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Dissociation of motor preparation from memory and attentional processes using movement-related cortical potentials.

The EEG activity preceding self-paced voluntary movements (movement-related cortical potential, MRCP) is smaller if subjects make the same movement each time (regular task) compared with when different movements are made each time (random task). To test whether extra activity in the random task is due to increased motor preparation needed to switch between different movements, or to memory/attentional processes needed to select movements randomly, we compared regular and random movements with an additional alternating task. This alternating task required subjects to make different movements each time as in the random task, but since the task was very simple, the memory/attentional load was similar to that in the regular task. The MRCP was equally large over motor areas in both random and alternating tasks, suggesting that the extra activity over sensorimotor areas reflected processes involved in motor preparation rather than memory/attention. We speculate that, in the regular task, some part of the instructions for the previous movement remains intact, reducing the amount of preparation needed for the next repetition. Thus the MRCP is smaller than in the alternating and random tasks. Although the MRCPs in alternating and random tasks were similar over the motor areas, the random task had more activity than the alternating task in contralateral frontal areas. This part of the MRCP may therefore be related to memory/attentional processes required to randomize the sequence of movements. We conclude that the MRCP contains dissociable components related to motor preparation and memory/attention.

Adult↗

Children with autism experience problems with both objects and people.

Kanner (1943), in his classic account, described autism as a specific impairment in interpersonal relations which leaves the child's uses of objects relatively unaffected. This combination of the difficulties in relating to people and the supposedly "excellent" relations to objects figures centrally within many of the current theories of autism, which have had relatively little to say on the question of object use. This paper draws attention to evidence of widespread impairments in relating to objects, not only in interpersonal aspects of object use but also in early sensorimotor exploration and the functional and conventional uses of objects. In stressing these problems with objects, our purpose is not to downplay the social dimension of autism, but rather to highlight the reciprocal nature of the interactions between the child, other people, and objects. Given the evidence that other people play an important role in introducing objects to children, we propose that an impairment in interpersonal relations should itself lead us to expect corresponding disruption in the autistic child's use of objects. Conversely, an unusual use of objects is likely to manifest itself in disturbances in relating to other people, given the importance of a shared understanding and use of objects in facilitating interaction.

Autistic Disorder↗

Amphetamine and task-specific practice augment recovery of vibrissae-evoked forelimb placing after unilateral sensorimotor cortical injury in the rat.

This study investigated the relative contribution of amphetamine administration and task-specific practice during the period of drug action to recovery of forelimb-placing ability after unilateral electrolytic lesions of the sensorimotor cortex (SMC) in rats. Subjects were divided into groups receiving amphetamine plus postinjection forelimb-placing practice, amphetamine only, saline plus postinjection forelimb-placing practice, or saline only. The results revealed that groups of subjects receiving either amphetamine, postinjection practice, or a combination of these treatments exhibited the greatest enhancement of rates of vibrissae-evoked forelimb-placing recovery. These data suggest that these treatments can have an enduring beneficial effect on vibrissae-evoked forelimb-placing recovery without any immediate restorative effect on forelimb-placing ability. The recovery patterns and experimental evidence (see Feeney and Sutton, 1988; Chaouloff, 1989) suggest that the beneficial effect of the two therapies may be mediated by catecholamine release.

Amphetamine↗

Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.

CONTEXT: Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits. OBJECTIVE: To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes. DESIGN AND SETTING: Case-control study conducted in 1998 and 1999 at 2 US university medical schools. PARTICIPANTS: A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status. MAIN OUTCOME MEASURES: Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children. RESULTS: Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P</=.005), amygdala (left, 20.2% [P =.001]; right, 30.0% [P<.001]), hippocampus (left, 16.0% [P =.001]; right, 12.0% [P =.007]), and corpus callosum (13.1%-35.2%; P</=.01 for all). Volumes of sensorimotor and midtemporal cortices were associated positively with full-scale, verbal, and performance IQ scores (P<.01 for all). CONCLUSIONS: Our data indicate that preterm birth is associated with regionally specific, long-term reductions in brain volume and that morphological abnormalities are, in turn, associated with poorer cognitive outcome. JAMA. 2000;284:1939-1947.

Brain↗

Phasic alterations in dopamine and serotonin release in striatum and prefrontal cortex in response to cocaine predictive cues in behaving rhesus macaques.

The ability of environmental cues associated with cocaine availability to cause relapse may result from conditioned activation of dopamine (DA) release. We examined this hypothesis in macaque monkeys by conducting microdialysis studies in animals during exposure to a cocaine predictive compound cue. In addition to studying DA release in mesolimbic and sensorimotor striatum, both DA and serotonin levels were determined in the prefrontal cortex (medial orbitofrontal and anterior cingulate). The compound cue employed visual, auditory, and olfactory components, and was salient to the animals as demonstrated by anticipatory lever pressing in the absence of cocaine. During a 10-min period of exposure prior to cocaine availability, there was no significant increase in striatal or cortical DA. The addition of a DA uptake inhibitor to the striatal perfusate to reduce the potential interference of neuronal uptake did not alter the results. In contrast to the lack of any change in striatal DA, a significant decrease in extracellular serotonin in the prefrontal cortex during the 10 min of cue exposure was observed.

Animals↗

Imaging in vivo brain-hormone interaction in the control of eating and obesity.

The field of neuroimaging has made great progress in the mapping of human brain function. In this article, we present a functional magnetic resonance imaging (fMRI) study on the hypothalamic regulation of satiety and its relationship with obesity. The fMRI techniques have been proven invaluable for analyzing changes in brain activity that are associated with most sensorimotor and cognitive functions. However, few studies have been successful in the delineation of the interaction between the central nervous system and the endocrine system, due to the lack of suitable mapping methods which can pinpoint the onset of changes in neuronal activity (e.g., those following eating or drug intake). We have recently introduced a new fMRI method known as temporal clustering analysis (TCA) for dynamically tracking the time course of brain activation. Along with simultaneous blood sampling for the circulating hormone levels, the fMRI techniques with TCA may provide an integrated view of the nervous and endocrine systems in vivo, and thus greatly enhance our understanding of the complex interplay between neural events and hormonal signals.

Cluster Analysis↗

Binding personal and peripersonal space: evidence from tactile extinction.

Behavioral and neurophysiological studies suggest that the brain constructs different representations of space. Among these representations are personal and peripersonal space. Personal space refers to the space occupied by our bodies. Peripersonal space refers to the space surrounding our bodies, which can be reached by our limbs. How these two representations are bound to give a unified sense of space in which humans act is not clear. We tested 10 patients with tactile extinction to investigate this issue. Tactile extinction is an attentional disorder in which patients are unaware of being touched on their contralesional limb if they are also touched simultaneously on their ipsilesional limb. We hypothesized that mechanisms that bind personal and peripersonal representations would improve these patients' awareness of being touched on their contralesional limbs. Visual--tactile integration and intentional movements were considered candidate mechanisms. Patients were more likely to be aware of contralesional touch when looking towards their contralesional limb than when looking towards their ipsilesional limb, and when actively moving on tactile probes than when receiving tactile stimuli passively. The improved awareness of being touched on the contralesional limb under these conditions suggests that cross-sensory and sensorimotor integration help bind personal and peripersonal space.

Aged↗

Exposure to stable flies reduces spatial learning in mice: involvement of endogenous opioid systems.

Biting flies influence both the physiology and behaviour of domestic and wild animals. This study demonstrates that relatively brief (60 min) exposure to stable flies, Stomoxys calcitrans (L.), affects the spatial abilities of male mice. Stable fly exposure resulted in poorer subsequent performance in a water maze task in which individual mice had to learn the spatial location of a submerged hidden platform using extramaze visual cues. Determinations of spatial acquisition and retention were made with mice that had been previously exposed for 60 min to either stable flies or house flies, Musca domestica (L.). Mice exposed to stable flies displayed over one day of testing (six blocks or sets of four trials) significantly poorer acquisition and retention of the water maze task than either mice that had been exposed to house flies or fly-naive mice. This attenuation of spatial learning occurred in the absence of any evident sensorimotor or motivational impairments. The reduction in spatial abilities involved endogenous opioid systems, as the decreased performance resulting from stable fly exposure was blocked by pre-treatment with the prototypic opiate antagonist, naltrexone. These results indicate that relatively brief exposure to biting flies can lead to a decrease in spatial abilities which is associated with enhanced endogenous opioid activity. These results support the involvement of endogenous opioid systems in the mediation of the behavioural and physiological effects of biting fly exposure. They further suggest that decreases in spatial abilities and performance may be part of the behavioural consequences of biting fly exposure in domestic and wild animals.

Animals↗

[Dissociation between movement disorders and EEG shifts in amphetamine-induced stereotypy in the cat].

In experiments on cats it is established that between the degree of EEG desynchronization in the sensorimotor cortex and expressiveness of the stereotype movements, a dissociation is possible which is most distinctly revealed in comparative studies of haloperidol, clozapine and metoclopramide--neuroleptics with different correlation of antipsychotic and extra-pyramidal properties. Local destruction of the ventral parts of the caudate nucleus head enhances motor disturbances resulting from amphetamine administration, but weakens its effect on the cortex. Elimination of the dorsal parts produces an opposite effect. It is suggested that the cause of the dissociation consists in different sensitivity to amphetamine of the dorsal and ventral parts of the neostriatum which are differently involved in organization of stereotype movements and EEG disturbances in amphetamine stereotypy.

Amphetamine↗

Opposite effects of 3,4-methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans.

RATIONALE: Prepulse inhibition of acoustic startle refers to the reduction in the startle response when the startling stimulus is preceded by a weak prepulse stimulus. This phenomenon provides an operational measure of sensorimotor gating that has been found to be reduced in patients with schizophrenia and rats treated with serotonin agonists or serotonin releasers. OBJECTIVE: In this study, we compared the effects of a serotonin releaser, MDMA, on prepulse inhibition in laboratory rats and healthy human volunteers. In particular, we investigated whether MDMA disrupts PPI in humans as observed in animal studies. METHODS: Rats were tested after placebo and MDMA in a counterbalanced order at an interval of 1 week, with separate groups of rats being used for each dose of MDMA (1.7, 5.4 and 17.0 mg/kg). On each test day, rats were first tested after no injections and retested 2 h later, 10 min after a subcutaneous injection of placebo or MDMA. For the human study, a placebo-controlled within-subject design and double-blind procedures were used. Subjects were examined twice at a 2 to 4 week interval after either placebo or drug administration (order being counterbalanced). On each test day, subjects underwent baseline testing including psychological and PPI measures. Ninety minutes later, subjects received placebo or MDMA (1.7 mg/kg PO) and were retested after 75 min during the peak of behavioral effects of MDMA. RESULTS: As expected, MDMA decreased prepulse inhibition in a dose-related fashion in rats. In contrast, a typical recreational dose of MDMA (1.7 mg/kg, orally) increased prepulse inhibition in subjects experiencing robust psychological effects. CONCLUSIONS: This surprising disparity between the effects of the drug in rats and humans may reflect a species-specific difference in the mechanism of action of MDMA or in the behavioral expression of a similar pharmacological effect, or both.

Acoustic Stimulation↗

Psychological development in children born with very low birth weight after severe intrauterine growth retardation: a 10-year follow-up study.

Children born small for gestational age (SGA) and children having very low birth weight, less than 1500 g, are claimed to be at risk of developmental problems, even when obvious pathology and disability are absent. In this study, sensorimotor and cognitive development of 14 medically healthy, very-low-birth-weight and small-for-gestational-age children were investigated. The children were born at the Karolinska Hospital between 1979 and 1981. At the time of the assessment, the children were aged 8.7-11.2 years. The assessment instruments included the Wechsler Intelligence Scale for Children, a modified version of the Bruininks-Oseretsky Test of Motor Proficiency, as well as selected subtests from the Halstead-Reitan Neuropsychological Battery and from the Southern California Tests of Sensory Integration. Information was also obtained from obstetric, neonatal and pediatric records, which included early developmental assessments. As a control group, 14 children were recruited and matched for age, sex and socio-economic background. The very-low-birth-weight-small-for-gestational-age group scored significantly lower on measures of visuospatial ability, non-verbal reasoning, strategy formation and gross-motor coordination. The group differences were largely attributable to the subnormal performance of eight of the very-low-birth-weight-small-for-gestational-age children. These children, who also tended to be born earliest (less than 33 weeks), had a high incidence of behavioral and educational problems. These findings are consistent with the view that the very preterm infant develops a different neurobehavioral organization than a full-term infant. Developmental deficits may become increasingly evident in the early school years.

Age Factors↗

An animal model of chronic placental insufficiency: relevance to neurodevelopmental disorders including schizophrenia.

Evidence now suggests that compromised prenatal brain development may increase the risk for the manifestation of neurological disorders such as schizophrenia. We present a guinea-pig model which mimics a condition of human pregnancy, namely, chronic placental insufficiency. Previously we reported that at term there are changes in the brains of these offspring which are relevant to changes in patients with schizophrenia. The aim of this study was to examine whether deficits in brain structure persist to adolescence and young adulthood (8-12 weeks) and have implications for behavioral function. Reduced uteroplacental blood flow was induced via unilateral ligation of the uterine artery at mid-gestation. The brain was examined in control and prenatally compromised (PC) animals 8 weeks after birth using morphometric and immunohistochemical markers. In a separate cohort of animals, prepulse inhibition (PPI) of the acoustic startle response was assessed at 4, 8 and 12 weeks of age. Brain neurochemistry was examined by determining the concentrations of dopamine and its metabolite, dihydroxyphenylacetic acid (DOPAC), at 12 weeks using high performance liquid chromatography. In PC animals compared with controls there was a reduction in brain weight, persistent enlargement of the lateral ventricles, a reduction in the volume of the basal ganglia and septal region and no evidence of gliosis. No differences were observed in concentration of catecholamines in any brain region examined. At 12, but not 4 or 8, weeks of age, PPI was reduced in PC animals compared with controls. The findings of reduced brain weight, ventriculomegaly, reduced basal ganglia volume and absence of astrogliosis in the PC guinea-pig brain at adolescence parallel some of the changes observed in patients with schizophrenia. The impairment of PPI is comparable to sensorimotor gating deficits observed in patients with schizophrenia. These results indicate that adverse prenatal conditions lead to long-term alterations in brain structure and function which resemble alterations seen in patients with schizophrenia and therefore support the early neurodevelopmental hypothesis of schizophrenia.

Animals↗

Effects of the indirect dopaminomimetic diethylpemoline on local cerebral glucose utilization and local cerebral blood flow in the conscious rat.

The changes in local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) following the systemic application of the indirect dopaminomimetic diethylpemoline (50 mg/kg i.v.) were measured in conscious rats using the autoradiographic [14C]2-deoxyglucose and the [14C] iodoantipyrine technique. Increased rates of glucose utilization were observed in the sensorimotor cortex, parafascicular nucleus, ventrolateral nucleus of the thalamus, substantia nigra, caudate nucleus, globus pallidus, red nucleus, subthalamic nucleus, cerebellar cortex and vermis. Cingulate cortex, anteromedial, anteroventral nucleus of the thalamus, habenula and nucleus accumbens showed a decreased LCGU. The determination of LCBF revealed a similar pattern of altered blood flow values. Statistical evaluation of the relationship between glucose utilization and blood flow by regression analysis did not reveal any distinguishable difference between diethylpemoline-treated rats and controls. The data suggest that it is mainly the altered neuronal activity and metabolic demand after dopaminergic stimulation that effect the changes in blood flow rather than a direct dopaminergic effect on brain vasculature.

Animals↗

Neural basis of pantomiming the use of visually presented objects.

UNLABELLED: Neuropsychological studies of patients suffering from apraxia strongly imply a left hemisphere basis for skillful object use, the neural mechanisms of which, however, remain to be elucidated. We therefore carried out a PET study in 14 healthy human volunteers with the aim to isolate the neural mechanisms underlying the sensorimotor transformation of object-triggers into skilled actions. We employed a factorial design with two factors ( RESPONSE: naming, pantomiming; and TRIGGER: actions, objects) and four conditions (IA: imitating the observed pantomime; IO: pantomiming the use of the object shown; NA: naming the observed pantomime; NO: naming the object shown). The design thus mainly aims at investigating the interaction [i.e. (IO-IA)-(NO-NA)] which allows the assessment of increased neural activity specific to the sensorimotor transformation of object-triggers into skilled actions. The results (P < 0.05, corrected) showed that producing a wide range of skilled actions triggered by objects (controlled for perceptual, motor, semantic, and lexical effects) activated left inferior parietal cortex. The data provide an explanation for why patients with lesions including left parietal cortex suffer from ideational apraxia as assessed by impaired object use and pantomining to visually presented objects.

Adult↗

Temporal window of vulnerability to repetitive experimental concussive brain injury.

OBJECTIVE: Repetitive concussive brain injury (CBI) is associated with cognitive alterations and increased risk of neurodegenerative disease. METHODS: To evaluate the temporal window during which the concussed brain remains vulnerable to a second concussion, anesthetized mice were subjected to either sham injury or single or repetitive CBI (either 3, 5, or 7 days apart) using a clinically relevant model of CBI. Cognitive, vestibular, and sensorimotor function (balance and coordination) were evaluated, and postmortem histological analyses were performed to detect neuronal degeneration, cytoskeletal proteolysis, and axonal injury. RESULTS: No cognitive deficits were observed in sham-injured animals or those concussed once. Mice subjected to a second concussion within 3 or 5 days exhibited significantly impaired cognitive function compared with either sham-injured animals (P < 0.05) or mice receiving a single concussion (P < 0.01). No cognitive deficits were observed when the interconcussion interval was extended to 7 days, suggestive of a transient vulnerability of the brain during the first 5 days after an initial concussion. Although all concussed mice showed transient motor deficits, vestibulomotor dysfunction was more pronounced in the group that sustained two concussions 3 days apart (P < 0.01 compared with all other groups). Although scattered degenerating neurons, evidence of cytoskeletal damage, and axonal injury were detected in selective brain regions between 72 hours and 1 week after injury in all animals sustaining a single concussion, the occurrence of a second concussion 3 days later resulted in significantly greater traumatic axonal injury (P < 0.05) than that resulting from a single CBI. CONCLUSION: These data suggest that a single concussion is associated with behavioral dysfunction and subcellular alterations that may contribute to a transiently vulnerable state during which a second concussion within 3 to 5 days can lead to exacerbated and more prolonged axonal damage and greater behavioral dysfunction.

Animals↗

Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating.

Serotonin(6) (5-HT(6)) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT(6) antagonists such as RO4368554 allows further characterization of the role of the 5-HT(6) receptor in these processes. Herein, we tested RO4368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, RO4368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. RO4368554 reversed the effects of scopolamine in novel object discrimination (active doses in mg/kg, i.p., 3, 10), social recognition (3, 10), social discrimination (1, 3, 10) and passive avoidance (10, 30 i.p. and 100 p.o.) tasks. In unimpaired rats, RO4368554 enhanced object discrimination (3, 10; 4-h forgetting interval) and autoshaping learning (3), but was inactive in a water maze task (doses tested: 1-10 mg/kg, i.p.). In tests sensitive to antipsychotics, RO4368554 did not reverse sensorimotor gating deficits induced by the psychostimulants dizocilpine and amphetamine (doses tested: 1-30 mg/kg, i.p.) or neonatal lesion of the ventral hippocampus (1-10 mg/kg, i.p.). In conclusion, RO4368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT(6) receptor antagonists involve modulation of cholinergic neurotransmission.

Acoustic Stimulation↗

Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen.

The SHIRPA primary screen comprises 40 measures covering various reflexes and basic sensorimotor functions. This multi-test battery was used to compare non-transgenic controls with APP23 transgenic mice, expressing the 751 isoform of human beta-amyloid precursor protein and characterized by amyloid deposits in parenchyma and vessel walls. The APP23 mice were distinguishable from controls by pathological limb reflexes, myoclonic jumping, seizure activity, and tail malformation. In addition, this mouse model of Alzheimer's disease was also marked by a crooked swimming trajectory. APP23 mice were also of lighter weight and were less inclined to stay immobile during a transfer arousal test. Despite the neurologic signs, APP23 transgenic mice were not deficient in stationary beam, coat-hanger, and rotorod tests, indicating intact motor coordination abilities.

Alzheimer Disease↗

Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice.

We have recently reported the neuroprotective effect of pranlukast (ONO-1078), a cysteinyl leukotriene receptor-1 (CysLT1) antagonist, on cerebral ischemia in rats and mice. In this study, we further determined whether the effect of pranlukast is long lasting and related to the formation of a glial scar in cerebral ischemic mice. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). After ischemia, pranlukast (0.1 mg/kg) was injected intraperitoneally for 5 consecutive days. Neurological deficits and sensorimotor function were determined during 70 days after ischemia. Brain lesion and glial scar formation were detected at the end of the experiment. Pranlukast did not reduce mortality, but significantly improved neurological deficits and promoted sensorimotor recovery during 70 days. At the end of the experiment, pranlukast significantly reduced lesion volume, and increased neuron densities in the cortex and hippocampal CA1 region in the ischemic hemispheres. Importantly, pranlukast also remarkably reduced the thickness of a scar wall in the ischemic hemispheres. These findings indicate that pranlukast has a long-lasting protective effect on focal cerebral ischemia in mice, and inhibit the ischemia-induced glial scar formation, providing further evidence of the therapeutic potential of pranlukast in the treatment of ischemic stroke.

Analysis of Variance↗

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