Neuroscience: rewiring the adult brain

Any analysis of plastic reorganization at a neuronal locus needs a veridical measure of changes in the functional output--that is, spiking responses of the neurons in question. In a study of the effect of retinal lesions on adult primary visual cortex (V1), Smirnakis et al. propose that there is no cortical reorganization. Their results are based, however, on BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging), which provides an unreliable gauge of spiking activity. We therefore question their criterion for lack of plasticity, particularly in the light of the large body of earlier work that demonstrates cortical plasticity.     

Receptive field dynamics in adult primary visual cortex.

The adult brain has a remarkable ability to adjust to changes in sensory input. Removal of afferent input to the somatosensory, auditory, motor or visual cortex results in a marked change of cortical topography. Changes in sensory activity can, over a period of months, alter receptive field size and cortical topography. Here we remove visual input by focal binocular retinal lesions and record from the same cortical sites before and within minutes after making the lesion and find immediate striking increases in receptive field size for cortical cells with receptive fields near the edge of the retinal scotoma. After a few months even the cortical areas that were initially silenced by the lesion recover visual activity, representing retinotopic loci surrounding the lesion. At the level of the lateral geniculate nucleus, which provides the visual input to the striate cortex, a large silent region remains. Furthermore, anatomical studies show that the spread of geniculocortical afferents is insufficient to account for the cortical recovery. The results indicate that the topographic reorganization within the cortex was largely due to synaptic changes intrinsic to the cortex, perhaps through the plexus of long-range horizontal connections.     

Absence of interhemispheric connections of area 17 during development in the monkey

Our understanding of the development of cortical connectivity largely stems from studies of the ontogeny of interhemispheric pathways in carnivores, rodents and lagomorphs. Early in development, cortical neurons projecting to the contralateral hemisphere through the corpus callosum (callosal projection neurons) have a widespread distribution. As maturation proceeds, callosal projection neurons become restricted to those cortical regions that are connected in the adult. In newborn cats and rats, for example, callosal projection neurons are not restricted to the 17-18 border as in the adult, but are found throughout areas 17 and 18. The macaque monkey is an exception, because at birth it has an adult-like distribution of callosal projection neurons in area 18, with practically none in area 17. Here we show that whereas area 17 is devoid of interhemispheric connections throughout prenatal development, the distribution of callosal projection neurons in area 18 shows the common sequence of an early widespread distribution followed by regression. The absence of callosal projection neurons in area 17 throughout ontogeny may well be a feature unique to Old World primates.     

Sensory experience modifies the short-term dynamics of neocortical synapses.

Many representations of sensory stimuli in the neocortex are arranged as topographic maps. These cortical maps are not fixed, but show experience-dependent plasticity. For instance, sensory deprivation causes the cortical area representing the deprived sensory input to shrink, and neighbouring spared representations to enlarge, in somatosensory, auditory or visual cortex. In adolescent and adult animals, changes in cortical maps are most noticeable in the supragranular layers at the junction of deprived and spared cortex. However, the cellular mechanisms of this experience-dependent plasticity are unclear. Long-term potentiation and depression have been implicated, but have not been proven to be necessary or sufficient for cortical map reorganization. Short-term synaptic dynamics have not been considered. We developed a brain slice preparation involving rat whisker barrel cortex in vitro. Here we report that sensory deprivation alters short-term synaptic dynamics in both vertical and horizontal excitatory pathways within the supragranular cortex. Moreover, modifications of horizontal pathways amplify changes in the vertical inputs. Our findings help to explain the functional cortical reorganization that follows persistent changes of sensory experience.     

Peripheral nerve injury triggers central sprouting of myelinated afferents.

The central terminals of primary afferent neurons are topographically highly ordered in the spinal cord. Peripheral receptor sensitivity is reflected by dorsal horn laminar location: low-threshold mechanoreceptors terminate in laminae III and IV (refs 2, 3) and high-threshold nociceptors in laminae I, II and V (refs 4,5). Unmyelinated C fibres, most of which are nociceptors, terminate predominantly in lamina II (refs 5, 7). There is therefore an anatomical framework for the transfer of specific inputs to localized subsets of dorsal horn neurons. This specificity must contribute to the relationship between a low-intensity stimulus and an innocuous sensation and a noxious stimulus and pain. We now show that after peripheral nerve injury the central terminals of axotomized myelinated afferents, including the large A beta fibres, sprout into lamina II. This structural reorganization in the adult central nervous system may contribute to the development of the pain mediated by A-fibres that can follow nerve lesions in humans.     

Segregation of pathways leading from area V2 to areas V4 and V5 of macaque monkey visual cortex

V5 and V4 are areas of macaque monkey prestriate visual cortex that are specialized for involvement in different aspects of visual perception, namely motion for V5 (refs 1-4) and colour vision, with other possible functions, for V4 (refs 2, 5-9). Thus, it is unlikely that they should be fed the same information for further processing, yet both receive a strong input from patches of the upper layers of V2 (refs 10, 11), the area immediately adjoining the primary visual cortex, V1. V2, however, seems to comprise functionally distinct subregions, which can be revealed by staining the tissue for the mitochondrial enzyme cytochrome oxidase. Here we report that V4 and V5 are connected with separate cytochrome oxidase-defined subregions of V2, suggesting that cortical pathways dealing with motion and colour perception are segregated in their passage through V2, and reinforcing evidence for functional specialization in the visual cortex.     

Receptive fields in the body-surface map in adult cortex defined by temporally correlated inputs

Receptive fields (RFs) obtained at specific cortical sites can be used to define a topographic map of the body surface in adult mammalian somatosensory cortex. This map is not static, and RFs at particular cortical sites can change in size and location throughout adult life. Conversely, the cortical loci at which a given skin surface is represented can shift hundreds of micrometres across the cortex in the koniocortical field, area 3b (refs 1-12). This plasticity suggests that RFs derive not from rigid anatomical connections, but by the selection of a subset of a large number of inputs. We have proposed that inputs are selected on the basis of temporal correlation 11-15. Here we test this idea by altering the correlation of inputs from two adjacent digits on the adult owl monkey hand by surgically connecting the skin surfaces of the two fingers (the formation of syndactyly). This manipulation increases the correlation of inputs from skin surfaces of adjacent fingers. The striking discontinuity between the zones of representation of adjacent digits on the somatosensory cortex disappeared. These results support the hypothesis that the topography of the body-surface map in the adult cortex is influenced by the temporal correlations of afferent inputs.     

The colour centre in the cerebral cortex of man

Anatomical and physiological studies have shown that there is an area specialized for the processing of colour (area V4) in the prestriate cortex of macaque monkey brain. Earlier this century, suggestive clinical evidence for a colour centre in the brain of man was dismissed because of the association of other visual defects with the defects in colour vision. However, since the demonstration of functional specialization in the macaque cortex, the question of a colour centre in man has been reinvestigated, based on patients with similar lesions in the visual cortex. In order to study the colour centre in normal human subjects, we used the technique of positron emission tomography (PET), which measures increases in blood flow resulting from increased activity in the cerebral cortex. A comparison of the results of PET scans of subjects viewing multi-coloured and black-and-white displays has identified a region of normal human cerebral cortex specialized for colour vision.     

Segregation of efferent connections and receptive field properties in visual area V2 of the macaque

V2 is a visual area of the macaque monkey which is at the second level in a recently proposed hierarchy of cortical visual areas. Histochemical staining for cytochrome oxidase (CO) in V2 reveals a pattern of alternate thick and thin CO-rich stripes separated by CO-sparse interstripes. These subregions receive distinct inputs from neurones in CO-rich and CO-sparse zones arrayed within the superficial layers of V1 (refs 4, 5). Are output projections from V2 to higher visual areas also segregated? Using an anatomical double-label paradigm, we have now demonstrated that V2 cells projecting to two of its major target areas, MT and V4 (refs 6, 7), are arranged in stripe-like clusters which are largely segregated from one another and which are closely related to the pattern of CO stripes. Concomitant electrophysiological recordings from V2 indicate that groups of cells having similar receptive field properties are clustered within the subregions defined by these anatomical techniques.     

Visualizing columnar architectures using high-field fMRI

Among the many neuroimaging tools available for studying human brain functions, functional magnetic resonance imaging (fMRI) is the most widely used today. One advantage of fMRI over other imaging techniques is its relatively high spatial resolution. High-resolution fMRI, with its superb signal-to-noise ratio and improved tissue-vessel specificity, has strengthened the capability of fMRI and allowed mapping of fine cortical architectures in the human brain. In this review, I will first explain the factors limiting the spatial specificity of the blood oxygenation level-dependent (BOLD) effect, based on which most of fMRI experiments are conducted, and the measures dealing with these factors, and then briefly introduce several high-resolution (sub-millimeter) studies on the functional organization of human primary visual cortex (V1), including mapping of ocular dominance columns, mapping of temporal frequency dependent domains and direct demonstration of tuning to stimulus orientation.     

Visualizing columnar architectures using high-field fMRI

Among the many neuroimaging tools available for studying human brain functions, functional magnetic resonance imaging (fMRI) is the most widely used today. One advantage of fMRI over other imaging techniques is its relatively high spatial resolution. High-resolution fMRI, with its superb signal-to-noise ratio and improved tissue-vessel specificity, has strengthened the capability of fMRI and allowed mapping of fine cortical architectures in the human brain. In this review, I will first explain the factors limiting the spatial specificity of the blood oxygenation level-dependent (BOLD) effect, based on which most of fMRI experiments are conducted, and the measures dealing with these factors, and then briefly introduce several high-resolution (sub-millimeter) studies on the functional organization of human primary visual cortex (V1), including mapping of ocular dominance columns, mapping of temporal frequency dependent domains and direct demonstration of tuning to stimulus orientation.     

A spatially organized representation of colour in macaque cortical area V2

Neurons responding selectively to different colours have been found in various cortical areas in macaque monkeys; however, little is known about whether and how the representation of colour is spatially organized in any cortical area. Cortical area V2 contains modules that respond preferentially to chromatic modulation, which are located in thin cytochrome oxidase stripes. Here we show that within and beyond these modules, gratings of different colours produce activations that peak at different locations. Optical recording of intrinsic signals revealed that the peak regions of the responses to different colours were spatially organized in the same order as colour stimuli are arranged in the DIN (German standard colour chart) colour system. Nearby regions represented colours of a similar hue. We found that the set of colour-specific regions formed 0.07-0.32-mm-wide and approximately 1.3-mm long bands that varied in shape from linear to nearly circular. Our finding suggests that thin stripes in V2 contain functional maps where the colour of a stimulus is represented by the location of its response activation peak.     

基于图论算法的脊髓损伤后大脑皮层运动区神经元网络分析

 脊髓损伤(SCI)后大脑皮层运动区神经元的功能重组对机体功能康复的影响仍然不为人知。脊髓损伤前后,对一只在跑步机上直立行走的恒河猴的大脑皮层运动区神经元信号进行记录,利用不同神经元动作电位序列间的相关系数建立神经元网络图。为了研究神经元活动模式的变化与功能康复之间的联系,利用图论算法计算了神经元网络图的全局效能指标和神经元脆弱性指标。结果显示,不同时期神经元活动模式的显著变化意味着运动区神经元的功能重组(神经可塑性)与脊髓损伤后猴子的功能康复状态紧密相关,且这种神经功能重组对于猴子步行功能的康复起了非常重要的积极作用。     

Gaze direction controls response gain in primary visual-cortex neurons

To localize objects in space, the brain needs to combine information about the position of the stimulus on the retinae with information about the location of the eyes in their orbits. Interaction between these two types of information occurs in several cortical areas, but the role of the primary visual cortex (area V1) in this process has remained unclear. Here we show that, for half the cells recorded in area V1 of behaving monkeys, the classically described visual responses are strongly modulated by gaze direction. Specifically, we find that selectivity for horizontal retinal disparity-the difference in the position of a stimulus on each retina which relates to relative object distance-and for stimulus orientation may be present at a given gaze direction, but be absent or poorly expressed at another direction. Shifts in preferred disparity also occurred in several neurons. These neural changes were most often present at the beginning of the visual response, suggesting a feedforward gain control by eye position signals. Cortical neural processes for encoding information about the three-dimensional position of a stimulus in space therefore start as early as area V1.     

Long-term motor cortex plasticity induced by an electronic neural implant

It has been proposed that the efficacy of neuronal connections is strengthened when there is a persistent causal relationship between presynaptic and postsynaptic activity. Such activity-dependent plasticity may underlie the reorganization of cortical representations during learning, although direct in vivo evidence is lacking. Here we show that stable reorganization of motor output can be induced by an artificial connection between two sites in the motor cortex of freely behaving primates. An autonomously operating electronic implant used action potentials recorded on one electrode to trigger electrical stimuli delivered at another location. Over one or more days of continuous operation, the output evoked from the recording site shifted to resemble the output from the corresponding stimulation site, in a manner consistent with the potentiation of synaptic connections between the artificially synchronized populations of neurons. Changes persisted in some cases for more than one week, whereas the output from sites not incorporated in the connection was unaffected. This method for inducing functional reorganization in vivo by using physiologically derived stimulus trains may have practical application in neurorehabilitation after injury.     

Acetylcholine contributes through muscarinic receptors to attentional modulation in V1

Attention exerts a strong influence over neuronal processing in cortical areas. It selectively increases firing rates and affects tuning properties, including changing receptive field locations and sizes. Although these effects are well studied, their cellular mechanisms are poorly understood. To study the cellular mechanisms, we combined iontophoretic pharmacological analysis of cholinergic receptors with single cell recordings in V1 while rhesus macaque monkeys (Macaca mulatta) performed a task that demanded top-down spatial attention. Attending to the receptive field of the V1 neuron under study caused an increase in firing rates. Here we show that this attentional modulation was enhanced by low doses of acetylcholine. Furthermore, applying the muscarinic antagonist scopolamine reduced attentional modulation, whereas the nicotinic antagonist mecamylamine had no systematic effect. These results demonstrate that muscarinic cholinergic mechanisms play a central part in mediating the effects of attention in V1.     

Mapping human visual cortex with positron emission tomography

Positron-emission tomography (PET) can localize functions of the human brain by imaging regional cerebral blood flow (CBF) during voluntary behaviour. Functional brain mapping with PET, however, has been hindered by PET's poor spatial resolution (typically greater than 1 cm). We have developed an image-analysis strategy that can map functional zones not resolved by conventional PET images. Brain areas selectively activated by a behavioural task can be isolated by subtracting a paired control-state image from the task-state image, thereby removing areas not recruited by the task. When imaged in isolation the centre of an activated area can be located very precisely. This allows subtle shifts in response locale due to changes in task to be detected readily despite poor spatial resolution. As an initial application of this strategy we mapped the retinal projection topography of human primary visual cortex. Functional zones separated by less than 3 mm (centre-to-centre) were differentiated using PET CBF images with a spatial resolution of 18 mm. This technique is not limited to a particular brain area or type of behaviour but does require that the increase in CBF produced by the task be both intense and focal.     

Orofacial somatomotor responses in the macaque monkey homologue of Broca's area

In the ventrolateral frontal lobe of the human brain there is a distinct entity, cytoarchitectonic area 44 (Broca's area), which is crucial in speech production. There has been controversy over whether monkeys possess an area comparable to human area 44. We have addressed this question in the macaque monkey by combining quantitative architectonic analysis of the cortical areas within the ventrolateral frontal region with electrophysiological recording of neuron activity and electrical intracortical microstimulation. Here we show that, immediately in front of the ventral part of the agranular premotor cortical area 6, there is a distinct cortical area that is architectonically comparable to human area 44 and that this monkey area 44 is involved with the orofacial musculature. We suggest that area 44 might have evolved originally as an area exercising high-level control over orofacial actions, including those related to communicative acts, and that, in the human brain, area 44 eventually also came to control certain aspects of the speech act.     

An evolutionary scaling law for the primate visual system and its basis in cortical function

A hallmark of mammalian brain evolution is the disproportionate increase in neocortical size as compared with subcortical structures. Because primary visual cortex (V1) is the most thoroughly understood cortical region, the visual system provides an excellent model in which to investigate the evolutionary expansion of neocortex. I have compared the numbers of neurons in the visual thalamus (lateral geniculate nucleus; LGN) and area V1 across primate species. Here I find that the number of V1 neurons increases as the 3/2 power of the number of LGN neurons. As a consequence of this scaling law, the human, for example, uses four times as many V1 neurons per LGN neuron (356) to process visual information as does a tarsier (87). I argue that the 3/2 power relationship is a natural consequence of the organization of V1, together with the requirement that spatial resolution in V1 should parallel the maximum resolution provided by the LGN. The additional observation that thalamus/neocortex follows the same evolutionary scaling law as LGN/V1 may suggest that neocortex generally conforms to the same organizational principle as V1.     

Time-dependent reorganization of brain circuitry underlying long-term memory storage.

Retrograde amnesia observed following hippocampal lesions in humans and animals is typically temporally graded, with recent memory being impaired while remote memories remain intact, indicating that the hippocampal formation has a time-limited role in memory storage. However, this claim remains controversial because studies involving hippocampal lesions tell us nothing about the contribution of the hippocampus to memory storage if this region was present at the time of memory retrieval. We therefore used non-invasive functional brain imaging using (14C)2-deoxyglucose uptake to examine how the brain circuitry underlying long-term memory storage is reorganized over time in an intact brain. Regional metabolic activity in the brain was mapped in mice tested at different times for retention of a spatial discrimination task. Here we report that increasing the retention interval from 5 days to 25 days resulted in both decreased hippocampal metabolic activity during retention testing and a loss of correlation between hippocampal metabolic activity and memory performance. Concomitantly, a recruitment of certain cortical areas was observed. These results indicate that there is a time-dependent reorganization of the neuronal circuitry underlying long-term memory storage, in which a transitory interaction between the hippocampal formation and the neocortex would mediate the establishment of long-lived cortical memory representations.