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It has previously been shown that cerebello-thalamo-cortical (CTC) hyperconnectivity is likely a state-independent neural signature for psychosis. However, the potential clinical utility of this change has not yet been evaluated. Here, using fMRI and clinical data acquired from 214 untreated first-episode patients with schizophrenia (62 of whom were clinically followed-up at least once at the 12th and 24th months after treatment initiation) and 179 healthy controls, we investigated whether CTC hyperconnectivity would serve as an individualized biomarker for diagnostic classification and prediction of long-term treatment outcome. Cross-validated LASSO regression was conducted to estimate the accuracy of baseline CTC connectivity for patient-control classification, with the generalizability of classification performance tested in an independent sample including 42 untreated first-episode patients and 65 controls. Associations between baseline CTC connectivity and clinical outcomes were evaluated using linear mixed model and leave-one-out cross validation. We found significantly increased baseline CTC connectivity in patients (P = .01), which remained stable after treatment. Measures of CTC connectivity discriminated patients from controls with moderate classification accuracy (AUC = 0.68, P < .001), and the classification model had good generalizability in the independent sample (AUC = 0.70, P < .001). Higher CTC connectivity at baseline significantly predicted poorer long-term symptom reduction in negative symptoms (R = 0.31, P = .01) but not positive or general symptoms. These findings provide initial evidence for the putative “CTC hyperconnectivity” anomaly as an individualized diagnostic and prognostic biomarker for schizophrenia, and highlight the potential of this measure in precision psychiatry.

Objective We designed a longitudinal cohort study on People with Epilepsy (PwE) with the aim of assessing the effect of Perampanel (PER) on cortico-subcortical networks, as measured by high-frequency oscillations of somatosensory evoked potentials (SEP-HFOs). SEP-HFOs measure the excitability of both thalamo-cortical projections (early HFOs) and intracortical GABAergic synapses (late HFOs), thus they could be used to study the anti-glutamatergic action of PER, a selective antagonist of the AMPA receptor. Methods 15 PwE eligible for PER add-on therapy, were enrolled prospectively. Subjects underwent SEPs recording from the dominant hand at two times: PwET0 (baseline, before PER titration) and PwET1 (therapeutic dose of 4 mg). HFOs were obtained by filtering N20 scalp response in the 400–800 Hz range. Patients were compared with a normative population of 15 healthy controls (HC) matched for age and sex. Results We found a significant reduction of Total HFOs and mostly early HFOs area between PwET0 and PwET1 (p = 0.05 and p = 0.045 respectively) and between HC and PwET1 (p = 0.01). Furthermore, we found a significant reduction of P24/N24 Amplitude between PwET0 and HC and between PwET0 and PwET1 (p = 0.006 and p = 0.032, respectively). Conclusions Introduction of PER as add-on therapy reduced the area of total HFOs, acting mainly on the early burst, related to thalamo-cortical pathways. Furthermore P24/N24 amplitude, which seems to reflect a form of cortico-subcortical integration, resulted increased in PwE at T0 and normalized at T1. Significance Our findings suggest that PER acts on cortico-subcortical excitability. This could explain the broad spectrum of PER and its success in forms of epilepsy characterized by thalamo-cortical hyperexcitability.

The neurobiology of environmentally induced stereotypic behaviours (SBs) (e.g., pacing in zoo carnivores, crib-biting in horses, tail chasing in dogs) is hypothesized to involve altered functioning within the basal ganglia (‘Basal Ganglia (BG) Pathways Hypotheses’) and/or between the basal ganglia and cortex (‘Cortico-Striatal-Thalamo-Cortical (CSTC) Circuits Hypotheses’). We review four decades of relevant studies, critically assessing support for both hypotheses. Currently no BG Pathways or CSTC Circuits hypothesis is fully supported. While some results are partially consistent with some hypotheses (decreased subthalamic nucleus activity in deer mice and C58 mice); others (nucleus accumbens activity in mink and C57 mice) seem to reflect individual differences in SB, but not environmental effects. Yet others can be tentatively rejected: neither elevated striatal dopamine nor the cortico-striatal connection of the sensorimotor circuit seem to be involved for most species studied to date. Further research is now important for understanding the impact of captivity on animals’ functioning.

The dentato-rubro-thalamo-cortical tract (DRTC) is the main outflow pathway of the cerebellum, contributing to a finely balanced corticocerebellar loop involved in cognitive and sensorimotor functions. Damage to the DRTC has been implicated in cerebellar mutism syndrome seen in up to 25% of children after cerebellar tumor resection. Multi-shell diffusion MRI (dMRI) combined with quantitative constrained spherical deconvolution tractography and multi-compartment spherical mean technique modeling was used to explore the frontocerebellar connections and microstructural signature of the DRTC in 30 healthy children. The highest density of DRTC connections were to the precentral (M1) and superior frontal gyri (F1), and from cerebellar lobules I–IV and IX. The first evidence of a topographic organization of anterograde projections to the frontal cortex at the level of the superior cerebellar peduncle (SCP) is demonstrated, with streamlines terminating in F1 lying dorsomedially in the SCP compared to those terminating in M1. The orientation dispersion entropy of DRTC regions appears to exhibit greater contrast than that shown by fractional anisotropy. Analysis of a separate reproducibility cohort demonstrates good consistency in the dMRI metrics described. These novel anatomical insights into this well-studied pathway may prove to be of clinical relevance in the surgical resection of cerebellar tumors.

A complete picture of how subcortical nodes, such as the thalamus, exert directional influence on large-scale brain network interactions across age remains elusive. Using directed functional connectivity and weighted net causal outflow on resting-state fMRI data, we provide evidence of a comprehensive reorganization within and between neurocognitive networks (default mode: DMN, salience: SN, and central executive: CEN) associated with age and thalamocortical interactions. We hypothesize that thalamus subserves both modality-specific and integrative hub role in organizing causal weighted outflow among large-scale neurocognitive networks. To this end, we observe that within-network directed functional connectivity is driven by thalamus and progressively weakens with age. Secondly, we find that age-associated increase in between CEN- and DMN-directed functional connectivity is driven by both the SN and the thalamus. Furthermore, left and right thalami act as a causal integrative hub exhibiting substantial interactions with neurocognitive networks with aging and play a crucial role in reconfiguring network outflow. Notably, these results were largely replicated on an independent dataset of matched young and old individuals. Our findings strengthen the hypothesis that the thalamus is a key causal hub balancing both within- and between-network connectivity associated with age and maintenance of cognitive functioning with aging.

Background: Diffusion-weighted 1H magnetic resonance spectroscopy (DW-MRS) allows to quantify creatine-phosphocreatine brain diffusivity (ADC(tCr)), whose reduction in multiple sclerosis (MS) has been proposed as a proxy of energy dysfunction. Objective: To investigate whether thalamic ADC(tCr) changes are associated with thalamo-cortical tract damage in MS. Methods: Twenty patients with MS and 13 healthy controls (HC) were enrolled in a DW-MRS and DW imaging (DWI) study. From DW-MRS, ADC(tCr) and total N-acetyl-aspartate diffusivity (ADC(tNAA)) were extracted in the thalami. Three thalamo-cortical tracts and one non-thalamic control tract were reconstructed from DWI. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD), reflecting microstructural integrity, were extracted for each tract. Associations between thalamic ADC(tCr) and tract metrics were assessed using linear regression models adjusting for age, sex, thalamic volume, thalamic ADC(tNAA), and tract-specific lesion load. Results: Lower thalamic ADC(tCr) was associated with higher MD and RD of thalamo-cortical projections in MS (MD: p = 0.029; RD: p = 0.017), but not in HC (MD: p = 0.625, interaction term between thalamic ADC(tCr) and group = 0.019; RD: p = 0.320, interaction term = 0.05). Thalamic ADC(tCr) was not associated with microstructural changes of the control tract. Conclusion: Reduced thalamic ADC(tCr) correlates with thalamo-cortical tract damage in MS, showing that pathologic changes in thalamic energy metabolism are associated with structural degeneration of connected fibers.

Recent studies of the neurobiology of the dorsal frontal cortex (FC) of the ferret have illuminated its key role in the attention network, top-down cognitive control of sensory processing, and goal directed behavior. To elucidate the neuroanatomical regions of the dorsal FC, and delineate the boundary between premotor cortex (PMC) and dorsal prefrontal cortex (dPFC), we placed retrograde tracers in adult ferret dorsal FC anterior to primary motor cortex and analyzed thalamo-cortical connectivity. Cyto- and myeloarchitectural differences across dorsal FC and the distinctive projection patterns from thalamic nuclei, especially from the subnuclei of the medial dorsal (MD) nucleus and the ventral thalamic nuclear group, make it possible to clearly differentiate three separate dorsal FC fields anterior to primary motor cortex: polar dPFC (dPFCpol), dPFC, and PMC. Based on the thalamic connectivity, there is a striking similarity of the ferret’s dorsal FC fields with other species. This possible homology opens up new questions for future comparative neuroanatomical and functional studies.

Recognition of previously encountered stimuli and their associated spatial and temporal information depends on neural activity within a brain-wide network in which the CA1 region of the hippocampus, nucleus reuniens of the thalamus (NRe) and medial prefrontal cortex (mPFC) are key nodes. However, the pathways crucial for coordinating activity during memory encoding and/or retrieval phases have been little explored. Here we opto- or chemo associative recognition memory. We discovered that encoding, but not retrieval depended on the CA1 to mPFC and NRe to mPFC projections. In contrast, retrieval depended on the mPFC to NRe projection. Interestingly the NRe to CA1 pathway was required for both memory phases. Our findings therefore reveal that encoding and retrieval engage dissociable sub-networks within a hippocampal-thalamo-cortical recognition memory circuit in order to enable binding of recent and related information, whilst ensuring a separation of processing.

Contains fulltext : 237073.pdf (Publisher’s version ) (Closed access) Introduction: The thalamus, a heterogeneous brain structure, is involved in the generation of sleep related thalamo-cortical oscillations. Higher-order nuclei might possess a distinct function compared to first-order nuclei in brain communication. Here it is investigated whether this distinction can also be found during the process of falling asleep and deepening of slow-wave-sleep. Methods: A non-linear version of Granger-Causality was used to describe changes in directed network activity between somatosensory-cortex and rostral and caudal reticular-thalamic-nucleus, the higher-order posterior- and anterior- thalamic nuclei and the first-order ventral-postero-medial thalamic nucleus as assessed in LFP recordings acquired during passive-wakefulness (PW), light and deep slow-wave sleep (LSWS, DSWS) in freely behaving rats. Surrogate statistics were used to assess significance. Results: Decreases in cortico-thalamo-cortical couplings were found. In contrast, multiple increases in intrathalamic couplings were observed. In particular, the rostral reticular-thalamic-nucleus (rRTN) increased its inhibition on the anterior (ATN) from PW to LSWS, and this was further strengthened from LSWS to DSWS. The caudal reticular-thalamic-nucleus (cRTN) increased its coupling to VPM and PO from PW to LSWS, but the coupling from cRTN to VPM weakened at the transition from LSWS to DSWS while its coupling to PO strengthened. Furthermore, intra-RTN coupling from PW to LSWS was differently changed compared to the change from LSWS to DSWS. Discussion: It can be inferred that higher-order (ATN and PO) and first-order nuclei (VPM) are differentially inhibited during DSWS, which might be relevant for a proper functioning of sleep related processes. 10 p.

Cortical projections to the thalamus arise from corticothalamic (CT) neurons in layer 6 and pyramidal tract-type (PT) neurons in layer 5B. We dissected the excitatory synaptic connections in the somatosensory thalamus formed by CT and PT neurons of the primary somatosensory (S1) cortex, focusing on mouse forelimb S1. Mice of both sexes were studied. The CT neurons in S1 synaptically excited S1-projecting thalamocortical (TC) neurons in subregions of both the ventral posterior lateral and posterior (PO) nuclei, forming a pair of recurrent cortico-thalamo-cortical (C-T-C) loops. The PT neurons in S1 also formed a recurrent loop with S1-projecting TC neurons in the same subregion of the PO. The PT neurons in the adjacent primary motor (M1) cortex formed a separate recurrent loop with M1-projecting TC neurons in a nearby subregion of the PO. Collectively, our results reveal that C-T-C circuits of mouse forelimb S1 are primarily organized as multiple cortical cell-type-specific and thalamic subnucleus-specific recurrent loops, with both CT and PT neurons providing the strongest excitatory input to TC neurons that project back to S1. The findings, together with those of related studies of C-T-C circuits, thus suggest that recurrently projecting thalamocortical neurons are the principal targets of cortical excitatory input to the mouse somatosensory and motor thalamus.SIGNIFICANCE STATEMENTBidirectional cortical communication with the thalamus is considered an important aspect of sensorimotor integration for active touch in the somatosensory system, but the cellular organization of the circuits mediating this process is not well understood. We used an approach combining cell-type-specific anterograde optogenetic excitation with single-cell recordings targeted to retrogradely labeled thalamocortical neurons to dissect these circuits. The findings reveal a consistent pattern: cortical projections to the somatosensory thalamus target thalamocortical neurons that project back to the same cortical area. Commonalities of these findings to previous descriptions of related circuits in other areas suggest that cortico-thalamo-cortical circuits may generally be organized primarily as recurrent loops.

In the theory of visual attention (TVA), it is suggested that objects in a visual scene compete for representation in a visual short-term memory (vSTM) store. The race towards the store is assumed to be biased by top-down controlled weighting of the objects according to their task relevance. Only objects that reach the store before its capacity limitation is reached are represented consciously in a given instant. TVA-based computational modeling of participants' performance in whole- and partial-report tasks permits independent parameters of individual efficiency of top-down control α and vSTM storage capacity K to be extracted. The neural interpretation of the TVA proposes recurrent loops between the posterior thalamus and posterior visual cortices to be relevant for generating attentional weights for competing objects and for maintaining selected objects in vSTM. Accordingly, we tested whether structural connectivity between posterior thalamus and occipital cortices (PT-OC) is associated with estimates of top-down control and vSTM capacity. We applied whole- and partial-report tasks and probabilistic tractography in a sample of 37 healthy adults. We found vSTM capacity K to be associated with left PT-OC structural connectivity and a trend-wise relation between top-down control α and right PT-OC structural connectivity. These findings support the assumption of the relevance of thalamic structures and their connections to visual cortex for top-down control and vSTM capacity.

The posterior hypothalamic nucleus (PH) has extensive anatomical connections to motor, cognitive, visceral, and homeostatic areas of the brain and serves as a crucial subcortical modulator of behaviour. Previous studies have demonstrated that deep brain stimulation (DBS) of this area can lead to powerful activation of motor behaviour, overcoming two rodent models of parkinsonian akinesia by increasing neocortical excitability. However, it is unclear how the PH may mediate this increase in neocortical excitability. In the present study, we examined the role of the thalamus in the PH-DBS mediated increase in neocortical excitability. In urethane anaesthetized animals, we demonstrate that PH-DBS elicits increased spiking activity in the motor thalamus (VL) that receives direct afferents from the PH that precedes the increase in spiking activity in the corresponding motor cortex. In contrast, in the somatosensory thalamus (VPM) where PH afferents are sparse at best, PH-DBS did not elicit an increase in thalamic activity despite of a slight increase in the corresponding somatosensory cortical spiking. Current source density analyses suggest a thalamo-cortical mechanism for motor cortex activation whereas a cortico-cortical activation mechanism is involved in somatosensory cortical activation. Inactivation of the VL resulted in the abolition of motor cortex spiking despite of the persistence of desynchronized field potential activity. Collectively, these data suggest indirect orthodromic activation of PH output fibres to the thalamus mediates increased neocortical excitation, which may spread through cortico-cortical connections and lead to an increase in integrated, non-stereotypical motor behaviour.

The interaction between the thalamus and sensory cortex plays critical roles in sensory processing. Previous studies have revealed pathway-specific synaptic properties of thalamo-cortical connections. However, few studies to date have investigated how each pathway routes moment-to-moment information. Here, we simultaneously recorded neural activity in the auditory thalamus (or ventral division of the medial geniculate body; MGv) and primary auditory cortex (A1) with a laminar resolution in anesthetized rats. Transfer entropy (TE) was used as an information theoretic measure to operationalize “information flow”. Our analyses confirmed that communication between the thalamus and cortex was strengthened during presentation of auditory stimuli. In the resting state, thalamo-cortical communications almost disappeared, whereas cortico-cortical communications were strengthened. The predominant source of information was the MGv at the onset of stimulus presentation and layer 5 during spontaneous activity. In turn, MGv was the major recipient of information from layer 6. TE suggested that a small but significant population of MGv-to-A1 pairs was “information-bearing,” whereas A1-to-MGv pairs typically exhibiting small effects played modulatory roles. These results highlight the capability of TE analyses to unlock novel avenues for bridging the gap between well-established anatomical knowledge of canonical microcircuits and physiological correlates via the concept of dynamic information flow.

Functions of the neocortex depend on its bidirectional communication with the thalamus, via cortico-thalamo-cortical (CTC) loops. Recent work dissecting the synaptic connectivity in these loops is generating a clearer picture of their cellular organization. Here, we review findings across sensory, motor and cognitive areas, focusing on patterns of cell type-specific synaptic connections between the major types of cortical and thalamic neurons. We outline simple and complex CTC loops, and note features of these loops that appear to be general versus specialized. CTC loops are tightly interlinked with local cortical and corticocortical (CC) circuits, forming extended chains of loops that are probably critical for communication across hierarchically organized cerebral networks. Such CTC-CC loop chains appear to constitute a modular unit of organization, serving as scaffolding for area-specific structural and functional modifications. Inhibitory neurons and circuits are embedded throughout CTC loops, shaping the flow of excitation. We consider recent findings in the context of established CTC and CC circuit models, and highlight current efforts to pinpoint cell type-specific mechanisms in CTC loops involved in consciousness and perception. As pieces of the connectivity puzzle fall increasingly into place, this knowledge can guide further efforts to understand structure-function relationships in CTC loops.

The idea that the thalamo-cortical system is the crucial constituent of the neurobiological mechanisms of consciousness has a long history. For the last few decades, however, consciousness research has to a large extent overlooked the interplay between the cortex and thalamus. Here we revive an integrated view of the neurobiology of consciousness by presenting and discussing several recent major findings about the role of the thalamocortical interactions in consciousness. Based on these findings we propose a specific cellular mechanism how thalamic nuclei modulate the integration of different processing streams within single cortical pyramidal neurons. This theory is inspired by recent work done in rodents, but it integrates decades of work conducted on various species. We illustrate how this new view readily explains various properties and experimental phenomena associated with conscious experience. We discuss the implications of this idea and some of the experiments that need to be done in order to test it. Our view bridges two long-standing perspectives on the neural mechanisms of consciousness and proposes that cortical and thalamo-cortical processing interact at the level of single pyramidal cells.

Ocular dominance columns correlate with patchy callosal connections in Long Evans rats (Laing et al., 2015). We explored in vivo manganese-enhanced magnetic resonance imaging (MEMRI) as a possible strategy for longitudinal studies of plastic changes in the retino-thalamo-cortical and callosal pathways. MnCl 2 was injected either intraocularly or intracortically to label these pathways, respectively. The transport of the paramagnetic ion Mn 2+ was evaluated by comparing images acquired both before and 36 or 12 hours after intraocular or cortical injections, respectively. Images were acquired on a 3T magnet (Philips Achieva, Philips Healthcare, Andover, MA), using a custom surface coil and a T1-weighted MPRAGE image sequence (TR/TE = 23/11 ms; Ti=1000 ms; FA= 10 deg acquired matrix 432x432 mm over 118 slices, voxel size 0.11x0.11x0.2 mm 3). To validate the transport of Mn 2+, each animal also received either an intraocular injection of the transneuronal tracer WGA-HRP, or cortical injections of HRP. Following monocular injections of MnCl 2, MRI images showed significant, bilateral accumulations of Mn 2+ in regions of the SC, LGN and visual cortex that corresponded with regions labeled with HRP. In adult rats monocularly enucleated at birth, we injected MnCl 2 in the hemisphere contralateral to the remaining eye in an attempt to detect anomalies reported previously in the callosal pattern ipsilateral to the remaining eye. After the scans, the hemisphere injected with MnCl 2was injected with HRP. MRI images revealed Mn 2+ patterns that closely resembled the callosal patterns demonstrated with HRP in the same animal. Our results suggest that both transneuronal retino-thalamo-cortical, as well as cortico-cortical transport of Mn 2+ provide potentially useful strategies for longitudinal studies of plastic changes in these pathways.

Background: The pathophysiology of patients with dry eye disease (DED) is associated with abnormal functional connectivity (FC). The present study aims to probe alterations of voxel-wise brain-wide FC in patient with DED at rest in an unbiased way. Method: A total of 20 patients with DED and 23 controls matched by age, sex, and years of education underwent resting-state functional magnetic resonance imaging scans. Global-brain FC (GFC) was adopted to analyze the images. Support vector machine (SVM) was utilized to differentiate the patients from the controls. Results: Compared with the controls, patients with DED exhibited decreased GFC in the right cerebellum lobule VIII/inferior semi-lunar lobule and left thalamus that belonged to the cerebello-thalamo-cortical network. The GFC values in the left thalamus were positively correlated to the illness duration (r = 0.589, p = 0.006) in the patients. Decreased GFC values in the left thalamus could be used to discriminate the patients from the controls with optimal accuracy, sensitivity and specificity (88.37, 85.00, and 91.30%). Conclusions: Our findings indicate that decreased GFC in the brain regions associated with cerebello-thalamo-cortical network may provide a new insight for understanding the pathological changes of FC in DED. GFC values in the left thalamus may be utilized as a potential biomarker to identify the patients from the controls.

Large scale brain models encompassing cortico-cortical, thalamo-cortical and basal ganglia processing are fundamental to understand the brain as an integrated system in healthy and disease conditions but are complex to analyze and interpret. Neuronal processes are typically segmented by region and modality in order to explain an experimental observation at a given scale, but integrative frameworks linking scales and modalities are scarce. Here, we present a set of functional requirements used to evaluate the recently developed large-scale brain model against a learning task involving coordinated learning between cortical and sub-cortical systems. The original Information Based Exchange Brain model (IBEx) is decomposed into functionally relevant subsystems, and each subsystem is analyzed and tuned independently and with regard to its relevant functional requirements. Intermediate conclusions are made for each subsystems according to the constraints imposed by these requirements. Subsystems are then re-introduced into the global framework. The relationship between the global framework and phenotypes associated with Huntington’s disease is then discussed and the framework considered in the context of other state-of-the-art integrative brain models.

Electroencephalography (EEG) spikes and focal epileptic seizures are generated in circumscribed cerebral networks that have been insufficiently described. For precise time and spatial domain network characterization, we applied in patients with focal epilepsy dense array 256-channel EEG recordings with causal connectivity estimation by using time-resolved partial directed coherence and 3T-magnetic resonance imaging-derived cortical and thalamus integrity reconstruction. Before spike generation, significant theta and alpha bands driven information flows alterations were noted from both temporal and frontal lobes to the thalamus and from the thalamus to the frontal lobe. Medial dorsal and ventral anterior nuclei of the thalamus were delimited as possible pacemakers. Markedly reduced thalamic volumes and impaired cortical integrity in widespread areas predicted the altered information flows. Our data reveal distinct patterns of connectivity involving the thalamus and frontal cortex that are both directly and causally involved in spike generation. These structures might play an essential role in epileptogenesis and could be targeted in future therapeutic approaches.

It has been reported that cross-frequency interactions may play an important role in local processing within thalamus and neocortex, as well as information transfer between subcortical and cortico-cortical brain regions. Strong commonalities in rhythmic network properties have been observed across recording techniques and task demands, but strong neuroscientific theories to situate such observations within a unified framework with direct relevance to explain neuropathologies remain scarce. Based on a comprehensive review of animal and human literature, we probe and introduce a neurophysiological framework to explain how coordinated cross-frequency and interregional oscillatory cortical dynamics underlie typical and atypical brain activation, and the formation of distributed functional ensembles supporting cortical networks underpinning perception and cognition. We propose that local regional activation by an external stimulus via a sensory pathway entails (1) attenuated alpha (8-14 Hz) and increased theta (4-8 Hz) and gamma (30-50 Hz) oscillatory activity, and (2) increased interactions among theta and gamma rhythms. These local dynamics also mediate the integration of activated neural populations into large-scale functional assemblies through neuronal synchronization. This comprehensive perspective into the animal and human literature indicates a further thinking beyond synchrony and connectivity and the readiness for more hypothesis-driven research and modeling toward unified principles of thalamo-cortical processing. We further introduced such a possible framework: "The ATG switch". We also discussed evidence that alpha-theta-gamma dynamics emerging from thalamocortical interactions may be implicated and disrupted in numerous neurological and neuropsychiatric conditions.

Across a range of motor and cognitive tasks, cortical activity can be accurately described by low-dimensional dynamics unfolding from specific initial conditions on every trial. These “preparatory states” largely determine the subsequent evolution of both neural activity and behavior, and their importance raises questions regarding how they are, or ought to be, set. Here, we formulate motor preparation as optimal anticipatory control of future movements and show that the solution requires a form of internal feedback control of cortical circuit dynamics. In contrast to a simple feedforward strategy, feedback control enables fast movement preparation by selectively controlling the cortical state in the small subspace that matters for the upcoming movement. Feedback but not feedforward control explains the orthogonality between preparatory and movement activity observed in reaching monkeys. We propose a circuit model in which optimal preparatory control is implemented as a thalamo-cortical loop gated by the basal ganglia.

Idiopathic normal pressure hydrocephalus (iNPH) is a disorder with unclear pathophysiology. The diagnosis of iNPH is challenging due to its radiological similarity with other neurodegenerative diseases and ischemic subcortical white matter changes. By using Diffusion Tensor Imaging (DTI) we explored differences in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in iNPH patients (before and after a shunt surgery) and healthy individuals (HI) and we correlated the clinical results with DTI parameters. Thirteen consecutive iNPH-patients underwent a pre- and post-operative clinical work-up: 10 m walk time (w10mt) steps (w10ms), TUG-time (TUGt) and steps (TUGs); for cognitive function MMSE. Nine HI were included. DTI was performed before and 3 months after surgery, HI underwent DTI once. DTI differences analyzed by manually placing 12 regions-of-interest. In patients motor and balance function improved significantly after surgery (p = 0.01, p = 0.025). Higher nearly significant FA values found in the patients vs HI pre-operatively in the thalamus (p = 0.07) accompanied by an almost significant lower ADC (p = 0.08). Significantly FA and ADC-values were found between patients and HI in FWM (p = 0.02, p = 0.001) and almost significant (p = 0.057) pre- vs postoperatively. Postoperatively we found a trend towards the HIs FA values and a strong significant negative correlation between FA changes vs. gait results in the FWM (r = -0.7, p = 0.008). Our study gives a clear indication of an ongoing pathological process in the periventricular white matter, especially in the thalamus and in the frontal white matter supporting the hypothesis of a shunt reversible thalamo-cortical circuit dysfunction in iNPH.

The human brain undergoes significant structural and functional changes across the lifespan. Our current understanding of the underlying causal relationships of dynamical changes in functional connectivity with age is limited. On average, functional connectivity within resting-state networks (RSNs) weakens in magnitude, while connections between RSNs tend to increase with age. Recent studies show that effective connectivity within and between large scale resting-state functional networks changes over the healthy lifespan. The vast majority of previous studies have focused primarily on characterizing cortical networks, with little work exploring the influence of subcortical nodes such as the thalamus on large-scale network interactions across the lifespan. Using directed connectivity and weighted net causal outflow measures applied to resting-state fMRI data, we examine the age-related changes in both cortical and thalamocortical causal interactions within and between RSNs. The three core neurocognitive networks from the triple network theory (default mode: DMN, salience: SN, and central executive: CEN) were identified independently using ICA and spatial matching of hub regions with these important RSNs previously reported in the literature. Multivariate granger causal analysis (GCA) was performed to test for directional connectivity and weighted causal outflow between selected nodes of RSNs accounting for thalamo-cortical interactions. Firstly, we observe that within-network causal connections become progressively weaker with age, and network dynamics are substantially reconfigured via strong thalamic drive particularly in the young group. Our findings manifest stronger between-network directional connectivity, which is further strongly mediated by the SN in flexible co-ordination with the CEN, and DMN in the old group compared with the young group. Hence, causal within- and between- triple network connectivity largely reflects age-associated effects of resting-state functional connectivity. Thalamo-cortical causality effects on the triple networks with age were next explored. We discovered that left and right thalamus exhibit substantial interactions with the triple networks and play a crucial role in the reconfiguration of directed connections and within network causal outflow. The SN displayed directed functional connectivity in strongly driving both the CEN and DMN to a greater extent in the older group. Notably, these results were largely replicated on an independent dataset of matched young and old individuals. Our findings based on directed functional connectivity and weighted causal outflow measures strengthen the hypothesis that balancing within and between network connectivity is perhaps critical for the preservation and flexibility of cognitive functioning with aging.

Background Fatigue and fatigability are common symptoms reported by patients affected by Multiple Sclerosis (MS). The pathogenic mechanisms of such symptoms are currently unknown, but increasing evidence suggests that thalamus could play a key-role. High-frequency oscillations (HFOs) are a neurophysiological measure reflecting the activity of thalamo-cortical network. In particular, the early component is generated from thalamic axons while the late part results from neurons located in somatosensory cortex. Objective To investigate the effect of a fatigue-inducing exercise on HFOs and on strength performances in MS patients and healthy controls (HCs). Methods Fifteen patients and fifteen HCs participated in this study. We recorded HFOs from median nerve somatosensory evoked potentials and assessed strength performances, before and after a fatigue-inducing exercise of hand muscles. Results Compared to HCs, after repeated fatiguing tasks, patients showed a significant reduction of early component of HFOs area and a significant increase of late component of HFOs duration. Strength performance declined both in patients and in HCs but remained lower in patients at all time-points. Conclusions HFOs, a neurophysiological marker of thalamo-cortical pathway, are significantly modified by fatiguing tasks in MS patients, in particular the early component that refers to the functionality of thalamic axons.

Animals use auditory cues generated by defensive responses of others to detect impending danger. Here we identify a neural circuit in rats involved in the detection of one such auditory cue, the cessation of movement-evoked sound resulting from freezing. This circuit comprises the dorsal sub-nucleus of the medial geniculate body (MGD) and downstream areas, the ventral area of the auditory cortex (VA) and the lateral amygdala (LA). This study suggests a role for the auditory offset pathway in processing a natural sound cue of threat.

Objectives Imaging and neurophysiological data shows that the cortical disfunction caused by focal epilepsy is not limited to the epileptic focus, thus raising the modern vision of focal epilepsy as a network disorder. The involvement of deep thalamo-cortical projections in temporal lobe epilepsy is a clear example. We aimed at demonstrating the interictal functional impairment of thalamo-cortical network in drug-naive TLE patients through the study of high frequency oscillations of somatosensory evoked potentials (HF-SEP). Methods Twelve healthy controls (HC; 8 females, 52.2 ± 17.3 years-old) and 12 drug-naive TLE patients (8 females, 55.5 ± 21.5 years-old) underwent bilateral median HF-SEP, recorded by scalp electrodes. Cp3′-Fz and Cp4′-Fz traces were filtered (400–800 Hz) to evidence HF-SEP. Results HF-SEP duration in the affected hemisphere was significantly longer when compared to that of both the unaffected hemisphere and HC hemispheres. No significant inter-hemispheric differences were found in areas, powers and latencies of HF-SEP wavelets. Conclusion Our results demonstrate that TLE induces early interictal functional impairments of the thalamo-cortical network. Significance Our data strongly corroborates the vision of focal epilepsy as a network disorder and offers a new neurophysiological tool to test pharmacological, surgical and neuromodulatory therapies.

BACKGROUND: Our recent study revealed that increased connectivity in the cerebello-thalamo-cortical (CTC) circuitry is a state-independent “trait” alteration that can potentially predict onset of psychosis in clinical high-risk population (Cao et al., 2018). One possible cause of such “trait” change would be genetic predisposition. Here we tested this hypothesis using two independent twin datasets: the Human Connectome Project (HCP) twin sample and the Swedish Schizophrenia Twin Study (STAR). METHODS: The HCP twin sample included a total of 137 healthy twin pairs, each of which received fMRI scans with a battery of eight paradigms. Among these twin pairs, 85 were monozygotic (MZ, age 29.32±3.39 years, 70 males) and 52 were dizygotic (DZ, age 28.50±3.50 years, 52 males). Following the procedure in our prior study (Cao et al., 2018), we constructed whole-brain connectivity matrices using the Power atlas (Power et al., 2011) for each of the eight paradigms. Measures of “cross-paradigm connectivity (CPC)”, representing the shared connectivity patterns across all paradigms, were computed for each individual using principal component analysis. The CPC measures for the previously identified CTC network were subsequently extracted. The similarities of the extracted CPC measures between twin pairs were assessed using intra-class correlation, and the heritability of the CPC measures for the CTC network was estimated by structural equation modeling (SEM). The STAR sample included 40 schizophrenia discordant co-twins (10 MZ (age 43.79±11.94 years, 7 males), 30 DZ (age 51.11±10.07 years, 16 males)) and 32 healthy twins (46.37±6.92 years, 14 males), each assessed with a battery of two fMRI paradigms. Using the same procedure as described above, we extracted the CTC network connectivity measures for each individual and compared the derived measures between the three groups using a linear regression model, in which the genetic distance to schizophrenia, age, sex and head motion were modeled as regressors. RESULTS: The intra-class correlation coefficients for CTC connectivity among MZ and DZ twin pairs in the HCP sample were 0.54 and 0.22, respectively, suggesting a genetic effect. Since the correlation between the MZ twins was larger than twice of that between the DZ twins, we evaluated an ADE model using SEM. The results revealed a heritability of 0.52 (95% CI: 0.36–0.64). Specifically, 52% of the variance in CTC connectivity was attributable to additive genetic effects (a2 = 0.52), and 48% was attributed to unique environmental effects (e2 = 0.48). In contrast, dominant genetic effects were negligible (d2 < 0.001). The further comparison between ADE and AE models confirmed that the AE model provided the best fit for the data (P = 1). A significant linear effect of genetic loading for schizophrenia was observed when examining CTC connectivity among schizophrenia MZ co-twins, DZ co-twins, and healthy twins in the STAR sample (P = 0.045). Specifically, the schizophrenia MZ co-twins showed the highest connectivity values, followed by the DZ co-twins, while the healthy twins had the lowest values, suggesting that the increased connectivity in the CTC circuitry is related to genetic risk of schizophrenia. This effect became even more significant when further including the HCP twin sample (as controls) in the analysis (P = 0.01). DISCUSSION: The findings from two independent twin cohorts have provided converging evidence that CTC hyper-connectivity is likely to be a heritable trait associated with risk for schizophrenia.

BACKGROUND: Although several studies report thalamo-cortical abnormalities in schizophrenia, there is a paucity of functional neuroimaging work in schizotypal personality disorder (SPD) examining these networks despite the advantage of being able to study unmedicated and primarily never-medicated participants. SPD is a schizophrenia spectrum disorder that shares common phenomenological, genetic, and biological characteristics with schizophrenia. METHODS: This presentation will review prior schizophrenia-spectrum work examining thalamo-cortical connectivity and present new fMRI findings in a relatively large demographically-matched spectrum sample with three diagnostic groups: 24 schizophrenia patients, 54 individuals with SPD, and 48 healthy controls (without Axis I or personality disorder diagnosis). Participants received a rigorous structured diagnostic interview, clinical assessments, and a 3T structural MRI and resting-state fMRI scan at Mount Sinai Hospital. Bilateral seed-based analyses were conducted using the whole thalamus as the seed. Group analysis was performed using FSL-FEAT with p-values set to p

Relations between cognitive and cerebello-thalamo-cortical functions in healthy elderly people (65-75 years old) were examined by longitudinal behavioral data. Based on the individually calculated cognitive decline ratio in D-CAT (digit cancelation test) and in LMT (Logical Memory Test) during the period of 11 years, participants were classified into the

The catatonic syndrome is an example of a multifactorial neurobehavioral disorder that causes much morbidity and mortality but also has the potential to unlock the mystery of how motivation and movement interact to produce behavior. In this chapter, an attempt is made to understand better the catatonic syndrome through the lens of neurobiology and neuropathophysiology updated by recent studies in molecular biology, genomics, inflammasomics, neuroimaging, neural network theory, and neuropsychopathology. This will result in a neurostructural model for the catatonic syndrome that centers on paralimbic regions including the anterior and midcingulate cortices, as they interface with striatal and thalamic nodes in the salience decision-making network. Examination of neurologic disorders like the abulic syndrome, which includes in its extreme catatonic form, akinetic mutism, will identify the cingulate cortex and paralimbic neighbors as regions of interest. This exploration has the potential to unlock mysteries of the brain cascade from motivation to movement and to clarify catatonia therapeutics. Such a synthesis may also help us discern meaning inherent in this complex neurobehavioral syndrome.

Schizophrenia has been understood as a network disease with altered functional and structural connectivity in multiple brain networks compatible to the extremely broad spectrum of psychopathological, cognitive and behavioral symptoms in this disorder. When building brain networks, functional and structural networks are typically modelled independently: functional network models are based on temporal correlations among brain regions, whereas structural network models are based on anatomical characteristics. Combining both features may give rise to more realistic and reliable models of brain networks. In this study, we applied a new flexible graph-theoretical-multimodal model called FD (F, the functional connectivity matrix, and D, the structural matrix) to construct brain networks combining functional, structural and topological information of MRI measurements (structural and resting state imaging) to patients with schizophrenia (N=35) and matched healthy individuals (N=41). As a reference condition, the traditional pure functional connectivity (pFC) analysis was carried out. By using the FD model, we found disrupted connectivity in the thalamo-cortical network in schizophrenic patients, whereas the pFC model failed to extract group differences after multiple comparison correction. We interpret this observation as evidence that the FD model is superior to conventional connectivity analysis, by stressing relevant features of the whole brain connectivity including functional, structural and topological signatures. The FD model can be used in future research to model subtle alterations of functional and structural connectivity resulting in pronounced clinical syndromes and major psychiatric disorders. Lastly, FD is not limited to the analysis of resting state fMRI, and can be applied to EEG, MEG etc.

The occurrence of sleep passed through the evolutionary sieve and is widespread in animal species. Sleep is known to be beneficial to cognitive and mnemonic tasks, while chronic sleep deprivation is detrimental. Despite the importance of the phenomenon, a complete understanding of its functions and underlying mechanisms is still lacking. In this paper, we show interesting effects of deep-sleep-like slow oscillation activity on a simplified thalamo-cortical model which is trained to encode, retrieve and classify images of handwritten digits. During slow oscillations, spike-timing-dependent-plasticity (STDP) produces a differential homeostatic process. It is characterized by both a specific unsupervised enhancement of connections among groups of neurons associated to instances of the same class (digit) and a simultaneous down-regulation of stronger synapses created by the training. This hierarchical organization of post-sleep internal representations favours higher performances in retrieval and classification tasks. The mechanism is based on the interaction between top-down cortico-thalamic predictions and bottom-up thalamo-cortical projections during deep-sleep-like slow oscillations. Indeed, when learned patterns are replayed during sleep, cortico-thalamo-cortical connections favour the activation of other neurons coding for similar thalamic inputs, promoting their association. Such mechanism hints at possible applications to artificial learning systems., 11 pages, 5 figures, v5 is the final version published on Scientific Reports journal

Spatial attention is discontinuous, sampling behaviorally relevant locations in theta-rhythmic cycles (3–6 Hz). Underlying this rhythmic sampling are intrinsic theta oscillations in frontal and parietal cortices that provide a clocking mechanism for two alternating attentional states that are associated with either engagement at the presently attended location (and enhanced perceptual sensitivity) or disengagement (and diminished perceptual sensitivity). It has remained unclear, however, how these theta-dependent states are coordinated across the large-scale network that directs spatial attention. The pulvinar is a candidate for such coordination, having been previously shown to regulate cortical activity. We therefore examined pulvino-cortical interactions during theta-rhythmic sampling by simultaneously recording from FEF, LIP, and the pulvinar. Neural activity propagated from (i) pulvinar to cortex during periods of engagement and (ii) from cortex to pulvinar during periods of disengagement. A rhythmic reweighting of pulvino-cortical interactions thus defines functional dissociations in the macaque attention network.

Detecting the direction of an object’s motion is essential for our representation of the visual environment. Visual cortex is one of the main stages in the mammalian nervous system where motion direction may be computed de novo. Experiments and theories indicate that cortical neurons respond selectively to motion direction by combining inputs that provide information about distinct spatial locations with distinct time-delays. Despite the importance of this spatiotemporal offset for direction selectivity its origin and cellular mechanisms are not fully understood. We show that ~80+/−10 thalamic neurons responding with distinct time-courses to stimuli in distinct locations contribute to the excitation of mouse visual cortical neurons during visual stimulation. Integration of thalamic inputs with the appropriate spatiotemporal offset provides cortical neurons with the primordial bias for direction selectivity. These data show how cortical neurons selectively combine the spatiotemporal response diversity of thalamic neurons to extract fundamental features of the visual world.

The exposed surface of the superior parietal lobule in macaque brain contains two architectonically defined areas named PEc and PE. The aim of the present study is the characterization of thalamic afferents of these two areas. For this purpose, retrograde neuronal tracers were injected, or placed in crystal form, in areas PEc and PE. We found that the two areas show a similar pattern of thalamic inputs, mainly originating from Lateral Posterior (LP), Pulvinar (Pul), Ventral Posterior Lateral (VPL), and Ventral Lateral (VL) nuclei, all structures known to be involved in visual, somatosensory, and/or sensorimotor processing. Minor afferents were observed from the Centromedian/Parafascicular complex (CM/PF), Central Lateral (CL), Ventral Anterior (VA), and Medial Dorsal (MD) nuclei. LP and VL were more strongly connected to PEc than to PE, while the other main thalamic inputs to the two areas showed slight differences in strength. The part of the Pul mostly connected with areas PEc and PE was the Medial Pul. No labeled cells were found in the retinotopically organized Lateral and Inferior Pul. In the somatotopically organized VPL and VL nuclei, labeled neurons were mainly found in regions likely to correspond to the trunk and limb representations (in particular the legs). These findings are in line with the sensory-motor nature of areas PEc and PE, and with their putative functional roles, being them suggested to be involved in the preparation and control of limb interaction with the environment, and in locomotion.

Understanding how neurons cooperate to integrate sensory inputs and guide behavior is a fundamental problem in neuroscience. A large body of methods have been developed to study neuronal firing at the single cell and population levels, generally seeking interpretability as well as predictivity. However, these methods are usually confronted with the lack of ground-truth necessary to validate the approach. Here, using neuronal data from the head-direction (HD) system, we present evidence demonstrating how gradient boosted trees, a non-linear and supervised Machine Learning tool, can learn the relationship between behavioral parameters and neuronal responses with high accuracy by optimizing the information rate. Interestingly, and unlike other classes of Machine Learning methods, the intrinsic structure of the trees can be interpreted in relation to behavior (e.g. to recover the tuning curves) or to study how neurons cooperate with their peers in the network. We show how the method, unlike linear analysis, reveals that the coordination in thalamo-cortical circuits is qualitatively the same during wakefulness and sleep, indicating a brain-state independent feed-forward circuit. Machine Learning tools thus open new avenues for benchmarking model-based characterization of spike trains., Author summary The thalamus is a brain structure that relays sensory information to the cortex and mediates cortico-cortical interaction. Unraveling the dialogue between the thalamus and the cortex is thus a central question in neuroscience, with direct implications on our understanding of how the brain operates at the macro scale and of the neuronal basis of brain disorders that possibly result from impaired thalamo-cortical networks, such as absent epilepsy and schizophrenia. Methods that are classically used to study the coordination between neuronal populations are usually sensitive to the ongoing global dynamics of the networks, in particular desynchronized (wakefulness and REM sleep) and synchronized (non-REM sleep) states. They thus fail to capture the underlying temporal coordination. By analyzing recordings of thalamic and cortical neuronal populations of the HD system in freely moving mice during exploration and sleep, we show how a general non-linear encoder captures a brain-state independent temporal coordination where the thalamic neurons leading their cortical targets by 20-50ms in all brain states. This study thus demonstrates how methods that do not assume any models of neuronal activity may be used to reveal important aspects of neuronal dynamics and coordination between brain regions.

Background: Defects in the thalamo-cortical connectivity, specifically the connection between the frontal lobe and the thalamus, have been frequently reported in schizophrenia and it is regarded as a core mechanism in their pathophysiology. The secondary complications in patients arising from the symptoms, such as the effect of medications, hospitalization and social exclusion etc., might have affected the reported anatomical connectivity alteration. Our previous reports of reduced thalamo-orbitofrontal white matter connection in the first-episode psychosis and subjects at clinical high risk, had suggested the thalamo-orbitofrontal connection as an endophenotype1. However, an endophenotype must also co-segregate with illness within families, being present at a higher rate within affected families than in the population. To determine this gap in knowledge, the connectivity of thalamo-cortical white matter in subjects at genetic-high risk for psychosis (GHR), who were defined as unaffected family member who had at least one first degree relative with schizophrenia and one or more affected third degree relatives, were compared to healthy controls (HCs).

Deep brain stimulation alleviates tremor of various origins. Several regions like the ventralis intermediate nucleus of thalamus, the caudal zona incerta, and the posterior subthalamic region are generally targeted. Previous work with fiber tractography has shown the involvement of the cerebello-thalamo-cortical network in tremor control.To report the results of a prospective trial in a group of patients with tremor who underwent post hoc tractographic analysis after treatment with traditional thalamic deep brain stimulation.A total of 11 patients (aged 64 ± 17 years, 6 male) were enrolled (essential tremor [6], Parkinson tremor [3], and myoclonic tremor in myoclonus dystonia [2]). Patients received 1 (3 patients), 2 (7 patients), or 3 (1 patient) quadripolar electrodes. A 32-direction diffusion tensor magnetic resonance imaging sequence was acquired preoperatively. Tractography was processed postoperatively for evaluation and the dentato-rubro-thalamic tract (DRT) was individually tracked. Electrode positions were determined with helical computed tomography. Electric fields (EFs) were simulated according to individual stimulation parameters in a standardized atlas brain space (ICBM-MNI 152).Tremor was reduced in all patients (69.4% mean) on the global (bilateral) tremor score. Effective contacts were located inside or in proximity to the DRT. In moderate tremor reduction (2 patients), the EFs were centered on its anterior border. In good and excellent tremor reduction (9 patients), EFs focused on its center.Deep brain stimulation of the cerebello-thalamo-cortical network reduces tremor. The DRT connects 3 traditional target regions for deep brain stimulation in tremor disease. Tractography techniques can be used to directly visualize the DRT and, therefore, optimize target definition in individual patients.