An Enhanced Model of Middle Cerebral Artery Occlusion in Nonhuman Primates Using an Endovascular Trapping Technique.

BACKGROUND AND PURPOSE: Current nonhuman primate stroke models are limited by either stroke variability or survivability. A new nonhuman primate stroke model was developed by using endovascular trapping techniques to limit collateral vessels with serial MR imaging and neurologic assessments. MATERIALS AND METHODS: Eight adult rhesus monkeys (female, 7-13 years of age) underwent MR imaging and Spetzler neurologic assessment followed by endovascular stroke induction consisting of superselective endovascular placement of surgical silk sutures into the right MCA by using a trapping technique. Two initial subjects were euthanized immediately following postocclusion MR imaging. The subsequent 6 subjects recovered and underwent follow-up MR imaging and Spetzler neurologic assessments at 48 hours, with 4 being followed to 96 hours. Stroke infarct volumes were measured, and the longitudinal Spetzler clinical neurologic scores were assessed. The brain tissues were harvested and prepared with hematoxylin-eosin staining. RESULTS: Focal permanent cerebral ischemia was induced in the targeted right MCA territory in all subjects. The volumes of the ischemic lesions at 6, 48, and 96 hours were 3.18 ± 1.007 mL (standard error of the mean) (n = 8), 6.70 ± 1.666 mL (standard error of the mean) (n = 6), and 7.23 ± 1.371 mL (standard error of the mean) (n = 4). For the survival animals, the immediate postsurgical Spetzler grading score improved from 60.7 at 24 hours to 68.7 at 48 hours. CONCLUSIONS: We report a trapping modification to an established endovascular suture stroke model that yielded reproducible ischemia and clinically quantifiable neurologic deficits with no strokes in nontarget areas. This technique may be useful in evaluating translational stroke and penumbral imaging research in addition to preclinical testing of neuroprotective therapies.

A massive binary black-hole system in OJ 287 and a test of general relativity.

Tests of Einstein's general theory of relativity have mostly been carried out in weak gravitational fields where the space-time curvature effects are first-order deviations from Newton's theory. Binary pulsars provide a means of probing the strong gravitational field around a neutron star, but strong-field effects may be best tested in systems containing black holes. Here we report such a test in a close binary system of two candidate black holes in the quasar OJ 287. This quasar shows quasi-periodic optical outbursts at 12-year intervals, with two outburst peaks per interval. The latest outburst occurred in September 2007, within a day of the time predicted by the binary black-hole model and general relativity. The observations confirm the binary nature of the system and also provide evidence for the loss of orbital energy in agreement (within 10 per cent) with the emission of gravitational waves from the system. In the absence of gravitational wave emission the outburst would have happened 20 days later.

A giant planet orbiting the 'extreme horizontal branch' star V 391 Pegasi.

After the initial discoveries fifteen years ago, over 200 extrasolar planets have now been detected. Most of them orbit main-sequence stars similar to our Sun, although a few planets orbiting red giant stars have been recently found. When the hydrogen in their cores runs out, main-sequence stars undergo an expansion into red-giant stars. This expansion can modify the orbits of planets and can easily reach and engulf the inner planets. The same will happen to the planets of our Solar System in about five billion years and the fate of the Earth is matter of debate. Here we report the discovery of a planetary-mass body (Msini = 3.2M(Jupiter)) orbiting the star V 391 Pegasi at a distance of about 1.7 astronomical units (au), with a period of 3.2 years. This star is on the extreme horizontal branch of the Hertzsprung-Russell diagram, burning helium in its core and pulsating. The maximum radius of the red-giant precursor of V 391 Pegasi may have reached 0.7 au, while the orbital distance of the planet during the stellar main-sequence phase is estimated to be about 1 au. This detection of a planet orbiting a post-red-giant star demonstrates that planets with orbital distances of less than 2 au can survive the red-giant expansion of their parent stars.

Clinicians and product sales representatives: developing a relationship that works.

In today's healthcare climate, clinicians in any specialty may be required to make product selections for their practice. The skills necessary to negotiate the world of sales include information about how sales relationships are conducted, product evaluations, negotiation management, and time management. Because these skills are not taught in traditional healthcare training programs, clinicians often learn these skills through trial and error. Credible and resourceful clinical experts have current information and a working knowledge about products that are available for patients. An excellent resource for this information is the product sales representative. Literature providing information for clinicians on how to establish and maintain productive relationships with medical product representatives is scarce. This article will explain what issues to address in discussions and negotiations with product representatives. Common pitfalls that often result from not understanding the agenda of the sales representative are identified. By employing the suggested strategies, a mutually beneficial relationship can be fostered.

Neuronal representations of stimulus associations develop in the temporal lobe during learning.

Visual stimuli that are frequently seen together become associated in long-term memory, such that the sight of one stimulus readily brings to mind the thought or image of the other. It has been hypothesized that acquisition of such long-term associative memories proceeds via the strengthening of connections between neurons representing the associated stimuli, such that a neuron initially responding only to one stimulus of an associated pair eventually comes to respond to both. Consistent with this hypothesis, studies have demonstrated that individual neurons in the primate inferior temporal cortex tend to exhibit similar responses to pairs of visual stimuli that have become behaviorally associated. In the present study, we investigated the role of these areas in the formation of conditional visual associations by monitoring the responses of individual neurons during the learning of new stimulus pairs. We found that many neurons in both area TE and perirhinal cortex came to elicit more similar neuronal responses to paired stimuli as learning proceeded. Moreover, these neuronal response changes were learning-dependent and proceeded with an average time course that paralleled learning. This experience-dependent plasticity of sensory representations in the cerebral cortex may underlie the learning of associations between objects.

Rats with lesions of the hippocampus are impaired on the delayed nonmatching-to-sample task.

Rats with ibotenic acid lesions of the hippocampus (H-IBO) were trained on the trial-unique delayed nonmatching-to-sample task (DNMS) using a short delay of 4 s. The H-IBO group learned the nonmatching rule as quickly as control animals. However, performance was impaired on the DNMS task when the delay between the sample and choice phase was increased to 1 or 2 min. The use of 4-s delay (probe) trials indicated that the H-IBO animals retained the nonmatching-to-sample rule throughout testing. In a second experiment, using the same groups of rats, extended training at the 1-min delay did not ameliorate the deficit produced by H-IBO lesions. The finding of impaired recognition memory in rats after hippocampal lesions is consistent with findings from humans and monkeys. Several methodological issues are considered that have complicated the interpretation of earlier studies of recognition memory in rats following hippocampal lesions. The capacity for recognition memory in humans, monkeys, and rodents is discussed as a straightforward example of hippocampus-dependent (declarative) memory.

Relationship between magnitude of damage to the hippocampus and impaired recognition memory in monkeys.

Two recent meta-analyses, drawing on data from many of the same studies with monkeys, reached different conclusions about the relationship between hippocampal damage and recognition memory performance. Both studies found evidence of recognition memory impairment following hippocampal damage. However, Zola et al. (J Neurosci 2000;20:451-463) found no significant correlation between extent of hippocampal damage and recognition memory performance, whereas Baxter and Murray (Hippocampus 2001;11:61-71) concluded that the extent of hippocampal damage in monkeys was inversely correlated with impaired performance. Here, we first consider the requirements for carrying out a valid meta-analysis, and point out that the analysis carried out by Baxter and Murray (Hippocampus 2001;11:61-71) is invalid on simple statistical grounds. We then adopt the appropriate statistical procedures (multiple regression analyses rather than simple correlational analysis) to assess the relationship between extent of hippocampal damage and recognition performance across different studies. None of these analyses, including a reanalysis of the data of Baxter and Murray (Hippocampus 2001;11:61-71), revealed a significant inverse relationship between lesion size and behavioral impairment. Most of the variance was explained by differences between the studies that contributed to the meta-analysis, not by lesion size itself. Indeed, analysis of covariance indicated that there were differences among the studies beyond lesion size that significantly affected performance. Finally, we consider what relationship might hold between lesion size and memory performance in the monkey.

Perception and recognition memory in monkeys following lesions of area TE and perirhinal cortex.

Monkeys with lesions of perirhinal cortex (PR group) and monkeys with lesions of inferotemporal cortical area TE (TE group) were tested on a modified version of the delayed nonmatching to sample (DNMS) task that included very short delay intervals (0.5 sec) as well as longer delay intervals (1 min and 10 min). Lesions of the perirhinal cortex and lesions of area TE produced different patterns of impairment. The PR group learned the DNMS task as quickly as normal monkeys (N) when the delay between sample and choice was very short (0.5 sec). However, performance of the PR group, unlike that of the N group, fell to chance levels when the delay between sample and choice was lengthened to 10 min. In contrast to the PR group, the TE group was markedly impaired on the DNMS task even at the 0.5-sec delay, and three of four monkeys with TE lesions failed to acquire the task. The results provide support for the idea that perirhinal cortex is important not for perceptual processing, but for the formation and maintenance of long-term memory. Area TE is important for the perceptual processing of visual stimuli.

Contrasting effects on discrimination learning after hippocampal lesions and conjoint hippocampal-caudate lesions in monkeys.

Eighteen monkeys with lesions of the hippocampal region (the hippocampus proper, the dentate gyrus, and the subiculum) made by an ischemic procedure, radio frequency, or ibotenic acid were tested on a simple, two-choice object discrimination learning task that has been shown to be sensitive to large lesions of the medial temporal lobe. The monkeys were also tested on two other discrimination tasks (pattern discrimination and eight-pair concurrent discrimination) that can be learned normally by monkeys with large medial temporal lobe lesions. All of the lesion groups were impaired at learning the simple object discrimination task. Seven of the monkeys who had sustained damage to the hippocampal region also sustained damage to the tail of the caudate nucleus. These seven monkeys, but not the other 11 monkeys with hippocampal lesions, were impaired on pattern discrimination and concurrent discrimination learning. The results suggest that the hippocampal region is important for learning easy, two-choice discriminations, whereas the caudate nucleus is necessary for the normal learning of more difficult, gradually acquired discrimination tasks. The findings support the distinction between declarative memory, which depends on the hippocampus and related medial temporal lobe structures, and habit learning, which depends on the caudate nucleus.

Impaired recognition memory in monkeys after damage limited to the hippocampal region.

Monkeys with lesions limited to the hippocampal region (the hippocampus proper, the dentate gyrus, and the subiculum) were impaired on two tasks of recognition memory: delayed nonmatching to sample and the visual paired-comparison task. Recognition memory was impaired in five different groups of monkeys, whether the lesions were made by an ischemic procedure, by radio frequency, or by ibotenic acid. The finding that the hippocampal region is essential for normal recognition memory performance is considered in the context of current ideas about the role of the hippocampus in declarative memory.

Impaired recognition memory in rats after damage to the hippocampus.

Rats with radio-frequency or ibotenic acid lesions of the hippocampus and rats with radio-frequency lesions of the fornix were tested on the visual paired comparison task (VPC), a test of recognition memory. Memory was assessed at five different delay intervals ranging from 10 sec to 24 hr. All operated groups performed normally at the shorter delays (10 sec and 1 min). Across longer delays, the two groups with hippocampal damage were impaired. Rats with fornix lesions performed well on the VPC task but were impaired on a spatial task (spontaneous alternation). The results show that the hippocampus is essential for normal recognition memory. Moreover, fornix lesions need not mimic the effects of direct damage to hippocampal tissue. The findings are discussed in the context of the contribution of the hippocampus to recognition memory.

Dissociation between the effects of damage to perirhinal cortex and area TE.

Perirhinal cortex and area TE are immediately adjacent to each other in the temporal lobe and reciprocally interconnected. These areas are thought to lie at the interface between visual perception and visual memory, but it has been unclear what their separate contributions might be. In three experiments, monkeys with bilateral lesions of the perirhinal cortex exhibited a different pattern of impairment than monkeys with bilateral lesions of area TE. In experiment 1, lesions of the perirhinal cortex produced a multimodal deficit in recognition memory (delayed nonmatching to sample), whereas lesions of area TE impaired performance only in the visual modality. In experiment 2, on a test of visual recognition memory (the visual paired comparison task) lesions of the perirhinal cortex impaired performance at long delays but spared performance at a very short delay. In contrast, lesions of area TE impaired performance even at the short delay. In experiment 3, lesions of the perirhinal cortex and lesions of area TE produced an opposite pattern of impairment on two visual discrimination tasks, simple object discrimination learning (impaired only by perirhinal lesions), and concurrent discrimination learning (impaired only by TE lesions). Taken together, the findings suggest that the perirhinal cortex, like other medial temporal lobe structures, is important for the formation of memory, whereas area TE is important for visual perceptual processing.

Trace eyeblink classical conditioning in the monkey: a nonsurgical method and behavioral analysis.

Classical eyeblink conditioning has been used extensively to study the neurobiology of associative learning and memory in rabbits and in humans. During the last several years, new developments have renewed interest in the possibility of studying classical conditioning in monkeys. Specifically, it is now known that impaired conditioning can be observed in humans with various neurologic problems, including amnesia, and thus there is now considerable interest in the neurobiology of human eyeblink conditioning. Research involving monkeys, in which discrete lesions of anatomically defined neural structures can be produced, has the potential to provide information that might not be readily available from work in humans. Here, the authors present a simple, nonsurgical method for classically conditioning the eyeblink response in monkeys and report behavioral results using a trace conditioning paradigm that is sensitive to hippocampal damage in both rabbits and humans. This method is reliable and effective for recording eyeblinks and shows that robust eyeblink classical conditioning can be readily established in the monkey.

Episodic memory, semantic memory, and amnesia.

Episodic memory and semantic memory are two types of declarative memory. There have been two principal views about how this distinction might be reflected in the organization of memory functions in the brain. One view, that episodic memory and semantic memory are both dependent on the integrity of medial temporal lobe and midline diencephalic structures, predicts that amnesic patients with medial temporal lobe/diencephalic damage should be proportionately impaired in both episodic and semantic memory. An alternative view is that the capacity for semantic memory is spared, or partially spared, in amnesia relative to episodic memory ability. This article reviews two kinds of relevant data: 1) case studies where amnesia has occurred early in childhood, before much of an individual's semantic knowledge has been acquired, and 2) experimental studies with amnesic patients of fact and event learning, remembering and knowing, and remote memory. The data provide no compelling support for the view that episodic and semantic memory are affected differently in medial temporal lobe/diencephalic amnesia. However, episodic and semantic memory may be dissociable in those amnesic patients who additionally have severe frontal lobe damage.

fMRI of monkey visual cortex.

While functional magnetic resonance imaging (fMRI) is now used widely for demonstrating neural activity-related signals associated with perceptual, motor, and cognitive processes in humans, to date this technique has not been developed for use with nonhuman primates. fMRI in monkeys offers a potentially valuable experimental approach for investigating brain function, which will complement and aid existing techniques such as electrophysiology and the behavioral analysis of the effects of brain lesions. There are, however, a number of significant technical challenges involved in using fMRI with monkeys. Here, we describe the procedures by which we have overcome these challenges to carry out successful fMRI experiments in an alert monkey, and we present the first evidence of activity-related fMRI signals from monkey cerebral cortex.

A reexamination of the concurrent discrimination learning task: the importance of anterior inferotemporal cortex, area TE.

For 30 years, the concurrent discrimination learning task has figured prominently in studies used to determine the effects of medial temporal lobe damage in monkeys. However, the findings from these studies have been contradictory. We explored the contribution to concurrent discrimination performance of inadvertent damage to area TE by reexamining the behavioral data and histological material from monkeys with medial temporal lobe lesions previously tested in our laboratory. The amount of inadvertent damage to area TE was more predictive of impaired performance on the concurrent discrimination learning task than was the amount of damage to any medial temporal lobe structure, including the perirhinal cortex. These findings resolve earlier inconsistent findings regarding the concurrent discrimination learning task by demonstrating that performance on this task depends on area TE and not on perirhinal cortex or other medial temporal lobe structures.

Memory, amnesia, and the issue of recovered memory: neurobiological aspects.

The main thesis of this article is that the debate about the credibility of "recovered memories"--reports by adults of recovered memories of childhood sexual abuse and trauma that were allegedly repressed for many years--can be usefully informed by considering the biological and behavioral facts and ideas about how memory works. Accordingly, the first section of this review describes current facts and ideas about the neurobiology and neuropsychology of memory and amnesia, including what parts of the brain are important for memory, distinctions between different memory systems in the brain, and the phenomena of infantile amnesia and source amnesia. The second section takes into account the information about the biological and behavioral bases of memory and addresses two questions about memory that have become a focus of debate in the recovered memory controversy, that is, whether memories for traumatic events change over time, and whether memories can be created for traumatic events that did not actually happen.

The neurobiology of recovery memory.

The so-called recovery memory syndrome--reports by adults of recovered memories of childhood sexual abuse and trauma that were allegedly "repressed" for many years--has become an important issue in the field of mental health. In particular, there is debate about the credibility of recovered memories. The author describes findings in several fields of brain science about the way memory works and how memory is organized in the brain. These findings clarify aspects of normal memory function and the process of memory distortion, and they provide a neurobiological perspective from which to approach the topic of recovered memory.

Amnesia, memory and brain systems.

Bilateral damage to either the medial temporal lobe or the diencephalic midline causes an amnesic syndrome, i.e. a global impairment in the ability to acquire new memories regardless of sensory modality, and a loss of some memories, especially recent ones, from the period before amnesia began. The memory deficit can occur against a background of intact intellectual and perceptual functions. Two themes have been prominent in recent work. First, the amnesic syndrome is narrower than once believed in the sense that a number of learning and memory abilities are preserved (e.g. skill and habit learning, simple forms of conditioning and the phenomenon of priming). Second, the brain system damaged in amnesia has only a temporary role in memory. As time passes after learning, memory is reorganized and consolidated within neocortex, such that eventually medial temporal lobe and diencephalic structures are not needed for storage or retrieval.