembrane protein helices. The bovine papillomavirus E5 protein, a 44-amino acid homodimeric protein that appears to traverse membranes as a left-handed coiled-coil, transforms fibroblasts by binding and activating the platelet-derived growth factor (PDGF) beta receptor. A heterologous dimerization domain was used to force E5 monomers to adopt all seven possible symmetric coiled-coil registries relative to one another within the dimer. Focus formation assays demonstrated that dimerization of the E5 protein is required for transformation and identified a single preferred orientation of the monomers. The essential glutamine residue at position 17 resided in the dimer interface in this active orientation. The active chimera formed complexes with the PDGF beta receptor and induced receptor tyrosine phosphorylation. We also identified E5-like structures that underwent non-productive interactions with the receptor.

A series of new acetogenin analogues incorporating a central catechol moiety instead of the tetrahydrofuran ring(s) have been prepared and tested against L1210 leukemia cells. Although less potent than bullatacinone, which has the same terminal lactone, these compounds display interesting cell cycle effects.

The striatum and cerebellum have been shown to be key structures of a distributed system for the control of skilled movements. However, the mechanisms under which they operate remain unclear. This study compared the performance of patients with Parkinson's disease (PD) or with cerebellar damage (CE) to that of age-matched controls. Each group performed two visuomotor paradigms: a random variant of the serial reaction time (SRT) task that tested the subject's ability to make efficient stimulus-response associations and an adapted version of the mirror-tracing task that measured their capacity to combine simple movements into complex ones. PD patients with bilateral striatal damage showed an impaired learning profile on the SRT task and a normal facilitation effect in the tracing task, while CE patients showed the reverse pattern. Although further research is needed, the present findings suggest that the striatum and cerebellum are involved in distinct learning mechanisms.

The deficits seen in frontal-lobe patients and in the elderly show clearly that spontaneous script generation depends on good frontal-lobe function. Shallice, however, has proposed that one aspect of script generation (contention scheduling, CS) which is involved in the activation and maintenance of overlearned or routine scripts may depend more on the basal ganglia. Patients with Parkinson's disease would thus be expected to manifest deficits somewhat different from those observed in frontal-lobe patients when generating scripts. The performances of 16 nondemented and nondepressed patients with idiopathic Parkinson's disease were compared to those of 16 age-matched normal control subjects under two experimental conditions; routine, forward script generation and nonroutine, backward script generation. Parkinsonian patients generated scripts significantly deprived of contextual elements in the forward condition and made significantly more sequencing and perseverative errors in both forward and backward conditions than did normal subjects. They also produced a significantly higher number of irrelevant intrusions, in both conditions, than did controls. These results support, in a general sense, Shallice's notion that the basal ganglia are important in script generation; however, other specific predictions of Shallice's model were not supported by our findings., (Copyright 2000 Academic Press.)

The stereo- and enantiocontrolled synthesis of substituted beta-hydroxy ethers based on glycol and catechol bearing an alkyne group and a series of substituents is reported. These substrates were designed to mimic the bis-THF array of annonaceous acetogenins and to provide an access to simplified and modified analogues. The key steps of the synthesis involve the condensation of the nonracemic mesylate of solketal with ethylene glycol and catechol, followed by an alkylation with a glycidyl derivative. Under appropriate conditions, the reaction is completely stereoselective and allows the synthesis of all the diastereomers. After the epoxide was opened with triethylsilylacetylene, the second epoxide was unmasked and reacted with a series of alkyl, aryl, amine, and alcohol reagents. A series of 28 analogues was prepared having a glycol or a catechol core, a stereodefined configuration of the flanking hydroxyl groups, and an acetylenic appendage suitable for a coupling to a lactone-bearing fragment.

We have prepared an atlas of the human cerebellum using high-resolution magnetic resonance-derived images warped into the proportional stereotaxic space of Talairach and Tournoux. Software that permits simultaneous visualization of the three cardinal planes facilitated the identification of the cerebellar fissures and lobules. A revised version of the Larsell nomenclature facilitated a simple description of the cerebellum. This atlas derived from a single individual was instrumental in addressing longstanding debates about the gross morphologic organization of the cerebellum. It may serve as the template for more precise identification of cerebellar topography in functional imaging studies in normals, for investigating clinical-pathologic correlations in patients, and for the development of future probabilistic maps of the human cerebellum., (Copyright 1999 Academic Press.)

Recently, Doyon et al. [20] demonstrated that lesions to both the striatum and to the cerebellum in humans produce a similar deficit in the learning of a repeated visuomotor sequence, which occurs late in the acquisition process. We now report the results of two experiments that were designed to examine whether this impairment was due to a lack of automatization of the repeating sequence of finger movements by using a dual-task paradigm and by testing for long-term retention of this skill. In Experiment 1, the performance of groups of patients with Parkinson's disease, or with damage to the cerebellum or to the frontal lobes, was compared to that of matched control subjects on the Repeated Sequence Test (primary task) and the Brooks' Matrices Test (secondary task). These two tests were administered concomitantly in both early and late learning phases of the visuomotor sequence. Overall, the groups did not differ in their ability to execute the primary task. By contrast, in accordance with the predictions, patients in Stages 2-3 of Parkinson's disease or with a cerebellar lesion failed to reveal the expected increase in performance on the secondary task seen with learning, suggesting that the latter groups of patients did not have access to the same level of residual cognitive resources to complete the matrices compared to controls. In Experiment 2, the same groups of patients and control subjects were retested again 10-18 months later. They were given four blocks of 100 trials each of the repeating sequence task, followed by a questionnaire and a self-generation task that measured their declarative knowledge of that sequence. The results revealed a long-term retention impairment only in patients who changed from Stage I to Stage II of the disease (suggesting further striatal degeneration) during the one-year interval, or who had a cerebellar lesion. By contrast, performance of the three clinical groups did not differ from controls on declarative memory tests. These findings suggest that both the striatum and the cerebellum participate to the automatization process during the late (slow) learning stage of a sequence of finger movements and that these structures also play a role in the neuronal mechanism subserving long-term retention of such a motor sequence behavior.

In this study we examined the effects of striatal dopamine depletion on cortical and subcortical blood flow changes during two tasks known to involve frontostriatal circuitry. Regional cerebral blood flow was measured in six patients with moderate Parkinson's disease and in six age-matched control subjects while they performed easy and difficult versions of a modified Tower of London planning task and a mnemonic variant of this task that required short-term retention and reproduction of problem solutions, as well as a control condition that involved identical visual stimuli and motor responses. Relative to control conditions, the planning task was associated with an increase in cerebral blood flow centred on the internal segment of the right globus pallidus in the age-matched control subjects, and a decrease in the same region in the patients with Parkinson's disease. A similar inverse relationship between the task-specific blood flow change observed in the control group and that observed in the Parkinson's disease patients was not found in any other subcortical or cortical area examined, including regions of the dorsolateral frontal cortex known to be involved in this task. When blood flow in the spatial working memory task was examined, a similarly specific dissociation between the two groups of subjects was observed at similar coordinates in the right pallidum. We conclude that striatal dopamine depletion disrupts the normal pattern of basal ganglia outflow in Parkinson's disease and consequently, affects the expression of frontal-lobe functions by interrupting normal transmission of information through frontostriatal circuitry.

Caregivers are often ill-equipped to cope with repeated verbal and physical aggression by geriatric residents with cognitive deficits. Cooperation from other members of the health care team is rarely automatic and there is little adherence to established interventions. This article offers valuable insights on patient care to caregivers who work with aggressive individuals in geriatric settings. With the consensual approach, nursing assistants and attendants who are assigned to these patients daily are able to participate in the problem-solving process. They help design the approach and willingly become stakeholders in the actions presented by the patient care plans. By the end of the process they are able to view the aggressive person as someone worthy of attention and love, rather than a disruptive element to be endured.

This chapter reviews recent experiments that have examined the functional neuroanatomy of motor and visuomotor skill learning using brain imaging techniques such as single photon emission computed tomography, positron emission tomography, and functional magnetic resonance imaging. Special attention has been given to the cerebral blood flow changes in the cerebellum that are associated with the acquisition of these skills, although localizations of other activated regions (cortical and subcortical) are also included. The cognitive processes involved in different skill acquisition paradigms are discussed with particular reference to the learning stages at which subjects were scanned. This approach examines the conditions that are likely to produce cerebellar activation and helps us understand the role of the cerebellum in acquiring skilled behaviors.

Background: The prognosis of patients with myxoid liposarcoma (ML) or round cell liposarcoma (RCL) has never been adequately defined., Methods: We evaluated the clinical and pathologic features of 95 patients with biopsy proven ML or RCL examined at the Mayo Clinic between 1971 and 1992. Routine hematoxylin and eosin stained slides of all cases were reviewed. Morphologic variable evaluated included percent of round cell differentiation, percent of lipoblastic differentiation, and presence of tumor necrosis. Clinical follow-up was available for 86 patients (range: 6 months-23.4 years; mean: 7.2 years; median: 5.9 years). Flow cytometry for determination of DNA ploidy was performed on paraffin embedded tissue available from 46 cases. Survival analyses for the 86 patients with adequate clinical follow-up were performed by the Kaplan-Meier test using the approximate chi-square statistic for the log rank test., Results: Age at diagnosis ranged from 16 to 81 years (median: 44 years). The extremities were involved in 91 cases, the retroperitoneum in 3 cases, and the perineum in 1 case. The single most common location was the thigh (61 cases). Histologically, round cell differentiation was present in 41 cases (43%) ranging from 5% to 100% of the tumor volume. Only one case of "pure" RCL was used in the study. Spontaneous tumor necrosis was noted in 4 cases. By flow cytometry, 38 tumors were diploid, 6 were aneuploid, and 1 was tetraploid. The data from 1 case was uninterpretable. Thirty patients (35%) developed metastasis; 27 (31%) died from the disease., Conclusions: With multivariate analysis, age ( > 45 years), percent of round cell differentiation ( > or = 25%), and the presence of spontaneous tumor necrosis are significantly associated with a poor prognosis. No correlation was observed between DNA ploidy (i.e., diploid vs. aneuploid) and percent of round cell differentiation or clinical outcome.

The present study was designed to examine patterns of regional cerebral blood flow (CBF) associated with the learning of a repeated visuomotor sequence both in the early and late phases of the acquisition process. In addition, changes in blood flow related to the implicit versus explicit aspects of learning such a skill were investigated. Fourteen normal control subjects were scanned while performing the task (i) in both early and advanced learning stages of the visuomotor sequence; (ii) after having acquired explicit knowledge of the sequences; and (iii) in two control conditions (perceptual and random sequence). Subtraction of the random condition from the highly learned condition revealed specific areas of activity in the right ventral striatum and dentate nucleus of the cerebellum. Blood flow changes in the right hemisphere were also seen in the medial posterior parietal and prestriate regions, as well as in the anterior cingulate cortex. Finally, once the subjects had acquired explicit knowledge of the embedded sequence that was presented in the highly learned condition, increased CBF activity was observed only in the mid-ventrolateral frontal area in the right hemisphere. These findings confirm that both the striatum and the cerebellum are involved in the implicit acquisition of a visuomotor skill, especially in the advanced stages of the learning process, and furthermore that the ventrolateral prefrontal cortex contributes preferentially to the declarative aspect of this task.

Previous work with both neurosurgical and neurodegenerative patient groups has suggested that high level planning is mediated by neural circuitry which includes both the prefrontal cortex and the striatum. In this study, the functional anatomy of cognitive planning was investigated further, using positron emission tomography (PET). Regional cerebral blood flow (rCBF) was measured in 12 normal volunteers while performing easy and difficult versions of (i) a modified Tower of London planning task; (ii) a mnemonic variant of this task that required short-term retention and reproduction of problem solutions; and (iii) a control condition that involved identical visual stimuli and motor responses. Significant increases in rCBF were observed in the left hemisphere, in both the mid-dorsolateral frontal cortex and in the head of the caudate nucleus, when the difficult planning task was compared with the control condition. Moreover, subtraction of a simple planning condition from the more difficult one revealed focal increases in rCBF in the caudate nucleus and the thalamus only. During both mnemonic variants of the planning task, changes were also observed in the mid-dorsolateral frontal cortex and in more ventral frontopolar regions, bilaterally. When compared directly, the planning and memory conditions differed in terms of these ventral activation foci, but not in the pattern of activation observed in mid-dorsolateral frontal cortex. These findings further implicate frontostriatal circuitry in high-level planning and provide evidence for functionally distinct contributions from ventral and dorsolateral frontal regions to spatial working memory.

Functional analysis is a research process that links problem behavior, its surrounding elements and the resulting consequences. The goal of this study was to decrease repetitive shouting of an elderly patient diagnosed with Alzheimer-like dementia. The analysis provided the following data: BEHAVIORS: Repetitive shouting by the patient lasting 80-115 seconds per 30 minutes during specific times of the day--accompanied by licking of the lips to moisten them. Environmental factors: Constant loud noise in the patient's room; the use of loud voices by staff and visitors; familiar objects out of the patient's reach. Individual factors: Diagnosis of the patient's blindness and auditory hypersensitivity; side-effects of psychotropic medications; a lack of social activities; inactivity because of the patient being bedridden 22 hours per day and the use of restraints when positioned in a chair., Surrounding Elements: The patients was isolated in a private room; psychotropic medication was increased; staff and other patients were less disrupted and the number of visitors to the patient was decreased., Consequences: The above data enabled the formulation of four hypotheses (with specific interventions for each) that assisted staff in planning the patient's care for a 10-day period; a reduction of anxiety; a reduction in discomfort; sensory hypostimulation; verbal hypostimulation. Following the application of these interventions for a 10-day period, a second set of data was gathered and the results showed a decrease in shouting by 40 per cent in the morning and 51 per cent in the afternoon.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical and morphologic findings of three patients with metabolic acidosis, methylmalonic aciduria, and homocystinuria are presented. The clinical evolution of the patients was similar and was characterized in the first weeks of life by failure to thrive, hypotonia, and lethargy associated with pancytopenia and hepatic dysfunction, eventually progressing to severe respiratory insufficiency and renal failure consistent with a hemolytic-uremic syndrome. The patients died at 40, 45, and 75 days of age. Biochemical analyses and complementation studies revealed a congenital anomaly of vitamin B12 metabolism (cobalamin C disease). Postmortem morphologic findings in all three cases were dominated by a thrombotic microangiopathy of the kidneys and lungs, diffuse hepatic steatosis, and megaloblastic changes in the bone marrow. A severe gastritis with striking cystic dysplastic mucosal changes and total absence of parietal and chief cells was a consistent finding in all three cases, the rest of the gastrointestinal tract appearing essentially normal. Cobalamin C disease is an intracellular defect of cobalamin metabolism with possible recessive inheritance that can result in multiorgan failure early in life, with a thrombotic microangiopathy and unusual changes in the gastric mucosa.

The performance of 92 patients with unilateral temporal- or frontal-lobe excisions and 35 normal control subjects was tested under two experimental conditions (global, local) of a Stroop-type reaction-time task, employing either hierarchically structured letters or abstract designs as stimuli. In the local condition, subjects were asked to focus their attention on the small forms and to ignore the large form, whereas they were instructed to do the reverse in the global condition. The results showed that, in the local condition, the patients with right temporal-lobe lesions were less affected than the other groups by interference from the global aspect of the stimulus. This reduced sensitivity to the overall configuration of the stimulus was unrelated to the extent of hippocampal removal or to the presence of visual-field defects. These findings support the hypothesis that the human right temporal neocortex contributes to the global processing of visual information.

The ability to acquire visual cues for discriminating between two targets against a background of visually similar items was examined in 64 patients with unilateral temporal- or frontal-lobe excisions and 20 normal control subjects. The subjects were tested on two versions (letters and abstract designs) of a visual cue-learning task that was an adaptation and extension of RABBITT's (Am. J. Psychol. 80, 1-13, 1967) visual-search paradigm. For both versions, the material consisted of two packs of cards, each containing a different set of background letters or designs. Subjects were required to sort the cards into two piles according to which of two targets was present on the card. On the letter task, all groups took longer to sort when the background letters were changed after three learning trials. With abstract designs, patients with right temporal-lobe lesions failed to show this interference effect after three learning trials, but they, like other groups, did so after six. This slowness in learning was related neither to the extent of hippocampal removal nor to visual-field defects. It is argued that the right temporal neocortex plays a role in incremental learning of visual cues during repeated pattern discriminations.

In order to assess the relative effectiveness of finger warming and temporal blood volume pulse reduction biofeedback in the treatment of migraine, 22 female migraine patients were assigned to one of three experimental conditions: temporal artery constriction feedback, finger temperature feedback, or waiting list. Biofeedback training consisted of 12 sessions over a 6-week period. All patients completed 5 weeks of daily self-monitoring of headache activity (frequency, duration, and intensity) and medication before and after treatment. Treatment credibility was assessed at the end of Sessions 1, 6, and 12. Results showed that temporal constriction and finger temperature biofeedback were equally effective in controlling migraine headaches and produced greater benefits than the waiting list condition. Power analyses indicated that very large sample sizes would have been required to detect any significant differences between the two treatment groups. No significant relationships were found between levels of therapeutic gains and levels of thermal or blood volume pulse self-regulation skills. Likewise, treatment outcome was not found to be related to treatment credibility. Further analyses revealed that changes in headache activity and medication were associated with changes in vasomotor variability. Because blood volume pulse variability was not significantly affected by biofeedback training, questions about its role in the therapeutic mechanism are raised.

In order to evaluate the specific effects of blood volume pulse (BVP) biofeedback in the treatment of migraine headaches, 21 female migraine patients were randomly assigned to one of three experimental conditions: temporal artery constriction feedback, temporal artery dilation feedback, or waiting list. Biofeedback training consisted of 15 sessions over an 8-week period. All patients completed 5 weeks of daily self-monitoring of headache activity and medication before and after treatment. Results showed that constriction and dilation biofeedback were equally effective in controlling migraines and produced greater benefits than the waiting-list condition. No significant relationships were found between therapeutic gains and BVP self-regulation skills. However, further analyses revealed that changes in headache activity and medication were associated with changes in vasomotor variability. The current rationale for the use of BVP biofeedback in the treatment of migraine is questioned and a new one is proposed.