Modelling corticothalamic feedback and the gating of the thalamus by the cerebral cortex

Morphological studies have shown that excitatory synapses from the cortex constitute the major source of synapses in the thalamus. However, the effect of these corticothalamic synapses on the function of the thalamus is not well understood because thalamic neurones have complex intrinsic firing properties and interact through multiple types of synaptic receptors. Here we investigate these complex interactions using computational models. We show first, using models of reconstructed thalamic relay neurones, that the effect of corticothalamic synapses on relay cells can be similar to that of afferent synapses, in amplitude, kinetics and timing, although these synapses are located in different regions of the dendrites. This suggests that cortical EPSPs may complement (or predict) the afferent information. Second, using models of reconstructed thalamic reticular neurones, we show that high densities of the low-threshold Ca2+ current in dendrites can give these cells an exquisite sensitivity to cortical EPSPs, but only if their dendrites are hyperpolarized. This property has consequences at the level of thalamic circuits, where corticothalamic EPSPs evoke bursts in reticular neurones and recruit relay cells predominantly through feedforward inhibition. On the other hand, with depolarized dendrites, thalamic reticular neurones do not generate bursts and the cortical influence on relay cells is mostly excitatory. Models therefore suggest that the cortical influence can either promote or antagonize the relay of information, depending on the state of the dendrites of reticular neurones. The control of these dendrites may therefore be a determinant of attentional mechanisms. We also review the effect of corticothalamic feedback at the network level, and show how the cortical control over the thalamus is essential in co-ordinating widespread, coherent oscillations. We suggest mechanisms by which different modes of corticothalamic interaction would allow oscillations of very different spatiotemporal coherence to coexist in the thalamocortical system.     

Thalamic circuitry and thalamocortical synchrony

The corticothalamic system has an important role in synchronizing the activities of thalamic and cortical neurons. Numerically, its synapses dominate the inputs to relay cells and to the gamma-amino butyric acid (GABA)ergic cells of the reticular nucleus (RTN). The capacity of relay neurons to operate in different voltage-dependent functional modes determines that the inputs from the cortex have the capacity directly to excite the relay cells, or indirectly to inhibit them via the RTN, serving to synchronize high- or low-frequency oscillatory activity respectively in the thalamocorticothalamic network. Differences in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subunit composition of receptors at synapses formed by branches of the same corticothalamic axon in the RTN and dorsal thalamus are an important element in the capacity of the cortex to synchronize low-frequency oscillations in the network. Interactions of focused corticothalamic axons arising from layer VI cortical cells and diffuse corticothalamic axons arising from layer V cortical cells, with the specifically projecting core relay cells and diffusely projecting matrix cells of the dorsal thalamus, form a substrate for synchronization of widespread populations of cortical and thalamic cells during high-frequency oscillations that underlie discrete conscious events.     

A minimal mechanistic model for temporal signal processing in the lateral geniculate nucleus

The receptive fields of cells in the lateral geniculate nucleus (LGN) are shaped by their diverse set of impinging inputs: feedforward synaptic inputs stemming from retina, and feedback inputs stemming from the visual cortex and the thalamic reticular nucleus. To probe the possible roles of these feedforward and feedback inputs in shaping the temporal receptive-field structure of LGN relay cells, we here present and investigate a minimal mechanistic firing-rate model tailored to elucidate their disparate features. The model for LGN relay ON cells includes feedforward excitation and inhibition (via interneurons) from retinal ON cells and excitatory and inhibitory (via thalamic reticular nucleus cells and interneurons) feedback from cortical ON and OFF cells. From a general firing-rate model formulated in terms of Volterra integral equations, we derive a single delay differential equation with absolute delay governing the dynamics of the system. A freely available and easy-to-use GUI-based MATLAB version of this minimal mechanistic LGN circuit model is provided. We particularly investigate the LGN relay-cell impulse response and find through thorough explorations of the model’s parameter space that both purely feedforward models and feedback models with feedforward excitation only, can account quantitatively for previously reported experimental results. We find, however, that the purely feedforward model predicts two impulse response measures, the time to first peak and the biphasic index (measuring the relative weight of the rebound phase) to be anticorrelated. In contrast, the models with feedback predict different correlations between these two measures. This suggests an experimental test assessing the relative importance of feedforward and feedback connections in shaping the impulse response of LGN relay cells.     

Corticofugal influences on pontine unit activity

Unit responses of the nuclei pontis (NP) and reticular pontine nuclei (RPN) to stimulation of the frontobasal cortex (proreal, orbital, and basal temporal regions) and of the dorsal hippocampus were studied in cats. Stimulation of the various cortical structures was found to induce phasic and (less frequently) tonic responses in neurons of NP and RPN. The main type of unit response in RPN was primary excitation, whereas in NP it was primary inhibition. The largest number of responding neurons in the pontine nuclei was observed to stimulation of the proreal gyrus. In the cerebro-cerebellar relay system neurons of the reticular tegmental nucleus and ventromedial portion of NP showed the highest ability to respond. In the oral and caudal reticular pontine nuclei the regions of predominant influence of cortical structures were located in zones of these nuclei where neurons with rostral and (to a lesser degree) caudal projections were situated.M. Gorkii Donetsk Medical Institute. Translated from Neirofiziologiya, Vol. 12, No. 4, pp. 358–367, July–August, 1980.     

Reciprocal inhibition and slow calcium decay in perigeniculate interneurons explain changes of spontaneous firing of thalamic cells caused by cortical inactivation

The role of cortical feedback in the thalamocortical processing loop has been extensively investigated over the last decades. With an exception of several cases, these searches focused on the cortical feedback exerted onto thalamo-cortical relay (TC) cells of the dorsal lateral geniculate nucleus (LGN). In a previous, physiological study, we showed in the cat visual system that cessation of cortical input, despite decrease of spontaneous activity of TC cells, increased spontaneous firing of their recurrent inhibitory interneurons located in the perigeniculate nucleus (PGN). To identify mechanisms underlying such functional changes we conducted a modeling study in NEURON on several networks of point neurons with varied model parameters, such as membrane properties, synaptic weights and axonal delays. We considered six network topologies of the retino-geniculo-cortical system. All models were robust against changes of axonal delays except for the delay between the LGN feed-forward interneuron and the TC cell. The best representation of physiological results was obtained with models containing reciprocally connected PGN cells driven by the cortex and with relatively slow decay of intracellular calcium. This strongly indicates that the thalamic reticular nucleus plays an essential role in the cortical influence over thalamo-cortical relay cells while the thalamic feed-forward interneurons are not essential in this process. Further, we suggest that the dependence of the activity of PGN cells on the rate of calcium removal can be one of the key factors determining individual cell response to elimination of cortical input.     

Analysis of the electroencephalographic activity associated with thalamic tumors

A physiologically based model of corticothalamic dynamics is used to investigate the electroencephalographic (EEG) activity associated with tumors of the thalamus. Tumor activity is modeled by introducing localized two-dimensional spatial non-uniformities into the model parameters, and calculating the resulting activity via the coupling of spatial eigenmodes. The model is able to reproduce various qualitative features typical of waking eyes-closed EEGs in the presence of a thalamic tumor, such as the appearance of abnormal peaks at theta ( approximately 3Hz) and spindle ( approximately 12Hz) frequencies, the attenuation of normal eyes-closed background rhythms, and the onset of epileptic activity, as well as the relatively normal EEGs often observed. The results indicate that the abnormal activity at theta and spindle frequencies arises when a small portion of the brain is forced into an over-inhibited state due to the tumor, in which there is an increase in the firing of (inhibitory) thalamic reticular neurons. The effect is heightened when there is a concurrent decrease in the firing of (excitatory) thalamic relay neurons, which are in any case inhibited by the reticular ones. This is likely due to a decrease in the responsiveness of the peritumoral region to cholinergic inputs from the brainstem, and a corresponding depolarization of thalamic reticular neurons, and hyperpolarization of thalamic relay neurons, similar to the mechanism active during slow-wave sleep. The results indicate that disruption of normal thalamic activity is essential to generate these spectral peaks. Furthermore, the present work indicates that high-voltage and epileptiform EEGs are caused by a tumor-induced local over-excitation of the thalamus, which propagates to the cortex. Experimental findings relating to local over-inhibition and over-excitation are discussed. It is also confirmed that increasing the size of the tumor leads to greater abnormalities in the observable EEG. The usefulness of EEG for localizing the tumor is investigated.     

A thalamo-cortical neural mass model for the simulation of brain rhythms during sleep

Cortico-thalamic interactions are known to play a pivotal role in many brain phenomena, including sleep, attention, memory consolidation and rhythm generation. Hence, simple mathematical models that can simulate the dialogue between the cortex and the thalamus, at a mesoscopic level, have a great cognitive value. In the present work we describe a neural mass model of a cortico-thalamic module, based on neurophysiological mechanisms. The model includes two thalamic populations (a thalamo-cortical relay cell population, TCR, and its related thalamic reticular nucleus, TRN), and a cortical column consisting of four connected populations (pyramidal neurons, excitatory interneurons, inhibitory interneurons with slow and fast kinetics). Moreover, thalamic neurons exhibit two firing modes: bursting and tonic. Finally, cortical synapses among pyramidal neurons incorporate a disfacilitation mechanism following prolonged activity. Simulations show that the model is able to mimic the different patterns of rhythmic activity in cortical and thalamic neurons (beta and alpha waves, spindles, delta waves, K-complexes, slow sleep waves) and their progressive changes from wakefulness to deep sleep, by just acting on modulatory inputs. Moreover, simulations performed by providing short sensory inputs to the TCR show that brain rhythms during sleep preserve the cortex from external perturbations, still allowing a high cortical activity necessary to drive synaptic plasticity and memory consolidation. In perspective, the present model may be used within larger cortico-thalamic networks, to gain a deeper understanding of mechanisms beneath synaptic changes during sleep, to investigate the specific role of brain rhythms, and to explore cortical synchronization achieved via thalamic influences.     

Unit activity of the reticular and relay nuclei of the cat thalamus

Relations between neurons of the reticular and specific relay nuclei of the thalamus were studied in cats immobilized with tubocurarine. Under the influence of stimulation of the reticular nucleus (RN) unit activity in the thalamic relay nuclei was found to be considerably modulated. Cases of the appearance of IPSPs (possibly of monosynaptic nature), evoked by stimulation of RN, in neurons of the ventroposterolateral nucleus (VPLN) and lateral geniculate body (LGB) are described. During simultaneous recording of unit activity in RN and VPLN or LGB by means of two electrodes interaction of several types was found: inhibition of discharges of VPLN or LGB neurons accompanied by excitation of RN neurons: alternation of excitation-inhibition in neuron pairs in RN and VPLN or RN and LGB during low-frequency afferent or cortical stimulation (in this case excitation of RN neurons is associated with inhibition of VPLN or LGB neurons), and strengthening of the discharge of VPLN or LGB neurons during excitation of RN neurons. The possibility of the existence both of direct monosynaptic inhibition of activity of VPLN or LGB relay neurons under the influence of excitation of RN neurons and of their inhibition by activation of hypothetical interneurons of the relay nuclei themselves is accepted.I. S. Beritashvili Institute of Physiology, Academy of Sciences of the Georgian SSR, Tbilisi. Translated from Neirofiziologiya, Vol. 13, No. 1, pp. 24–31, January–February, 1981.     

A method for the estimation of functional brain connectivity from time-series data

A central issue in cognitive neuroscience is which cortical areas are involved in managing information processing in a cognitive task and to understand their temporal interactions. Since the transfer of information in the form of electrical activity from one cortical region will in turn evoke electrical activity in other regions, the analysis of temporal synchronization provides a tool to understand neuronal information processing between cortical regions. We adopt a method for revealing time-dependent functional connectivity. We apply statistical analyses of phases to recover the information flow and the functional connectivity between cortical regions for high temporal resolution data. We further develop an evaluation method for these techniques based on two kinds of model networks. These networks consist of coupled Rössler attractors or of coupled stochastic Ornstein–Uhlenbeck systems. The implemented time-dependent coupling includes uni- and bi-directional connectivities as well as time delayed feedback. The synchronization dynamics of these networks are analyzed using the mean phase coherence, based on averaging over phase-differences, and the general synchronization index. The latter is based on the Shannon entropy. The combination of these with a parametric time delay forms the basis of a connectivity pattern, which includes the temporal and time lagged dynamics of the synchronization between two sources. We model and discuss potential artifacts. We find that the general phase measures are remarkably stable. They produce highly comparable results for stochastic and periodic systems. Moreover, the methods proves useful for identifying brief periods of phase coupling and delays. Therefore, we propose that the method is useful as a basis for generating potential functional connective models.     

Communication through Resonance in Spiking Neuronal Networks

The cortex processes stimuli through a distributed network of specialized brain areas. This processing requires mechanisms that can route neuronal activity across weakly connected cortical regions. Routing models proposed thus far are either limited to propagation of spiking activity across strongly connected networks or require distinct mechanisms that create local oscillations and establish their coherence between distant cortical areas. Here, we propose a novel mechanism which explains how synchronous spiking activity propagates across weakly connected brain areas supported by oscillations. In our model, oscillatory activity unleashes network resonance that amplifies feeble synchronous signals and promotes their propagation along weak connections (“communication through resonance”). The emergence of coherent oscillations is a natural consequence of synchronous activity propagation and therefore the assumption of different mechanisms that create oscillations and provide coherence is not necessary. Moreover, the phase-locking of oscillations is a side effect of communication rather than its requirement. Finally, we show how the state of ongoing activity could affect the communication through resonance and propose that modulations of the ongoing activity state could influence information processing in distributed cortical networks.     

Role of frequency mismatch in neuronal communication through coherence

Neuronal gamma oscillations have been described in local field potentials of different brain regions of multiple species. Gamma oscillations are thought to reflect rhythmic synaptic activity organized by inhibitory interneurons. While several aspects of gamma rhythmogenesis are relatively well understood, we have much less solid evidence about how gamma oscillations contribute to information processing in neuronal circuits. One popular hypothesis states that a flexible routing of information between distant populations occurs via the control of the phase or coherence between their respective oscillations. Here, we investigate how a mismatch between the frequencies of gamma oscillations from two populations affects their interaction. In particular, we explore a biophysical model of the reciprocal interaction between two cortical areas displaying gamma oscillations at different frequencies, and quantify their phase coherence and communication efficiency. We observed that a moderate excitatory coupling between the two areas leads to a decrease in their frequency detuning, up to ～6 Hz, with no frequency locking arising between the gamma peaks. Importantly, for similar gamma peak frequencies a zero phase difference emerges for both LFP and MUA despite small axonal delays. For increasing frequency detunings we found a significant decrease in the phase coherence (at non-zero phase lag) between the MUAs but not the LFPs of the two areas. Such difference between LFPs and MUAs behavior is due to the misalignment between the arrival of afferent synaptic currents and the local excitability windows. To test the efficiency of communication we evaluated the success of transferring rate-modulations between the two areas. Our results indicate that once two populations lock their peak frequencies, an optimal phase relation for communication appears. However, the sensitivity of locking to frequency mismatch suggests that only a precise and active control of gamma frequency could enable the selection of communication channels and their directionality.     

Correlations of neuronal spike discharges of VL neurons during spontaneous firing and during the activity evoked by peripheral stimulation

The temporal relations between simultaneously recorded neurons of the nucleus ventralis lateralis (VL) of cat thalamus were studied. The interaction and the functional connections between individual VL neurons are described. This was achieved with an application of cross correlation techniques. The response patterns of different individual neurons to somatic sensory and photic stimuli were also analyzed. For the purpose of classifying neurons as thalamocortical relay cells (T-C) and non relay cells (N-C) which do not project to the motor sensory cortex antidromic cortical stimulation was used. This stimulation was also used as conditioning one when proceeded peripheral stimuli. To analyze the nonspecific specific interactions upon single neurons conditioning photic stimuli were applied. The results show that T-C neurons are antidromically excited from a wide cortical areas and that the functional interaction between T-C neurons is mediated by a shared input from common sources. It is further postulated that N-C cells interposed between relay neurons subserve the functions of gating units modifying the neuronal network of lateral ventral nucleus of the thalamus.     

Event-related coherence and event-related desynchronization/synchronization in the 10 Hz and 20 Hz EEG during self-paced movements

To investigate the activity of cortical regions in the control of movement, we studied event-related desynchronization/synchronization (ERD/ERS), event-related coherence (ERC), and phase coherence in 29-channel EEGs from 9 subjects performing self-paced movements of the right index finger. Movement preparation and execution produced ERD over the sensorimotor areas at 10 Hz and 20 Hz, followed by ERS. ERD corresponded spatiotemporally to an increase in coherence over the frontocentral areas. For both frequency bands, ERD began over the left sensorimotor areas and became bilateral at the time of movement onset. The coherence increase with frontal areas began in the left central areas and became symmetrical after EMG onset. The ERD and coherence increase was longer at 10 Hz than at 20 Hz. Phase coherence at 10 Hz showed a lead of anterior regions to posterior regions throughout the time period, and at 20 Hz showed a tendency toward zero phase delay corresponding with the movement. EEG desynchronization parallels functional coupling over sensorimotor and frontal areas. Event-related coherence and phase coherence findings implicate the frontal lobes in control of movement planning and execution. The involvement of different frequency bands with different timings may represent parallel changes in the cortical network.     

Intercentral reticulo-cortical relations of brain electrical activity during "animal hypnosis" in rabbits

The electrical activity of the right and left sensorimotor and premotor cortical areas and right and left medulary reticular formation was recorded during "animal hypnosis" in rabbits. In this state, the spectral power of potentials (predominantly, in the delta-range) recorded from the left reticular formation was higher than that recorded from the right side. The value of the function of coherence between the right and left reticular recordings was decreased to 0.1-0.2 in the whole frequency range. The tight-side intrahemispheric coherence between the activities recorded from the sensorimotor cortex and reticular formation was higher than respective left-side values, whereas the coherent relations between the activities recorded from the reticular formation and premotor cortex were not changed (as compared to nonhypnotic state).     

Differentiation of efferent projections of the medial (cuneiform nucleus) and lateral regions of the reticular formation in cat midbrain

Efferent connections of medial (nucleus cuneiformis) and lateral regions of the midbrain reticular formation (MRF) were investigated using an anterograde autoradiographic technique in cats. Efferent fibers from the MRF ascend to the globus pallidus, substantia innominata, hypothalamus, subthalamus, and nonspecific associative and relay nuclei of the thalamus. Descending pathways to the conclusion that the cuneiform nucleus is more of a nonspecific structure than an association auditory center. The lateral reticular region had numerous projections to the lateral geniculate body and, together with the parabigeminal nucleus, forms the midbrain visual complex.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 17, No. 5, pp. 646–652, September–October, 1985.     

The effects of DBS patterns on basal ganglia activity and thalamic relay

Thalamic neurons receive inputs from cortex and their responses are modulated by the basal ganglia (BG). This modulation is necessary to properly relay cortical inputs back to cortex and downstream to the brain stem when movements are planned. In Parkinson's disease (PD), the BG input to thalamus becomes pathological and relay of motor-related cortical inputs is compromised, thereby impairing movements. However, high frequency (HF) deep brain stimulation (DBS) may be used to restore relay reliability, thereby restoring movements in PD patients. Although therapeutic, HF stimulation consumes significant power forcing surgical battery replacements, and may cause adverse side effects. Here, we used a biophysical-based model of the BG-Thalamus motor loop in both healthy and PD conditions to assess whether low frequency stimulation can suppress pathological activity in PD and enable the thalamus to reliably relay movement-related cortical inputs. We administered periodic pulse train DBS waveforms to the sub-thalamic nucleus (STN) with frequencies ranging from 0-140 Hz, and computed statistics that quantified pathological bursting, oscillations, and synchronization in the BG as well as thalamic relay of cortical inputs. We found that none of the frequencies suppressed all pathological activity in BG, though the HF waveforms recovered thalamic reliability. Our rigorous study, however, led us to a novel DBS strategy involving low frequency multi-input phase-shifted DBS, which successfully suppressed pathological symptoms in all BG nuclei and enabled reliable thalamic relay. The neural restoration remained robust to changes in the model parameters characterizing early to late PD stages.     

Discovery of the sources of some descending forebrain systems by the retrograde axonal transport of horseradish peroxidase method

The location of neurons forming fiber systems descending into the brain-stem reticular formation, red nucleus, and relay nuclei of the dorsal columns was studied in cats by the retrograde axonal transport of horseradish peroxidase method. The cortical projection regions, structures of the limbic system, and the hypothalamus were shown to form fiber systems that descend to the brain stem, whereas the orbito-frontal cortex is the chief source of cortico-reticular projections. The possible functional role of these descending systems in the central control of somatic and visceral functions is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 11, No. 3, pp. 218–226, May–June, 1979.     

Bursting as an Effective Relay Mode in a Minimal Thalamic Model

In recent years, accumulating evidence indicates that thalamic bursts are present during wakefulness and participate in information transmission as an effective relay mode with distinctive properties from the tonic activity. Thalamic bursts originate from activation of the low threshold calcium cannels via a local feedback inhibition, exerted by the thalamic reticular neurons upon the relay neurons. This article, examines if this simple mechanism is sufficient to explain the distinctive properties of thalamic bursting as an effective relay mode. A minimal model of thalamic circuit composed of a retinal spike train, a relay neuron and a reticular neuron is simulated to generate the tonic and burst firing modes. The integrate-and-fire-or-burst model is used to simulate the neurons. After discriminating the burst events with criteria based on inter-spike-intervals, statistical indices show that the bursts of the minimal model are stereotypic events. The relation between the rate of bursts and the parameters of the input spike train demonstrates marked nonlinearities. Burst response is shown to be selective to spike-silence-spike sequences in the input spike train. Moreover, burst events represent the input more reliably than the tonic spike in a considerable range of the parameters of the model. In conclusion, many of the distinctive properties of thalamic bursts such as stereotypy, nonlinear dependence on the sensory stimulus, feature selectivity and reliability are reproducible in the minimal model. Furthermore, the minimal model predicts that while the bursts are more frequent in the spike train of the off-center X relay neurons (corresponding to off-center X retinal ganglion cells), they are more reliable when generated by the on-center ones (corresponding to on-center X ganglion cells).     

Redox status of the eye lens: a regional study

The aim of this work was to study the regional variation of some antioxidant systems in calf lens. Specific lens regions of nearly same age were obtained by a microsectioning technique, and the concentration of reduced and oxidized glutathione, protein sulfhydryl groups, and iron were measured in each lens region. The concentration of reduced glutathione, the major redox buffer in lens, exponentially decreased from the cortical regions to the nucleus. In contrast, the concentration of protein sulfhydryl groups gradually increased from the cortex toward the nucleus. The protein-bound disulfides remained constant throughout the lens. Iron was concentrated in the outer cortical region. The results show that the most dynamic redox-active zone in the lens is the subcapsular cortical region where the oxidant flux meets a highly reducing environment containing a potent redox catalyst.     

Redox status of the eye lens

The aim of this work was to study the regional variation of some antioxidant systems in calf lens. Specific lens regions of nearly same age were obtained by a microsectioning technique, and the concentration of reduced and oxidized glutathione, protein sulfhydryl groups and iron were measured in each lens region. The concentration of reduced glutathione, the major redox buffer in lens, exponentially decreased from the cortical regions to the nucleus. In contrast, the concentration of protein sulfhydryl groups gradually increased from the cortex toward the nucleus. The protein-bound disulfides remained constant throughout the lens. Iron was concentrated in the outer cortical region. The results show that the most dynamic redox-active zone in the lens is the subcapsular cortical region where the oxidant flux meets a highly reducing environment containing a potent redox catalyst.