The effects of ablation of visual cortex in neonatal rabbits on the organization of retinothalamic and retinopretectal projections

Primary visual cortex was ablated unilaterally in neonatal rabbits. Following a survival of 2-4 months, retrograde degeneration of the dorsal lateral geniculate nucleus (LGd) was assessed, and reorganization of retinofugal pathways was studied using methods of anretrograde transport of [3H]proline or of horseradish peroxidase. A complete lesion of primary visual cortex resulted in complete retrograde degeneration of the LGd with no sparing of any class of neurons. The terminations of retinofugal axons in the pretectum and thalamus were compared with those observed in normal animals. No major reorganization of ipsilateral retinofugal projections was observed in either the thalamus and pretectum ipsilateral to the ablated cortex, or in the thalamus and pretectum contralateral to the ablated cortex. However, contralateral retinofugal projections to the thalamus and to the pretectum ipsilateral to the ablated cortex were significantly different from normal. In the thalamus, the projections to the lateral posterior nucleus were expanded in area and increased in density. In the pretectum, the projections to the rostral pretectal areas were greatly increased in area, especially in the region of the olivary pretectal nucleus and posterior pretectal nucleus. However, the density of these projections was not increased relative to normal. Consideration of these results in relation to other published data on the anatomical consequences of neonatal visual cortex lesions, both in mammals which show behavioral sparing following neonatal visual cortex lesions and in mammals which, like the rabbit, show no behavioral sparing, suggests that: (1) behavioral sparing may correlate with patterns of survival or death of neurons in the thalamus and retina; and (2) reorganization of retinofugal pathways is not necessarily associated with behavioral sparing.     

Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury.

Limb denervation leads to reorganization of the representational zones of the somatosensory cortex. Using [11C](R)-PK11195, a sensitive in vivo marker of glial cell activation, and PET, we provide first evidence that limb denervation induces a trans-synaptic increase in [11C](R)-PK11195 binding in the human thalamus but not somatosensory cortex: these brain structures appeared morphologically normal on magnetic resonance imaging (MRI). The increased thalamic signal was detectable many years after nerve injury, indicating persistent reorganization of the thalamus. This glial activation, beyond the first-order projection area of the injured neurons, may reflect continually altered afferent activity. Our findings support the view that long-term rearrangement of cortical representational maps is significantly determined within the thalamus.     

Complexities in the Thalamocortical and Corticothalamic Pathways

It is now a century since Kölliker ( Handbuch der Gewebelehre des Menschen. Nervensystemen des Menschen und der Thiere, Vol. 2 , 6th edn. Engelmann, Leipzig, 1896) described the thalamic reticular nucleus as the 'Gitterkern' or lattice nucleus on the basis of the fibrous latticework that is the characteristic feature of this part of the ventral thalamus and adjacent parts of the internal capsule. We suggest that the fibre reorganization produced in this lattice is a fundamental requirement for linking orderly maps in the thalamus to corresponding cortical maps by two-way thalamocortical and corticothalamic connections; these connections involve divergence, convergence and mirror reversals, which all have to occur between the thalamus and the cortex. Apart from the thalamic reticular nucleus, two transient groups of cells, the perireticular nucleus (located in the internal capsule lateral to the reticular nucleus) and the cells of the cortical subplate, are prominent along the course of axons linking the cortex and thalamus early in development. The functions of these two cell groups are not known. However, since early in development complex patterns of reorganization, defasciculation and crossings occur in the regions of these cells, it is likely that they play a role in creating the latticework of the adult. The latticework that characterizes the thalamic reticular nucleus of mammals can also be identified in the ventral thalamus of non-mammalian brains, formed along the course of the fibres that join the dorsal thalamus to the telencephalon. We suggest that the ubiquitous presence of such a zone of fibre reorganization is integral to the functioning of the thalamocortical pathways, and that the complexity of thalamic connections produced in the lattice has been central to the evolutionary success of the thalamotelencephalic system.     

Dissociation of the immunoreactivity of synaptophysin and GAP-43 during the acute and latent phases of the lithium-pilocarpine model in the immature and adult rat

RATIONALE: Lithium-pilocarpine-induced status epilepticus (SE) generates neuronal lesions in the limbic forebrain, cerebral cortex and thalamus that lead to circuit reorganization and spontaneous recurrent seizures. The process of reorganization in regions with neuronal damage is not fully clarified. METHODS: In the present study, we evaluated by immunohistochemistry the early reorganization during the latent period with two neuronal markers, synaptophysin and growth-associated protein 43 (GAP-43) in rats subjected to SE at PN21 and as adults. RESULTS: Synaptophysin immunoreactivity increased between 24 h and 3 weeks post-SE in regions with severe and rapidly occurring neuronal loss, namely thalamus, amygdala, piriform and entorhinal cortices. GAP-43 expression decreased at 1 and 3 weeks in the same regions. The immunoreactivity of synaptophysin and GAP-43 increased in the inner molecular layer of dentate gyrus from 24 h after SE, and decreased in the outer molecular layer from 72 h after SE. These changes likely result from the death of hilar neurons and the reduction of the input from the entorhinal cortex. In 21-day-old rats that experience less SE-induced neuronal loss, increased immunoreactivity of synaptophysin was only found in piriform and entorhinal cortex while no changes occurred in GAP-43 expression. CONCLUSION: These findings suggest that there is an age-related relation between the extent and rapidity of the process of neuronal death and the expression of these markers. Synaptophysin appears to be a more sensitive marker of plasticity induced by SE than GAP-43.     

Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation

Recovery of function after acute injury to the central nervous system may be controlled by the availability of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex. Acute lesions as well as manipulation of sensory inputs can lead to rapid reorganization of the cerebral cortex, occurring within minutes to hours. Reduction of cortical inhibitory tone through a decrease in the availability of GABA has been suggested as a possible mechanism; however, the degree and temporal course of the changes in brain GABA are not known. A novel method using two-dimensional J-resolved magnetic resonance spectroscopy showed that GABA levels in the human sensorimotor cortex are quickly reduced within minutes of deafferentation. This finding strongly supports the view that the release of latent corticocortical projections from tonic inhibition through decreased GABA availability is a mechanism of rapid cortical plasticity. Reduction of brain GABA can play a pivotal role in regulating the extent of rapid cortical reorganization after lesions or changes in sensory input.     

Changes in the organization of the ventroposterior lateral thalamic nucleus after digit removal in adult raccoon

The ventroposterior lateral nucleus of the thalamus was studied in seven raccoons that had undergone amputation of the fourth digit between 2 and 5 months previously. Extracellular recordings were made in a series of closely spaced penetrations through the thalamus in chloralose anesthetized animals. The responses to cutaneous stimulation of the forepaw were used to reconstruct the somatotopic organization of the thalamus and to identify recording sites believed to be located in the digit zone that had lost its peripheral input. Twelve penetrations that passed through both of the adjacent fifth and third digit regions were analyzed in detail to delineate this deafferented region. None of the recording sites in this region were completely silent, indicating that the deafferented thalamus had undergone significant reorganization of its inputs. At most sites, the neurons had receptive fields on the skin surrounding the amputation wound and including one of the adjacent digits. Approximately half of the sites had low thresholds in the range of normal thalamic neurons. These results indicate that the ventroposterior thalamus is capable of substantial reorganization, which may account for much of the reorganization seen in somatosensory cortex. © 1996 Wiley-Liss, Inc.     

Changes in efferent and afferent connectivity in rats with induced cerebrocortical microgyria

Freezing injury to the cortical plate at postnatal day (P) 1 initiates a cascade of events that ultimately result in a focal neocortical malformation resembling human 4-layered microgyria. This malformation has been associated with widespread changes in neocortical and thalamic architecture and physiology. It was hypothesized that at least some of these alterations could result from connectional reorganization following early injury. The current experiment was designed to delineate the efferent and afferent connections between the cerebral hemispheres and between the cortex and thalamus of rats with induced cerebrocortical microgyria. Microgyria were induced in the parietal cortex of rats by freezing injury on postnatal day 1. In adulthood, injections of biotinylated dextran amine were made either in the microgyric cortex, in homologous regions of the opposite hemisphere, or in ipsilateral ventrobasal complex of the thalamus. Appropriately directed connections to homotopic areas were seen in some but not all microgyric rats. In addition, heterotopic projections to frontal and secondary sensorimotor cortices were noted. Projections from homotopic regions in the hemisphere opposite to the malformation terminated most often in the medial portions of the microgyrus or avoided it entirely. There were almost no thalamocortical or corticothalamic projections between the ventrobasal complex and the microgyrus itself, although a dense plexus of thalamocortical fibers was often noted at the border between the malformed and normal cortex. These connectional changes may help explain disturbances in architecture, physiology, and behavior associated with these focal malformations.     

Modification of the projection from the sensory cortex to the motor cortex following the elimination of thalamic projections to the motor cortex in cats

Examination of the projection from area 2 of the sensory cortex to the motor cortex revealed substantial changes following lesion of the ventrolateral nucleus of the thalamus. These observed changes were as follows. (1) The polarity of the evoked potentials elicited by area 2 stimulation reversed in the depth of the motor cortex whereas in normal animals, there was no reversal. (2) The amplitude of area 2-elicited EPSPs in the motor cortical neurons became greater following the lesion of VL. (3) The shape of the observed EPSPs was characterized by multiple peaks whereas in normal animals, the EPSPs were generally smooth and monophasic. (4) Neurons receiving a short-latency input from area 2 were distributed throughout the depths of the motor cortex whereas in normal animals, they were located only in the upper layers (layers II and III). (5) Intracellular injection of HRP revealed that the neurons receiving short-latency input were not restricted to typical stellate type cells, but also included bipolar or bitufted neurons with elongated cell bodies and polarized arborizations. These neurons were located in the superficial (II and III) as well as in the deep (V) layer. It is concluded that the elimination of thalamic input resulted in the reinforcement of the corticocortical input to the motor cortex. The subsequently observed corticocortical projection extended to neurons did not originally innervated by the association fibers. The results suggested that functional recovery following thalamic lesion is partly due to reorganization of projections from the sensory cortex to the motor cortex.     

How does the human brain deal with a spinal cord injury?

The primary sensorimotor cortex of the adult brain is capable of significant reorganization of topographic maps after deafferentation and de-efferentation. Here we show that patients with spinal cord injury exhibit extensive changes in the activation of cortical and subcortical brain areas during hand movements, irrespective of normal (paraplegic) or impaired (tetraplegic patients) hand function. Positron emission tomography ([¹⁵O]-H₂O-PET) revealed not only an expansion of the cortical ‘hand area’ towards the cortical ‘leg area’, but also an enhanced bilateral activation of the thalamus and cerebellum. The areas of the brain which were activated were qualitatively the same in both paraplegic and tetraplegic patients, but differed quantitatively as a function of the level of their spinal cord injury. We postulate that the changes in brain activation following spinal cord injury may reflect an adaptation of hand movement to a new body reference scheme secondary to a reduced and altered spino-thalamic and spino-cerebellar input.     

The thalamo-cortical resting state functional connectivity and abstinence-induced craving in young smokers

Craving is a significant predicator of smoking relapse. Thus, revealing the neural correlates of craving to smoke in young smokers is important to improve the success of quit attempts. The abstinence-induced craving to smoke has not been explored extensively, although previous studies had investigated the neural substrates of cue-induced craving. Especially, the critical roles of thalamus had been revealed in cigarettes smoking. However, the implication of thalamus resting state functional connectivity (RSFC) in abstinence-induced craving remains unclear. In the current study, by employing a within-subject design in 25 young smokers, both the left and right thalamus RSFC patterns differences were investigated between smoking abstinence condition and smoking satiety condition in young smokers. Moreover, a correlation analysis was employed to assess the relationship between these RSFC changes and abstinence-induced changes in subjective craving. We found young smokers in abstinence state showed reduced RSFC between the left thalamus and right dorsal lateral prefrontal cortex (dlPFC) as well as the right anterior cingulate cortex (ACC) compared with smoking satiety state. There were no significant different RSFC of right thalamus detected across the two sessions. Additionally, the left thalamus-right dlPFC RSFC changes were correlated with the changes in craving induced by 12-h abstinence (i.e., abstinence minus satiety). The present findings provides new evidence that abstinence-induced cravings to smoke are associated with abnormal thalamus RSFC and may shed new insights into the neural mechanism of abstinence-induced craving in young smokers.     

Time-course of changes in water,sodium, potassium and calcium contents of various brain regions in rats after systemic kainic acid administration

Summary The changes in the water, sodium, potassium and calcium content of the frontoparietal cortex, hippocampus, thalamus and cerebellum in rats were investigated 2, 4, 8, 12 and 24 h and 3 and 7 days after systemic kainic acid administration. The water content was significantly increased in the thalamus and hippocampus 4 and 8 h, respectively, after the kainic acid injection and remained elevated at each subsequent time point. No change was found in the water content of the frontoparictal cortex and cerebellum. The sodium content of the frontoparietal cortex, hippocampus and thalamus was increased 4 h after kainic acid administration, and that of the cerebellum after 8 h. These levels remained elevated throughout the 7 days, with the exception of that for the frontoparietal cortex. A significant potassium decrease was observed in all brain regions investigated. Calcium accumulation was found to begin 4 h after kainic acid administration and was the most pronounced on the 7th day in the thalamus and hippocampus. Electron microscope investigations revealed a mainly intramitochondrial calcium accumulation in these brain regions. Pretreatment with Verapamil did not prevent calcium accumulation. The ion shifts and the development of edema in the thalamus and hippocampus in the early period, and also the changes of the sodium and potassium contents in the frontoparietal cortex and cerebellum in the early and late (12 h and later) periods, can be regarded as concomitant events of epileptic activity. In the hippocampus and thalamus, severe secondary necrotic and hemorrhagic neuropathological damage was accompained by ion shifts and edema in the late period after systemic kainic acid administration.     

Functional relevance of abnormal fMRI activation pattern after unilateral schizencephaly

Brain plasticity was investigated in a child with a hemiplegia due to unilateral schizencephaly involving the sensorimotor cortex. This focal lesion led to a dramatic functional reorganization of the undamaged hemisphere, as evidenced by the unusual pattern of fMRI activation during paretic finger movements. The functional relevance of the activation in the undamaged motor cortex was supported by the finding that TMS of this area yielded a response in the paretic hand, indicating that it controls both hands. However, this reorganization was not restricted to the primary motor cortex, but also concerned other structures involved in the control of movements, as shown by the activation of contralesional SMA and thalamus. In contrast, the fMRI activation in the damaged sensorimotor cortex during paretic hand movements appears functionally irrelevant.     

Reassemblage of primary cell aggregates and modulation of subcortical connections in the thalamic relay nucleus: Effects of vibrissal damage in the developing whisker-to-barrel pathway in the mouse

To investigate the mechanisms underlying the reorganization of barrels in the whisker-to-barrel pathway, the facial vibrissae of mice were damaged by electrocauterization at alternate positions on either postnatal day 0 (P0) or P3, before or after the onset of cell aggregation in the thalamus and cortex. Animals were subsequently killed on P8, topographical changes were examined by cytochrome C oxidase histochemistry, and afferent connections were identified using DiI tracer. The cytoarchitecture was characterized with bisbenzimide counterstain. Regardless of when damage was done, the reorganized barreloids and barrels in the thalamus and cortex, respectively, were integrated in an array that represented the topography of undamaged vibrissae. In the brainstem, although the original framework of the array was preserved, defective cell aggregates remained, possibly still in contact with damaged vibrissae. During normal development, on P0 cell aggregates are formed only in the brainstem, and begin to be organized at the other levels of the pathway on P3. Therefore, when damage is induced on P3, the primary cell aggregates are replaced by new, possibly recombined, cell aggregates in the thalamus and cortex to represent the new peripheral topography. The presumably recombined aggregates indicate that cell reassemblage occurred between neighboring cell aggregates. Concomitant with these changes, afferent fibers originating in the brainstem and thalamus extended their terminal arborizations to delineate the new cell aggregates in the thalamus and cortex, respectively. These findings indicate that activity-dependent competitive interactions of afferents may play a crucial role in organizing the topography of cell aggregation and reassemblage in response to vibrissal damage at each level of the pathway. J Comp Neurol 403:517–533, 1999. © 1999 Wiley-Liss, Inc.     

An in vitro electrophysiological and Co2+-uptake study on the effect of infraorbital nerve transection on the cortical and thalamic neuronal activity.

Changes of neuronal membrane characteristics in somatosensory barrel cortex and barreloid thalamus were investigated in rats following unilateral transection of the infraorbital nerve. Kainate induced Co2+-uptake method and image analysis were used to assess the Ca2+ permeability of non-NMDA (N-methyl-D-aspartate) glutamate receptors. Changes in some biophysical parameters of the affected cortical neurons were also investigated by intracellular recording in slice experiments. The altered neuronal activity was measured on days 1, 5 and 14 after surgery. Kainate induced Co2+ uptake increased markedly reflecting enhanced Ca2+ permeability of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate (AMPA/KAIN)-type receptors. Changes were more pronounced in the cortex than in the thalamus and peaked on the first day following nerve transection. After that, parameters gradually returned to the normal level. However, a small enhancement was still detectable in the cortex at the end of the 2-week-long observation period. In parallel with the increased Co2+-uptake, moderate membrane potential changes, stronger spiking activity and enhanced excitability were characteristic for cortical neurons. The observed alterations in neuronal characteristics underlie the reorganization and regeneration processes following injuries or surgeries. We can conclude that immediate change of the receptive field in the barrel cortex following unilateral nerve transection is based on changes in biophysical parameters of the neurons. Altered peripheral activation evokes changes in the neuronal activity, thus providing opportunity for a quick synaptic rearrangement. AMPA/KAIN-type glutamate receptors have a decisive role in the regulation of these processes. This kind of synaptic plasticity is more significant in the cortex than in the thalamus.     

Juvenile myoclonic epilepsy may be a disorder of cortex rather than thalamus: An effective connectivity analysis

Although juvenile myoclonic epilepsy has been considered as a disorder of thalamo-cortical circuit, it is not determined the causality relationship between thalamus and cortex. The aim of this study was to evaluate whether juvenile myoclonic epilepsy is a disorder of thalamus or cortex. Twenty-nine patients with juvenile myoclonic epilepsy and 20 normal controls were enrolled in this study. In addition, we included 10 patients with childhood absence epilepsy as a disease control group. Using whole-brain T1-weighted MRIs, we analyzed the volumes of the structures, including hippocampus, thalamus, and total cortex, with FreeSurfer 5.1. We also investigated the effective connectivity among these structures using SPSS Amos 21 based on these volumetric measures. The structural volumes in juvenile myoclonic epilepsy were not different from those in normal controls. There was a statistically significant effective connectivity from the total cortex to the thalamus in the patients with juvenile myoclonic epilepsy. In addition, a significant effective connectivity from the hippocampus to the ipsilateral thalamus was revealed. Unlike the patients with juvenile myoclonic epilepsy, neither the patients with childhood absence epilepsy nor normal controls had a significant effective connectivity from the total cortex to the thalamus or from the thalamus to the cortex. The connectivity of brain in patients with juvenile myoclonic epilepsy could be different from that in patients with childhood absence epilepsy, and the cortex rather than the thalamus might play a critical role in the pathogenesis of juvenile myoclonic epilepsy.     

The characteristics of the synaptic reorganization in the sensorimotor cortex of cats after the destruction of the symmetrical portion of the cortex in the opposite hemisphere

Intracellular recording technique has been used to study reactions of corticospinal neurons (CSN) to stimulation of the ipsilateral ventrolateral nucleus (VLN) of the thalamus in acute experiments on adult intact cats and on cats after lesion on the contralateral sensorimotor cortex (exposition from 6 months to 1.5 years). Acceleration of the monosynaptic EPSPs rise phase in slow CSN was revealed in operated animals, which presumed the reorganization of the synaptic contacts in the SD membrane of flow CSN. Detailed analysis of features and branching of CSN axon, collaterals passing to VLN of the thalamus and participating in formation of the ipsilateral pyramidal tract was made by the method of collision test. The significance of the plastic synaptic reconstruction in the ipsilateral thalamo-cortex reverberating system during the outflow formation under conditions of the partial cortex interhemisphere deafferentation is discussed.     

Compromise of auditory cortical tuning and topography after cross-modal invasion by visual inputs

Brain damage resulting in loss of sensory stimulation can induce reorganization of sensory maps in cerebral cortex. Previous research on recovery from brain damage has focused primarily on adaptive plasticity within the affected modality. Less attention has been paid to maladaptive plasticity that may arise as a result of ectopic innervation from other modalities. Using ferrets in which neonatal midbrain damage results in diversion of retinal projections to the auditory thalamus, we investigated how auditory cortical function is impacted by the resulting ectopic visual activation. We found that, although auditory neurons in cross-modal auditory cortex (XMAC) retained sound frequency tuning, their thresholds were increased, their tuning was broader, and tonotopic order in their frequency maps was disturbed. Multisensory neurons in XMAC also exhibited frequency tuning, but they had longer latencies than normal auditory neurons, suggesting they arise from multisynaptic, non-geniculocortical sources. In a control group of animals with neonatal deafferentation of auditory thalamus but without redirection of retinal axons, tonotopic order and sharp tuning curves were seen, indicating that this aspect of auditory function had developed normally. This result shows that the compromised auditory function in XMAC results from invasion by ectopic visual inputs and not from deafferentation. These findings suggest that the cross-modal plasticity that commonly occurs after loss of sensory input can significantly interfere with recovery from brain damage and that mitigation of maladaptive effects is critical to maximizing the potential for recovery.     

Somatotopic reorganization in the brainstem and thalamus following peripheral nerve injury in adult primates

Injury-induced reorganization of central somatotopic maps is a phenomenon that has proven to be useful for elucidating the mechanisms and time course of neural plasticity. To date, the overwhelming majority of this line of research has focused on such plastic events in cortical areas, at the expense of subcortical structures. In this study, we used multi-unit electrophysiological recording techniques to assess the somatotopic organization of brainstem and thalamic areas following chronic survival from paired median and ulnar nerve section in adult squirrel monkeys. We report that the extent of cutaneously-driven reorganization in both the cuneate nucleus of the brainstem and the ventroposterior lateral nucleus of the thalamus is comparable to that previously documented for area 3b of cortex. These observations are consistent with those previously reported in thalamus, and are unique for brainstem.     

Cortical reorganization in NT3-treated experimental spinal cord injury: Functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) studies were performed for visualizing ongoing brain plasticity in Neurotrophin-3 (NT3)-treated experimental spinal cord injury (SCI). In response to the electrical stimulation of the forepaw, the NT3-treated animals showed extensive activation of brain structures that included contralateral cortex, thalamus, caudate putamen, hippocampus, and periaqueductal gray. Quantitative analysis of the fMRI data indicated significant changes both in the volume and center of activations in NT3-treated animals relative to saline-treated controls. A strong activation in both ipsi- and contralateral periaqueductal gray and thalamus was observed in NT3-treated animals. These studies indicate ongoing brain reorganization in the SCI animals. The fMRI results also suggest that NT3 may influence nociceptive pathways.     

Corticothalamic modulation on formalin-induced change of VPM thalamic activities

Spontaneous activities of single cells were extracellularly recorded in ventral posterior medial (VPM) thalamus of anesthetized rats to characterize the corticothalamic modulation on formalin-induced changes of spontaneous thalamic firing. Formalin injected into the peripheral receptive field, dose-dependently induced the reversible facilitation of spontaneous activities of VPM. However, when the primary somatosensory (SI) cortex was inactivated by muscimol, the pattern of formalin-induced changes of VPM firing was altered. This altered responsiveness included both first and second phase of facilitated spontaneous activities. Bicuculline infused into SI cortex did not alter the pattern of formalin-induced thalamic changes. These results suggest that the pain reactivity of VPM thalamus may be modulated by cortex via corticothalamic pathway during the generation of inflammatory pain.