The cortical control of movement revisited

Recently, we found that electrical stimulation of motor cortex caused monkeys to make coordinated, complex movements. These evoked movements were arranged across the cortex in a map of spatial locations to which the hand moved. We suggest that some of the subdivisions previously described within primary motor and premotor cortex may represent different types of actions that monkeys tend to make in different regions of space. According to this view, primary and premotor cortex may fit together into a larger map of manual space.     

The functional organization of the barrel cortex

The tactile somatosensory pathway from whisker to cortex in rodents provides a well-defined system for exploring the link between molecular mechanisms, synaptic circuits, and behavior. The primary somatosensory cortex has an exquisite somatotopic map where each individual whisker is represented in a discrete anatomical unit, the "barrel," allowing precise delineation of functional organization, development, and plasticity. Sensory information is actively acquired in awake behaving rodents and processed differently within the barrel map depending upon whisker-related behavior. The prominence of state-dependent cortical sensory processing is likely to be crucial in our understanding of active sensory perception, experience-dependent plasticity and learning.     

ERK is involved in the reorganization of somatosensory cortical maps in adult rats submitted to hindlimb unloading

Sensorimotor restriction by a 14-day period of hindlimb unloading (HU) in the adult rat induces a reorganization of topographic maps and receptive fields. However, the underlying mechanisms are still unclear. Interest was turned towards a possible implication of intracellular MAPK signaling pathway since Extracellular-signal-Regulated Kinase 1/2 (ERK1/2) is known to play a significant role in the control of synaptic plasticity. In order to better understand the mechanisms underlying cortical plasticity in adult rats submitted to a sensorimotor restriction, we analyzed the time-course of ERK1/2 activation by immunoblot and of cortical reorganization by electrophysiological recordings, on rats submitted to hindlimb unloading over four weeks. Immunohistochemistry analysis provided evidence that ERK1/2 phosphorylation was increased in layer III neurons of the somatosensory cortex. This increase was transient, and parallel to the changes in hindpaw cortical map area (layer IV). By contrast, receptive fields were progressively enlarged from 7 to 28 days of hindlimb unloading. To determine whether ERK1/2 was involved in cortical remapping, we administered a specific ERK1/2 inhibitor (PD-98059) through osmotic mini-pump in rats hindlimb unloaded for 14 days. Results demonstrate that focal inhibition of ERK1/2 pathway prevents cortical reorganization, but had no effect on receptive fields. These results suggest that ERK1/2 plays a role in the induction of cortical plasticity during hindlimb unloading.     

The modification of cortical reorganization and chronic pain by sensory feedback

Recent neuroscientific evidence has revealed that the adult brain is capable of substantial plastic change in areas such as the primary somatosensory cortex that were formerly thought to be modifiable only during early experience. We discuss research on phantom limb pain as well as chronic back pain that revealed functional reorganization in both the somatosensory and the motor system in these chronic pain states. In phantom limb pain patients, cortical reorganization is correlated with the amount of phantom limb pain; in low back pain patients the amount of reorganizational change increases with chronicity. We present a model of the development of chronic pain that assumes an important role of somatosensory pain memories. In phantom limb pain, we propose that those patients who experienced intense pain prior to the amputation will later likely develop enhanced cortical reorganization and phantom limb pain. We show that cortical plasticity related to chronic pain can be reduced by behavioral interventions that provide feedback to the brain areas that were altered by somatosensory pain memories.     

Functional imaging of perceptual learning in human primary and secondary somatosensory cortex

Cellular mechanisms underlying synaptic plasticity are in line with the Hebbian concept. In contrast, data linking Hebbian learning to altered perception are rare. Combining functional magnetic resonance imaging with psychophysical tests, we studied cortical reorganization in primary and secondary somatosensory cortex (SI and SII) and the resulting changes of tactile perception before and after tactile coactivation, a simple type of Hebbian learning. Coactivation on the right index finger (IF) for 3 hr lowered its spatial discrimination threshold. In parallel, blood-oxygen level-dependent (BOLD) signals from the right IF representation in SI and SII enlarged. The individual threshold reduction was linearly correlated with the enlargement in SI, implying a close relation between altered discrimination and cortical reorganization. Controls consisting of a single-site stimulation did not affect thresholds and cortical maps. Accordingly, changes within distributed cortical networks based on Hebbian mechanisms alter the individual percept.     

对侧外周神经移位到损伤手臂引起的体感皮层功能动态重组

单侧肢体的外周神经损伤通常导致对侧体感皮层的功能重组. 然而,接受了对侧颈 7 (C7) 外周神经移位手术治疗单侧手臂臂丛全撕脱的病人,在术后早期当其患手被触摸时,只在其健手产生感觉. 在术后晚期,病人才逐渐恢复其患手和健手的正常、独立的功能. 我们在模拟对侧颈 7 (C7) 外周神经移位手术病例的大鼠模型上,用记录体感诱发电位的方法研究了患手和健手的体感代表区. 患手的体感和运动功能由于 C7 神经的再生而逐渐恢复. 术后第 5 个月始, 13 只大鼠患手的体感代表区只出现在其同侧的皮层,同时患手和健手的代表区在该皮层内是高度重叠的 (除掉一个例外),虽然刺激它们产生的体感诱发电位的潜伏期和反应幅度有很大的不同. 结果表明,移位到患手的对侧外周神经能够导致同侧体感皮层动态的功能重组,提示身体另侧感觉输入的介入激发了大脑显著的可塑性.     

“面口合谷收”的脑机制

"面口合谷收"是上千年来祖国医学在医疗实践中的经验总结,指位于手阳明大肠经的"合谷穴"能有效治疗大肠经远端循行所过部位"面口部"的疾患(如牙痛、面神经麻痹等).本研究采用单电极和阵列电极电生理技术探讨来自口面部和手部的传入在恒河猴感觉皮层神经元的位域关系,探讨"面口合谷收"的脑机制.在3b区可以记录到外周感受野分布在合谷穴区和口面部相互毗邻的神经元,也记录到合谷-下唇双感受野的会聚神经元.电生理学绘制3b皮层位域图的结果表明,这些神经元确实是在3b皮层并不重合但相互接壤.结扎正中神经和桡神经3个月后3b皮层拇指-口面交接部神经元能够发生可塑性变化.口面部刺激引起反应皮层位域明显扩大深入到拇指的皮层1~2 mm处,表明拇指皮层位域发生了明显的功能重组.本研究表明,"面口合谷收"的脑机制是相互间的接壤关系,并在神经损伤情况下会发生相互"入侵"的脑功能重组的可塑性变化.     

The anatomy of the cerebral cortex of the echidna (Tachyglossus aculeatus)

The cerebral cortex of the echidna is notable for its extensive folding and the positioning of major functional areas towards its caudal extremity. The gyrification of the echidna cortex is comparable in magnitude to prosimians and cortical thickness and neuronal density are similar to that seen in rodents and carnivores. On the other hand, many pyramidal neurons in the cerebral cortex of the echidna are atypical with inverted somata and short or branching apical dendrites. All other broad classes of neurons noted in therian cortex are also present in the echidna, suggesting that the major classes of cortical neurons evolved prior to the divergence of proto- and eutherian lineages. Dendritic spine density on dendrites of echidna pyramidal neurons in somatosensory cortex and apical dendrites of motor cortex pyramidal neurons is lower than that found in eutheria. On the other hand, synaptic morphology, density and distribution in somatosensory cortex are similar to that in eutheria. In summary, although the echidna cerebral cortex displays some structural features, which may limit its functional capacities (e.g. lower spine density on pyramidal neurons), in most structural parameters (e.g. gyrification, cortical area and thickness, neuronal density and types, synaptic morphology and density), it is comparable to eutheria.     

Reorganization of the Intact Somatosensory Cortex Immediately after Spinal Cord Injury

Sensory deafferentation produces extensive reorganization of the corresponding deafferented cortex. Little is known, however, about the role of the adjacent intact cortex in this reorganization. Here we show that a complete thoracic transection of the spinal cord immediately increases the responses of the intact forepaw cortex to forepaw stimuli (above the level of the lesion) in anesthetized rats. These increased forepaw responses were independent of the global changes in cortical state induced by the spinal cord transection described in our previous work (Aguilar et al., J Neurosci 2010), as the responses increased both when the cortex was in a silent state (down-state) or in an active state (up-state). The increased responses in the intact forepaw cortex correlated with increased responses in the deafferented hindpaw cortex, suggesting that they could represent different points of view of the same immediate state-independent functional reorganization of the primary somatosensory cortex after spinal cord injury. Collectively, the results of the present study and of our previous study suggest that both state-dependent and state-independent mechanisms can jointly contribute to cortical reorganization immediately after spinal cord injury.     

Visualizing myeloarchitecture with magnetic resonance imaging in primates

The pattern of myelination over the cerebral cortex, termed myeloarchitecture, is an established and often-used feature to visualize cortical organization with histology in a variety of primate species. In this paper, we use in vivo magnetic resonance imaging (MRI) and advanced image processing using surface rendering to visualize and characterize myeloarchitecture in a small nonhuman primate, the common marmoset (Callithrix jacchus). Through images made in four female adult marmosets, we produce a representative 3D map of marmoset myeloarchitecture and flatten and annotate this map to show the location and extent of a variety of major areas of the cortex, including the primary visual, auditory, and somatosensory areas. By treating our MRI data as a surface, we can measure the surface area of cortical areas, and we present these measurements here to summarize cortical organization in the marmoset.     

Dynamic Changes in Brain Activations and Functional Connectivity during Affectively Different Tactile Stimuli

In the present study, we compared brain activations produced by pleasant, neutral and unpleasant touch, to the anterior lateral surface of lower leg of human subjects. It was found that several brain regions, including the contralateral primary somatosensory area (SI), bilateral secondary somatosensory area (SII), as well as contralateral middle and posterior insula cortex were commonly activated under the three touch conditions. In addition, pleasant and unpleasant touch conditions shared a few brain regions including the contralateral posterior parietal cortex (PPC) and bilateral premotor cortex (PMC). Unpleasant touch specifically activated a set of pain-related brain regions such as contralateral supplementary motor area (SMA) and dorsal parts of bilateral anterior cingulated cortex, etc. Brain regions specifically activated by pleasant touch comprised bilateral lateral orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), intraparietal cortex and left dorsal lateral prefrontal cortex (DLPFC). Using a novel functional connectivity model based on graph theory, we showed that a series of brain regions related to affectively different touch had significant functional connectivity during the resting state. Furthermore, it was found that such a network can be modulated between affectively different touch conditions.     

Bilateral receptive field neurons and callosal connections in the somatosensory cortex

Earlier studies recording single neuronal activity with bilateral receptive fields in the primary somatosensory cortex of monkeys and cats agreed that the bilateral receptive fields were related exclusively to the body midline and that the ipsilateral information reaches the cortex via callosal connections since they are dense in the cortical region representing the midline structures of the body while practically absent in the regions representing the distal extremities. We recently found a substantial number of neurons with bilateral receptive fields on hand digits, shoulders-arms or legs-feet in the caudalmost part (areas 2 and 5) of the postcentral gyrus in awake Japanese monkeys (Macaca fuscata). I review these results, discuss the functional implications of this bilateral representation in the postcentral somatosensory cortex from a behavioural standpoint and give a new interpretation to the midline fusion theory.     

The emergence of somatotopic maps of the body in S1 in rats: the correspondence between functional and anatomical organization

Most of what we know about cortical map development and plasticity comes from studies in mice and rats, and for the somatosensory cortex, almost exclusively from the whisker-dominated posteromedial barrel fields. Whiskers are the main effector organs of mice and rats, and their representation in cortex and subcortical pathways is a highly derived feature of murine rodents. This specialized anatomical organization may therefore not be representative of somatosensory cortex in general, especially for species that utilize other body parts as their main effector organs, like the hands of primates. For these reasons, we examined the emergence of whole body maps in developing rats using electrophysiological recording techniques. In P5, P10, P15, P20 and adult rats, multiple recordings were made in the medial portion of S1 in each animal. Subsequently, these functional maps were related to anatomical parcellations of S1 based on a variety of histological stains. We found that at early postnatal ages (P5) medial S1 was composed almost exclusively of the representation of the vibrissae. At P10, other body part representations including the hindlimb and forelimb were present, although these were not topographically organized. By P15, a clear topographic organization began to emerge coincident with a reduction in receptive field size. By P20, body maps were adult-like. This study is the first to describe how topography of the body develops in S1 in any mammal. It indicates that anatomical parcellations and functional maps are initially incongruent but become tightly coupled by P15. Finally, because anatomical and functional specificity of developing barrel cortex appears much earlier in postnatal life than the rest of the body, the entire primary somatosensory cortex should be considered when studying general topographic map formation in development.     

Anteroposterior somatotopy of innocuous cooling activation focus in human dorsal posterior insular cortex

Prior data indicate that graded activation by innocuous thermal stimuli occurs in the dorsal posterior insular (dpIns) cortex of humans, rather than the parietal somatosensory regions traditionally thought necessary for discriminative somatic sensations. We hypothesized that if the dpIns subserves the haptic capacity of localization in addition to discrimination, then it should be somatotopically organized. Using functional magnetic resonance imaging to detect activation in the dpIns by graded cooling stimuli applied to the hand and neck, we found unimodal foci arranged in an anteroposterior somatotopographic pattern, consistent with participation of the dpIns in localization as well as discrimination. This gradient is orthogonal to the mediolateral somatotopy of parietal somatosensory regions, which supports the fundamental conceptual differentiation of the interoceptive somatic representation in the dpIns from the parietal exteroceptive representations. These data also support the suggestion that the poststroke central pain syndrome associated with lesions of the dpIns is a thermoregulatory dysfunction. Finally, another focus of strongly graded activation, which we interpret to represent thermoregulatory behavioral motivation elicited by dynamic cooling, was observed in the dorsal medial cortex.     

Chronological observations of primary somatosensory cortical maps in kittens following low thoracic (T12) spinal cord transection at 2 weeks of age.

The present study investigated the reorganization of the somatosensory cortex in kittens following T12 spinal cord transection at 2 weeks of age. Multiunit electrophysiological methods were used to map the somatosensory cortex of kittens at 3, 6, and 9 weeks after the transection. The entire reorganized cortical region was driven by substitute cutaneous inputs, primarily from the trunk, at 3 weeks after spinal cord transection. Although the level of cortical responsiveness remained the same throughout the 9 weeks studied, internal trunk representation changed, and there was an increase in shoulder girdle representation and emergence of forelimb representation. Poor somatotopic and topographic order was observed in the reorganized cortex, regardless of time posttransection. Finally, trunk receptive fields displayed a wide variety of shapes, sizes, and orientations not seen in the normal cortex.     

Failed Stabilization for Long-Term Potentiation in the Auditory Cortex of Fmr1 Knockout Mice

Fragile X syndrome is a developmental disorder that affects sensory systems. A null mutation of the Fragile X Mental Retardation protein 1 (Fmr1) gene in mice has varied effects on developmental plasticity in different sensory systems, including normal barrel cortical plasticity, altered ocular dominance plasticity and grossly impaired auditory frequency map plasticity. The mutation also has different effects on long-term synaptic plasticity in somatosensory and visual cortical neurons, providing insights on how it may differentially affect the sensory systems. Here we present evidence that long-term potentiation (LTP) is impaired in the developing auditory cortex of the Fmr1 knockout (KO) mice. This impairment of synaptic plasticity is consistent with impaired frequency map plasticity in the Fmr1 KO mouse. Together, these results suggest a potential role of LTP in sensory map plasticity during early sensory development.     

Hevin–calcyon interaction promotes synaptic reorganization after brain injury

Hevin, also known as SPARC-like protein 1 (SPARCL1 or SC1), is a synaptogenic protein secreted by astrocytes and modulates the formation of glutamatergic synapses in the developing brain by interacting with synaptic adhesion proteins, such as neurexin and neuroligin. Here, we identified the neuron-specific vesicular protein calcyon as a novel interaction partner of hevin and demonstrated that this interaction played a pivotal role in synaptic reorganization after an injury in the mature brain. Astrocytic hevin was upregulated post-injury in a photothrombotic stroke model. Hevin was fragmented by MMP3 induced during the acute stage of brain injury, and this process was associated with severe gliosis. At the late stage, the functional hevin level was restored as MMP3 expression decreased. The C-terminus of hevin interacted with the N-terminus of calcyon. By using RNAi and binding competitor peptides in an ischemic brain injury model, we showed that this interaction was crucial in synaptic and functional recoveries in the sensory-motor cortex, based on histological and electrophysiological analyses. Regulated expression of hevin and calcyon and interaction between them were confirmed in a mouse model of traumatic brain injury and patients with chronic traumatic encephalopathy. Our study provides direct evidence for the causal relationship between the hevin–calcyon interaction and synaptic reorganization after brain injury. This neuron-glia interaction can be exploited to modulate synaptic reorganization under various neurological conditions.Subject terms: Astrocyte, Neurological disorders     

Maximizing Sensory Dynamic Range by Tuning the Cortical State to Criticality

Modulation of interactions among neurons can manifest as dramatic changes in the state of population dynamics in cerebral cortex. How such transitions in cortical state impact the information processing performed by cortical circuits is not clear. Here we performed experiments and computational modeling to determine how somatosensory dynamic range depends on cortical state. We used microelectrode arrays to record ongoing and whisker stimulus-evoked population spiking activity in somatosensory cortex of urethane anesthetized rats. We observed a continuum of different cortical states; at one extreme population activity exhibited small scale variability and was weakly correlated, the other extreme had large scale fluctuations and strong correlations. In experiments, shifts along the continuum often occurred naturally, without direct manipulation. In addition, in both the experiment and the model we directly tuned the cortical state by manipulating inhibitory synaptic interactions. Our principal finding was that somatosensory dynamic range was maximized in a specific cortical state, called criticality, near the tipping point midway between the ends of the continuum. The optimal cortical state was uniquely characterized by scale-free ongoing population dynamics and moderate correlations, in line with theoretical predictions about criticality. However, to reproduce our experimental findings, we found that existing theory required modifications which account for activity-dependent depression. In conclusion, our experiments indicate that in vivo sensory dynamic range is maximized near criticality and our model revealed an unanticipated role for activity-dependent depression in this basic principle of cortical function.     

Training-Dependent Associative Learning Induced Neocortical Structural Plasticity: A Trace Eyeblink Conditioning Analysis

Studies utilizing general learning and memory tasks have suggested the importance of neocortical structural plasticity for memory consolidation. However, these learning tasks typically result in learning of multiple different tasks over several days of training, making it difficult to determine the synaptic time course mediating each learning event. The current study used trace-eyeblink conditioning to determine the time course for neocortical spine modification during learning. With eyeblink conditioning, subjects are presented with a neutral, conditioned stimulus (CS) paired with a salient, unconditioned stimulus (US) to elicit an unconditioned response (UR). With multiple CS-US pairings, subjects learn to associate the CS with the US and exhibit a conditioned response (CR) when presented with the CS. Trace conditioning is when there is a stimulus free interval between the CS and the US. Utilizing trace-eyeblink conditioning with whisker stimulation as the CS (whisker-trace-eyeblink: WTEB), previous findings have shown that primary somatosensory (barrel) cortex is required for both acquisition and retention of the trace-association. Additionally, prior findings demonstrated that WTEB acquisition results in an expansion of the cytochrome oxidase whisker representation and synaptic modification in layer IV of barrel cortex. To further explore these findings and determine the time course for neocortical learning-induced spine modification, the present study utilized WTEB conditioning to examine Golgi-Cox stained neurons in layer IV of barrel cortex. Findings from this study demonstrated a training-dependent spine proliferation in layer IV of barrel cortex during trace associative learning. Furthermore, findings from this study showing that filopodia-like spines exhibited a similar pattern to the overall spine density further suggests that reorganization of synaptic contacts set the foundation for learning-induced neocortical modifications through the different neocortical layers.