Interhemispheric connections of the ventral premotor cortex in a new world primate

This study describes the pattern of interhemispheric connections of the ventral premotor cortex (PMv) distal forelimb representation (DFL) in squirrel monkeys. Our objectives were to describe qualitatively and quantitatively the connections of PMv with contralateral cortical areas. Intracortical microstimulation techniques (ICMS) guided the injection of the neuronal tract tracers biotinylated dextran amine or Fast blue into PMv DFL. We classified the interhemispheric connections of PMv into three groups. Major connections were found in the contralateral PMv and supplementary motor area (SMA). Intermediate interhemispheric connections were found in the rostral portion of the primary motor cortex, the frontal area immediately rostral and ventral to PMv (FR), cingulate motor areas (CMAs), and dorsal premotor cortex (PMd). Minor connections were found inconsistently across cases in the anterior operculum (AO), posterior operculum/inferior parietal cortex (PO/IP), and posterior parietal cortex (PP), areas that consistently show connections with PMv in the ipsilateral hemisphere. Within-case comparisons revealed that the percentage of PMv connections with contralateral SMA and PMd are higher than the percentage of PMv connections with these areas in the ipsilateral hemisphere; percentages of PMv connections with contralateral M1 rostral, FR, AO, and the primary somatosensory cortex are lower than percentages of PMv connections with these areas in the ipsilateral hemisphere. These studies increase our knowledge of the pattern of interhemispheric connection of PMv. They help to provide an anatomical foundation for understanding PMv's role in motor control of the hand and interhemispheric interactions that may underlie the coordination of bimanual movements.     

An additional motor-related field in the lateral frontal cortex of squirrel monkeys

Our earlier efforts to document the cortical connections of the ventral premotor cortex (PMv) revealed dense connections with a field rostral and lateral to PMv, an area we called the frontal rostral field (FR). Here, we present data collected in FR using electrophysiological and anatomical methods. Results show that FR contains an isolated motor representation of the forelimb that can be differentiated from PMv based on current thresholds and latencies to evoke electromyographic activity using intracortical microstimulation techniques. In addition, FR has a different pattern of cortical connections compared with PMv. Together, these data support that FR is an additional, previously undescribed motor-related area in squirrel monkeys.     

An animal model of capsular infarct: endothelin-1 injections in the rat

In this study stereotaxic injections of the vasoconstrictive peptide endothelin-1 (ET-1) were used to create infarcts in the white matter of the internal capsule underlying sensorimotor cortex in rats. Resulting deficits were assessed using established sensorimotor tests conducted on each rat before and after the ET-1-induced infarct. After a 14-day survival period, histological examination revealed tissue necrosis and demyelination in the infarcted white matter of ET-1-injected rats, but not saline-injected control rats. Infarcts resulted in measurable sensorimotor deficits in rats that received ET-1 injections. The same sensorimotor tests showed no deficits in surgical-control rats. The present model of white matter infarct should be valuable in examining the underlying mechanisms of subcortical ischemic stroke and to evaluate potential therapeutic interventions.     

Scopolamine facilitates recovery of function following unilateral electrolytic sensorimotor cortex lesions in the rat

Following brain injury there is an excessive release of excitatory neurotransmitters that may lead to secondary cell death. Although much research has focused on glutamate-NMDA receptor interactions, acetylcholine-muscarinic receptor interactions may also prove to be important for an understanding of the pathophysiological events that lead to secondary degeneration after brain damage. Previous experiments have shown that the muscarinic receptor antagonist scopolamine facilitates recovery from very transient (1 h-10 days) behavioral deficits after fluid percussion injury. The present study extends these findings by investigating whether scopolamine can facilitate recovery from the more enduring behavioral deficits (14-60 days) that follow electrolytic lesions of the rat somatic sensorimotor cortex (SMC). Rats received unilateral lesions of the SMC and a regimen of scopolamine (1 mg/kg) or saline beginning 15 min after surgery. Following SMC lesions rats exhibited an impairment in placing the forelimb contralateral to the lesion as well as an ipsilateral somatosensory asymmetry on a bilateral tactile stimulation test. Rats treated with scopolamine showed a reduction in the initial magnitude of the contralateral placing deficit and an accelerated rate of recovery compared with saline-treated control rats. In contrast, scopolamine had no effect on recovery from the ipsilateral somatosensory asymmetry. These data are consistent with the idea that muscarinic receptor stimulation plays a role in the production of secondary brain damage, that blockade of this receptor leads to a facilitation of recovery on some behavioral tasks, and that electrolytic lesions may trigger some of the same posttraumatic events described in other models of neural trauma.     

Protéine Z,polymorphismes du gène de la protéine Z et thromboses

Protein Z (PZ) is a vitamin K dependent protein acting as the cofactor of the protein Z dependent inhibitor (ZPI), in the inhibition of activated factor X bound on the phospholipids. Normal plasma protein Z concentrations have wide variations among individuals, partly explained by a genetic control. Several protein Z gene polymorphisms influence plasma concentration, separately and in combination. The role of PZ in blood coagulation regulation has been demonstrated in vitro. The responsibility of low PZ level in the occurrence of thrombosis has been questioned. However, the roles of PZ plasma level and PZ gene polymorphisms remain debated with conflicting results in arterial, venous, or placental thrombosis. These discrepancies can be explained by the heterogeneity of populations chosen as control, by the PZ interindividual variability, by the small size of the cohorts in mainly retrospective studies and perhaps by the lack of real important influence of this protein on coagulation. PZ measurement is not actually considered as a biological marker of thrombophilia. Large prospective studies remain to be done to investigate its possible role in thrombosis.     

Comparison of markers of coagulation activation and thrombin generation test in uncomplicated pregnancies

Introduction

Pregnancy is a well-established risk factor for venous thromboembolism, and is associated with a state of hypercoagulability or parameters of thrombin generation. Currently, there is a lack of consensual data on thrombin generation during pregnancy. This study aimed to find a sensitive and specific biological marker of coagulation activation and to identify parameters of thrombin generation.

Patients and methods

The population included 101 women with uncomplicated pregnancies. The objective of this study was to correlate thrombin generation test (measured at 5pM tissue factor, 4 μM lipids and without thrombomodulin), with fibrinogen and markers of blood coagulation activation: D-dimer, prothrombin fragments 1+2 (F1+2), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) in these women. Internal quality control was performed in each set of experiments.

Results

Fibrinogen, D-dimer, F1+2, and TAT concentrations increased significantly throughout pregnancy, and were correlated with term of pregnancy. In our study, thrombin generation seemed to increase early on, and then remained stable throughout normal pregnancy, in contrast with other markers of blood coagulation activation, excepting FMC. The latter are subject to large inter-individual variations, especially during second trimester. No correlation was demonstrated between thrombin generation parameters and other activation markers.

Conclusion

While markers of coagulation activation significantly increased during pregnancy, thrombin generation increased only early on and remains stable during pregnancy. Finding a sensitive and specific biological marker for vascular pregnancy complications, such as FMC and thrombin generation levels, requires further investigation.     

Restoration of function after brain damage using a neural prosthesis

Neural interface systems are becoming increasingly more feasible for brain repair strategies. This paper tests the hypothesis that recovery after brain injury can be facilitated by a neural prosthesis serving as a communication link between distant locations in the cerebral cortex. The primary motor area in the cerebral cortex was injured in a rat model of focal brain injury, disrupting communication between motor and somatosensory areas and resulting in impaired reaching and grasping abilities. After implantation of microelectrodes in cerebral cortex, a neural prosthesis discriminated action potentials (spikes) in premotor cortex that triggered electrical stimulation in somatosensory cortex continuously over subsequent weeks. Within 1 wk, while receiving spike-triggered stimulation, rats showed substantially improved reaching and grasping functions that were indistinguishable from prelesion levels by 2 wk. Post hoc analysis of the spikes evoked by the stimulation provides compelling evidence that the neural prosthesis enhanced functional connectivity between the two target areas. This proof-of-concept study demonstrates that neural interface systems can be used effectively to bridge damaged neural pathways functionally and promote recovery after brain injury.The view of the brain as a collection of independent anatomical modules, each with discrete functions, is currently undergoing radical change. New evidence from neurophysiological and neuroanatomical experiments in animals, as well as neuroimaging studies in humans, now suggests that normal brain function can be best appreciated in the context of the complex arrangements of functional and structural interconnections among brain areas. Although mechanistic details are still under refinement, synchronous discharge of neurons in widespread areas of the cerebral cortex appears to be an emergent property of neuronal networks that functionally couple remote locations (1). It is now recognized that not only are discrete regions of the brain damaged in injury or disease but, perhaps more importantly, the interconnections among uninjured areas are disrupted, potentially leading to many of the functional impairments that persist after brain injury (2). Likewise, plasticity of brain interconnections may partially underlie recovery of function after injury (3).Technological efforts to restore brain function after injury have focused primarily on modulating the excitability of focal regions in uninjured parts of the brain (4). Purportedly, increasing the excitability of neurons involved in adaptive plasticity expands the neural substrate potentially involved in functional recovery. However, no methods are yet available to alter the functional connectivity between spared brain regions directly, with the intent to restore normal communication patterns. The present paper tests the hypothesis that an artificial communication link between uninjured regions of the cerebral cortex can restore function in a rodent model of traumatic brain injury (TBI). Development of such neuroprosthetic approaches to brain repair may have important implications for the millions of individuals who are left with permanent motor and cognitive impairments after acquired brain injury, as occurs in stroke and trauma.For the present experiment, we used a rodent model of focal brain injury to the caudal forelimb area (CFA), a region that is part of the cortical sensorimotor system. This area in the frontal cortex shares many properties with primary motor cortex (M1) of primates; injury to M1 results in long-term impairment in reaching and grasping functions (5). Traditionally, it has been thought that impairment occurs because M1 provides substantial outputs to the motor apparatus in the spinal cord, thus directly affecting motor output function. However, M1 also has important interconnections with the primary somatosensory cortex (S1) located in the parietal lobe (Fig. 1A). Long-range corticocortical fibers from S1 provide critical information to M1 about the position of the limb in space. Thus, injury to M1 results in impaired motor performance due, at least in part, to disruption in communication between the somatosensory and motor cortex (6).Open in a separate windowFig. 1.Theoretical model of neuroprosthetic treatment approach after brain injury. (A) Normal connectivity of M1, S1, and PM. Both M1 (CFA in rat) and PM (RFA in rat) send substantial outputs to the spinal cord via the corticospinal tract. Also, extensive reciprocal connections exist between M1 and PM, as well as between M1 and S1. (B) Effects of focal M1 injury on brain connectivity and the hypothetical effect of a BMBI to restore somatosensory-motor communication. An injury to M1, as might occur in stroke or brain trauma, results in a focal area of necrosis, as well as loss of M1 outputs to the spinal cord. Corticocortical communication between M1 and S1 (and between M1 and PM) is also disrupted, further contributing to functional impairment. Because the uninjured PM also contains corticospinal neurons, it might have the ability to serve in a vicarious role. The dotted line indicates enhanced functional connection between PM and S1 that we propose is established after treatment with a BMBI. (C) Location of target areas in rat cerebral cortex. A topographic map of the somatosensory representation in S1 is superimposed on the cortex.To test our hypothesis that functional recovery can be facilitated by creating an artificial communication link between spared somatosensory and motor regions of the brain, we focused on the rat’s premotor cortex (PM). The rostral forelimb area (RFA) is a premotor area in the rodent’s frontal cortex that shares many properties with PM of primates and is thought to participate in recovery of function after injury to M1 (5, 7–9). PM areas are so-named because the principal target of their output fibers is M1 (10). PM areas also have long-range corticocortical connections with somatosensory areas, but at least in intact animals, they appear to be relatively weak compared with M1’s connections with the somatosensory cortex (9, 11, 12).Our approach was to link the neural activity of the PM forelimb area (RFA) functionally with activation of the S1 forelimb area following a controlled cortical impact (CCI) to M1 (Fig. 1 B and C). To this end, a microdevice was developed with the ability to deliver activity-dependent stimulation (ADS) through recording and digitizing extracellular neural activity from an implanted microelectrode, discriminating individual action potentials (spikes), and delivering small amounts of electrical current to another microelectrode implanted in a distant population of neurons (13, 14). This closed-loop system was similar, in principle, to the “Neurochip” used previously by other investigators to demonstrate the effects of local ADS in intact animals (15), but it was miniaturized for head-mounted, wireless operation (Fig. 2A and Fig. S1). By linking the activity of one area of the cortex with that of a distant area of the cortex, a closed-loop brain–machine–brain interface (BMBI) for artificial corticocortical communication between PM and S1 was created.Open in a separate windowFig. 2.ADS protocol. After injury to the CFA, a recording microelectrode was placed in the RFA, whereas a stimulating microelectrode was placed in the distal forelimb field of S1. A BMBI discriminated action potentials in the RFA, and after a 7.5-ms delay, it delivered a low-level electrical current pulse to S1 (13). (A) Sketch of a rat retrieving a food pellet with a BMBI attached to the skull. (B) Sample traces of recordings from the RFA showing action potentials and stimulus artifacts from an ICMS current delivered to S1. Time-amplitude window discriminators are indicated by red boxes. A total of 100 superimposed traces are shown.Individual spikes were detected in PM, and subsequent stimulation was delivered to S1 after a 7.5-ms delay (Fig. 2B). (Because connections between distant cortical areas are commonly reciprocal, enhanced communication theoretically could be established by ADS in either direction.) After the M1 injury, rats were implanted with microelectrodes connected to the BMBI microdevice (Fig. 2A). The microdevice delivered ADS 24 h per day up to 28 d postinjury, except for brief motor assessment sessions on predetermined days. Behavioral recovery in ADS rats was compared with recovery in rats with open-loop stimulation (OLS), in which S1 stimulation was uncorrelated with spikes in PM, and with control rats that had no microdevice implanted.     

Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys

A focal injury within the cerebral cortex results in functional reorganization within the spared cortex through time-dependent metabolic and physiological reactions. Physiological changes are also associated with specific post-injury behavioral experiences. Knowing how these factors interact can be beneficial in planning rehabilitative intervention after a stroke. The purpose of this study was to assess the functional impact of delaying the rehabilitative behavioral experience upon movement representations within the primary motor cortex (M1) in an established nonhuman primate, ischemic infarct model. Five adult squirrel monkeys were trained on a motor-skill task prior to and 1 month after an experimental ischemic infarct was induced in M1. Movement representations of the hand were derived within M1 using standard electrophysiological procedures prior to the infarct and again one and two months after the infarct. The results of this study show that even though recovery of motor skills was similar to that of a previous study in squirrel monkeys after early training, unlike early training, delayed training did not result in maintenance of the spared hand representation within the M1 peri-infarct hand area. Instead, delaying training resulted in a large decrease in spared hand representation during the spontaneous recovery period that persisted following the delayed training. In addition, delayed training resulted in an increase of simultaneously evoked movements that are typically independent. These results indicate that post-injury behavioral experience, such as motor skill training, may modulate peri-infarct cortical plasticity in different ways in the acute versus chronic stages following stroke.