Efficient mapping of the thalamocortical monosynaptic connectivity in vivo by tangential insertions of high-density electrodes in the cortex.

The thalamus provides the principal input to the cortex and therefore understanding the mechanisms underlying cortical integration of sensory inputs requires to characterize the thalamocortical connectivity in behaving animals. Here, we propose tangential insertions of high-density electrodes into mouse cortical layer 4 as a method to capture the activity of thalamocortical axons simultaneously with their synaptically connected cortical neurons. This technique can reliably monitor multiple parallel thalamic synaptic inputs to cortical neurons, providing an efficient approach to map thalamocortical connectivity in both awake and anesthetized mice.

Propofol disrupts alpha dynamics in functionally distinct thalamocortical networks during loss of consciousness.

During propofol-induced general anesthesia, alpha rhythms measured using electroencephalography undergo a striking shift from posterior to anterior, termed anteriorization, where the ubiquitous waking alpha is lost and a frontal alpha emerges. The functional significance of alpha anteriorization and the precise brain regions contributing to the phenomenon are a mystery. While posterior alpha is thought to be generated by thalamocortical circuits connecting nuclei of the sensory thalamus with their cortical partners, the thalamic origins of the propofol-induced alpha remain poorly understood. Here, we used human intracranial recordings to identify regions in sensory cortices where propofol attenuates a coherent alpha network, distinct from those in the frontal cortex where it amplifies coherent alpha and beta activities. We then performed diffusion tractography between these identified regions and individual thalamic nuclei to show that the opposing dynamics of anteriorization occur within two distinct thalamocortical networks. We found that propofol disrupted a posterior alpha network structurally connected with nuclei in the sensory and sensory associational regions of the thalamus. At the same time, propofol induced a coherent alpha oscillation within prefrontal cortical areas that were connected with thalamic nuclei involved in cognition, such as the mediodorsal nucleus. The cortical and thalamic anatomy involved, as well as their known functional roles, suggests multiple means by which propofol dismantles sensory and cognitive processes to achieve loss of consciousness.

Rapid synaptic and gamma rhythm signature of mouse critical period plasticity.

Early-life experience enduringly sculpts thalamocortical (TC) axons and sensory processing. Here, we identify the very first synaptic targets that initiate critical period plasticity, heralded by altered cortical oscillations. Monocular deprivation (MD) acutely induced a transient (<3 h) peak in EEG γ-power (~40 Hz) specifically within the visual cortex, but only when the critical period was open (juvenile mice or adults after dark-rearing, Lynx1-deletion, or diazepam-rescued GAD65-deficiency). Rapid TC input loss onto parvalbumin-expressing (PV) inhibitory interneurons (but not onto nearby pyramidal cells) was observed within hours of MD in a TC slice preserving the visual pathway - again once critical periods opened. Computational TC modeling of the emergent γ-rhythm in response to MD delineated a cortical interneuronal gamma (ING) rhythm in networks of PV-cells bearing gap junctions at the start of the critical period. The ING rhythm effectively dissociated thalamic input from cortical spiking, leading to rapid loss of previously strong TC-to-PV connections through standard spike-timing-dependent plasticity rules. As a consequence, previously silent TC-to-PV connections could strengthen on a slower timescale, capturing the gradually increasing γ-frequency and eventual fade-out over time. Thus, ING enables cortical dynamics to transition from being dominated by the strongest TC input to one that senses the statistics of population TC input after MD. Taken together, our findings reveal the initial synaptic events underlying critical period plasticity and suggest that the fleeting ING accompanying a brief sensory perturbation may serve as a robust readout of TC network state with which to probe developmental trajectories.

Visual Corticotectal Neurons in Awake Rabbits: Receptive Fields and Driving Monosynaptic Thalamocortical Inputs.

The superior colliculus receives powerful synaptic inputs from corticotectal neurons in the visual cortex. The function of these corticotectal neurons remains largely unknown due to a limited understanding of their response properties and connectivity. Here, we use antidromic methods to identify corticotectal neurons in awake male and female rabbits, and measure their axonal conduction times, thalamic inputs and receptive field properties. All corticotectal neurons responded to sinusoidal drifting gratings with a nonlinear (nonsinusoidal) increase in mean firing rate but showed pronounced differences in their ON-OFF receptive field structures that we classified into three groups, Cx, S2, and S1. Cx receptive fields had highly overlapping ON and OFF subfields as classical complex cells, S2 had largely separated ON and OFF subfields as classical simple cells, and S1 had a single ON or OFF subfield. Thus, all corticotectal neurons are homogeneous in their nonlinear spatial summation but very heterogeneous in their spatial integration of ON and OFF inputs. The Cx type had the fastest conducting axons, the highest spontaneous activity, and the strongest and fastest visual responses. The S2 type had the highest orientation selectivity, and the S1 type had the slowest conducting axons. Moreover, our cross-correlation analyses found that a subpopulation of corticotectal neurons with very fast conducting axons and high spontaneous firing rates (largely "Cx" type) receives monosynaptic input from retinotopically aligned thalamic neurons. This previously unrecognized fast-conducting thalamic-mediated corticotectal pathway may provide specialized information to superior colliculus and prime recipient neurons for subsequent corticotectal or retinal synaptic input.

Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity.

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PV grm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.

Dysfunction of thalamocortical circuits in early-onset schizophrenia.

Previous studies have demonstrated that the thalamus is involved in multiple functional circuits in participants with schizophrenia. However, less is known about the thalamocortical circuit in the rare subtype of early-onset schizophrenia. A total of 110 participants with early-onset schizophrenia (47 antipsychotic-naive patients) and 70 matched healthy controls were recruited and underwent resting-state functional and diffusion-weighted magnetic resonance imaging scans. A data-driven parcellation method that combined the high spatial resolution of diffusion magnetic resonance imaging and the high sensitivity of functional magnetic resonance imaging was used to divide the thalamus. Next, the functional connectivity between each thalamic subdivision and the cortex/cerebellum was investigated. Compared to healthy controls, individuals with early-onset schizophrenia exhibited hypoconnectivity between subdivisions of the thalamus and the frontoparietal network, visual network, ventral attention network, somatomotor network and cerebellum, and hyperconnectivity between subdivisions of thalamus and the parahippocampal and temporal gyrus, which were included in limbic network. The functional connectivity between the right posterior cingulate cortex and 1 subdivision of the thalamus (region of interest 1) was positively correlated with the general psychopathology scale score. This study showed that the specific thalamocortical dysconnection in individuals with early-onset schizophrenia involves the prefrontal, auditory and visual cortices, and cerebellum. This study identified thalamocortical connectivity as a potential biomarker and treatment target for early-onset schizophrenia.

A layered microcircuit model of somatosensory cortex with three interneuron types and cell-type-specific short-term plasticity.

Three major types of GABAergic interneurons, parvalbumin-, somatostatin-, and vasoactive intestinal peptide-expressing (PV, SOM, VIP) cells, play critical but distinct roles in the cortical microcircuitry. Their specific electrophysiology and connectivity shape their inhibitory functions. To study the network dynamics and signal processing specific to these cell types in the cerebral cortex, we developed a multi-layer model incorporating biologically realistic interneuron parameters from rodent somatosensory cortex. The model is fitted to in vivo data on cell-type-specific population firing rates. With a protocol of cell-type-specific stimulation, network responses when activating different neuron types are examined. The model reproduces the experimentally observed inhibitory effects of PV and SOM cells and disinhibitory effect of VIP cells on excitatory cells. We further create a version of the model incorporating cell-type-specific short-term synaptic plasticity (STP). While the ongoing activity with and without STP is similar, STP modulates the responses of Exc, SOM, and VIP cells to cell-type-specific stimulation, presumably by changing the dominant inhibitory pathways. With slight adjustments, the model also reproduces sensory responses of specific interneuron types recorded in vivo. Our model provides predictions on network dynamics involving cell-type-specific short-term plasticity and can serve to explore the computational roles of inhibitory interneurons in sensory functions.

Thalamocortical axons regulate neurogenesis and laminar fates in the early sensory cortex.

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons are required for the production and specification of the proper number of layer 4 neurons in primary sensory areas by the neonatal stage. Part of these area-specific roles is played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.

Conserved patterns of functional organization between cortex and thalamus in mice.

Higher-order thalamic nuclei contribute to sensory processing via projections to primary and higher cerebral cortical areas, but it is unknown which of their cortical and subcortical inputs contribute to their distinct output pathways. We used subpopulation specific viral strategies in mice to anatomically and physiologically dissect pathways of the higher-order thalamic nuclei of the somatosensory and visual systems (the posterior medial nucleus and pulvinar). Employing a complementary optogenetics and electrical stimulation strategy, we show that synapses in cortex from higher-order thalamus have functionally divergent properties in primary vs. higher cortical areas. Higher-order thalamic projections onto excitatory targets in S1 and V1 were weakly modulatory, while projections to S2 and higher visual areas were strong drivers of postsynaptic targets. Then, using transsynaptic tracing verified by optogenetics to map inputs to higher-order thalamus, we show that posterior medial nucleus cells projecting to S1 are driven by neurons in layer 5 of S1, S2, and M1 and that pulvinar cells projecting to V1 are driven by neurons in layer 5 of V1 and higher visual areas. Therefore, in both systems, layer 5 of primary and higher cortical areas drives transthalamic feedback modulation of primary sensory cortex through higher-order thalamus. These results highlight conserved organization that may be shared by other thalamocortical circuitry. They also support the hypothesis that direct corticocortical projections in the brain are paralleled by transthalamic pathways, even in the feedback direction, with feedforward transthalamic pathways acting as drivers, while feedback through thalamus is modulatory.

The Arousal-Related "Central Thalamus" Stimulation Site Simultaneously Innervates Multiple High-Level Frontal and Parietal Areas.

In human and nonhuman primates, deep brain stimulation applied at or near the internal medullary lamina of the thalamus [a region referred to as "central thalamus," (CT)], but not at nearby thalamic sites, elicits major changes in the level of consciousness, even in some minimally conscious brain-damaged patients. The mechanisms behind these effects remain mysterious, as the connections of CT had not been specifically mapped in primates. In marmoset monkeys (Callithrix jacchus) of both sexes, we labeled the axons originating from each of the various CT neuronal populations and analyzed their arborization patterns in the cerebral cortex and striatum. We report that, together, these CT populations innervate an array of high-level frontal, posterior parietal, and cingulate cortical areas. Some populations simultaneously target the frontal, parietal, and cingulate cortices, while others predominantly target the dorsal striatum. Our data indicate that CT stimulation can simultaneously engage a heterogeneous set of projection systems that, together, target the key nodes of the attention, executive control, and working-memory networks of the brain. Increased functional connectivity in these networks has been previously described as a signature of consciousness.SIGNIFICANCE STATEMENT In human and nonhuman primates, deep brain stimulation at a specific site near the internal medullary lamina of the thalamus ["central thalamus," (CT)] had been shown to restore arousal and awareness in anesthetized animals, as well as in some brain-damaged patients. The mechanisms behind these effects remain mysterious, as CT connections remain poorly defined in primates. In marmoset monkeys, we mapped with sensitive axon-labeling methods the pathways originated from CT. Our data indicate that stimulation applied in CT can simultaneously engage a heterogeneous set of projection systems that, together, target several key nodes of the attention, executive control, and working-memory networks of the brain. Increased functional connectivity in these networks has been previously described as a signature of consciousness.

Altered Thalamocortical Signaling in a Mouse Model of Parkinson's Disease.

Activation of the primary motor cortex (M1) is important for the execution of skilled movements and motor learning, and its dysfunction contributes to the pathophysiology of Parkinson's disease (PD). A well-accepted idea in PD research, albeit not tested experimentally, is that the loss of midbrain dopamine leads to decreased activation of M1 by the motor thalamus. Here, we report that midbrain dopamine loss altered motor thalamus input in a laminar- and cell type-specific fashion and induced laminar-specific changes in intracortical synaptic transmission. Frequency-dependent changes in synaptic dynamics were also observed. Our results demonstrate that loss of midbrain dopaminergic neurons alters thalamocortical activation of M1 in both male and female mice, and provide novel insights into circuit mechanisms for motor cortex dysfunction in a mouse model of PD.SIGNIFICANCE STATEMENT Loss of midbrain dopamine neurons increases inhibition from the basal ganglia to the motor thalamus, suggesting that it may ultimately lead to reduced activation of primary motor cortex (M1). In contrast with this line of thinking, analysis of M1 activity in patients and animal models of Parkinson's disease report hyperactivation of this region. Our results are the first report that midbrain dopamine loss alters the input-output function of M1 through laminar and cell type specific effects. These findings support and expand on the idea that loss of midbrain dopamine reduces motor cortex activation and provide experimental evidence that reconciles reduced thalamocortical input with reports of altered activation of motor cortex in patients with Parkinson's disease.

Inhibitory Gating of Thalamocortical Inputs onto Rat Gustatory Insular Cortex.

In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABAA and GABAB receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing.SIGNIFICANCE STATEMENT We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.

High-Resolution Tractography Protocol to Investigate the Pathways between Human Mediodorsal Thalamic Nucleus and Prefrontal Cortex.

Animal studies have established that the mediodorsal nucleus (MD) of the thalamus is heavily and reciprocally connected with all areas of the prefrontal cortex (PFC). In humans, however, these connections are difficult to investigate. High-resolution imaging protocols capable of reliably tracing the axonal tracts linking the human MD with each of the PFC areas may thus be key to advance our understanding of the variation, development, and plastic changes of these important circuits, in health and disease. Here, we tested in adult female and male humans the reliability of a new reconstruction protocol based on in vivo diffusion MRI to trace, measure, and characterize the fiber tracts interconnecting the MD with 39 human PFC areas per hemisphere. Our protocol comprised the following three components: (1) defining regions of interest; (2) preprocessing diffusion data; and, (3) modeling white matter tracts and tractometry. This analysis revealed largely separate PFC territories of reciprocal MD-PFC tracts bearing striking resemblance with the topographic layout observed in macaque connection-tracing studies. We then examined whether our protocol could reliably reconstruct each of these MD-PFC tracts and their profiles across test and retest sessions. Results revealed that this protocol was able to trace and measure, in both left and right hemispheres, the trajectories of these 39 area-specific axon bundles with good-to-excellent test-retest reproducibility. This protocol, which has been made publicly available, may be relevant for cognitive neuroscience and clinical studies of normal and abnormal PFC function, development, and plasticity.SIGNIFICANCE STATEMENT Reciprocal MD-PFC interactions are critical for complex human cognition and learning. Reliably tracing, measuring and characterizing MD-PFC white matter tracts using high-resolution noninvasive methods is key to assess individual variation of these systems in humans. Here, we propose a high-resolution tractography protocol that reliably reconstructs 39 area-specific MD-PFC white matter tracts per hemisphere and quantifies structural information from diffusion MRI data. This protocol revealed a detailed mapping of thalamocortical and corticothalamic MD-PFC tracts in four different PFC territories (dorsal, medial, orbital/frontal pole, inferior frontal) showing structural connections resembling those observed in tracing studies with macaques. Furthermore, our automated protocol revealed high test-retest reproducibility and is made publicly available, constituting a step forward in mapping human MD-PFC circuits in clinical and academic research.

Spatiotemporal Developmental Gradient of Thalamic Morphology, Microstructure, and Connectivity fromthe Third Trimester to Early Infancy.

Thalamus is a critical component of the limbic system that is extensively involved in both basic and high-order brain functions. However, how the thalamic structure and function develops at macroscopic and microscopic scales during the perinatal period development is not yet well characterized. Here, we used multishell high-angular resolution diffusion MRI of 144 preterm-born and full-term infants in both sexes scanned at 32-44 postmenstrual weeks (PMWs) from the Developing Human Connectome Project database to investigate the thalamic development in morphology, microstructure, associated connectivity, and subnucleus division. We found evident anatomic expansion and linear increases of fiber integrity in the lateral side of thalamus compared with the medial part. The tractography results indicated that thalamic connection to the frontal cortex developed later than the other thalamocortical connections (parieto-occipital, motor, somatosensory, and temporal). Using a connectivity-based segmentation strategy, we revealed that functional partitions of thalamic subdivisions were formed at 32 PMWs or earlier, and the partition developed toward the adult pattern in a lateral-to-medial pattern. Collectively, these findings revealed faster development of the lateral thalamus than the central part as well as a posterior-to-anterior developmental gradient of thalamocortical connectivity from the third trimester to early infancy.SIGNIFICANCE STATEMENT This is the first study that characterizes the spatiotemporal developmental pattern of thalamus during the third trimester to early infancy. We found that thalamus develops in a lateral-to-medial pattern for both thalamic microstructures and subdivisions; and thalamocortical connectivity develops in a posterior-to-anterior gradient that thalamofrontal connectivity appears later than the other thalamocortical connections. These findings may enrich our understanding of the developmental principles of thalamus and provide references for the atypical brain growth in neurodevelopmental disorders.

Organization of thalamocortical structural covariance and a corresponding 3D atlas of the mouse thalamus.

For information from sensory organs to be processed by the brain, it is usually passed to appropriate areas of the cerebral cortex. Almost all of this information passes through the thalamus, a relay structure that reciprocally connects to the vast majority of the cortex. The thalamus facilitates this information transfer through a set of thalamocortical connections that vary in cellular structure, molecular profiles, innervation patterns, and firing rates. Additionally, corticothalamic connections allow for intracortical information transfer through the thalamus. These efferent and afferent connections between the thalamus and cortex have been the focus of many studies, and the importance of cortical connectivity in defining thalamus anatomy is demonstrated by multiple studies that parcellate the thalamus based on cortical connectivity profiles. Here, we examine correlated morphological variation between the thalamus and cortex, or thalamocortical structural covariance. For each voxel in the thalamus as a seed, we construct a cortical structural covariance map that represents correlated cortical volume variation, and examine whether high structural covariance is observed in cortical areas that are functionally relevant to the seed. Then, using these cortical structural covariance maps as features, we subdivide the thalamus into six non-overlapping regions (clusters of voxels), and assess whether cortical structural covariance is associated with cortical connectivity that specifically originates from these regions. We show that cortical structural covariance is high in areas of the cortex that are functionally related to the seed voxel, cortical structural covariance varies along cortical depth, and sharp transitions in cortical structural covariance profiles are observed when varying seed locations in the thalamus. Subdividing the thalamus based on structural covariance, we additionally demonstrate that the six thalamic clusters of voxels stratify cortical structural covariance along the dorsal-ventral, medial-lateral, and anterior-posterior axes. These cluster-associated structural covariance patterns are prominently detected in cortical regions innervated by fibers projecting out of their related thalamic subdivisions. Together, these results advance our understanding of how the thalamus and the cortex couple in their volumes. Our results indicate that these volume correlations reflect functional organization and structural connectivity, and further provides a novel segmentation of the mouse thalamus that can be used to examine thalamic structural variation and thalamocortical structural covariation in disease models.

Non-invasive electrical brain stimulation modulates human conscious perception of mental representation.

Mental representation is a key concept in cognitive science; nevertheless, its neural foundations remain elusive. We employed non-invasive electrical brain stimulation and functional magnetic resonance imaging to address this. During this process, participants perceived flickering red and green visual stimuli, discerning them either as distinct, non-fused colours or as a mentally generated, fused colour (orange). The application of transcranial alternating current stimulation to the medial prefrontal region (a key node of the default-mode network) suppressed haemodynamic activation in higher-order subthalamic and central executive networks associated with the perception of fused colours. This implies that higher-order thalamocortical and default-mode networks are crucial in humans' conscious perception of mental representation.

Altered thalamocortical tract trajectory growth with undisrupted thalamic parcellation pattern in human lissencephaly brain at mid-gestational stage.

Proper topographically organized neural connections between the thalamus and the cerebral cortex are mandatory for thalamus function. Thalamocortical (TC) fiber growth begins during the embryonic period and completes by the third trimester of gestation, so that human neonates at birth have a thalamus with a near-facsimile of adult functional parcellation. Whether congenital neocortical anomaly (e.g., lissencephaly) affects TC connection in humans is unknown. Here, via diffusion MRI fiber-tractography analysis of long-term formalin-fixed postmortem fetal brain diagnosed as lissencephaly in comparison with an age-matched normal one, we found similar topological patterns of thalamic subregions and of internal capsule parcellated by TC fibers. However, lissencephaly fetal brain showed white matter structural changes, including fewer/less organized TC fibers and optic radiations, and much less cortical plate invasion by TC fibers - particularly around the shallow central sulcus. Diffusion MRI fiber tractography of normal fetal brains at 15, 23, and 26 gestational weeks (GW) revealed dynamic volumetric change of each parcellated thalamic subregion, suggesting coupled developmental progress of the thalamus with the corresponding cortex. Moreover, from GW23 and GW26 normal fetal brains, TC endings in the cortical plate could be delineated to reflect cumulative progressive TC invasion of cortical plate. By contrast, lissencephaly brain showed a dramatic decrease in TC invasion of the cortical plate. Our study thus shows the feasibility of diffusion MRI fiber tractography in postmortem long-term formalin-fixed fetal brains to disclose the developmental progress of TC tracts coordinating with thalamic and neocortical growth both in normal and lissencephaly fetal brains at mid-gestational stage.

Sleep spindles as neurophysiological biomarkers of schizophrenia.

Schizophrenia (SCZ) is a complex psychiatric disorder characterized by a wide range of clinical symptoms, including disrupted sleep. In recent years, there has been growing interest in assessing alterations in sleep parameters in patients with SCZ. Sleep spindles are brief (0.5-2 s) bursts of 12- to 16-Hz rhythmic electroencephalogram (EEG) oscillatory activity occurring during non-rapid eye movement (NREM) sleep. Spindles have been implicated in several critical brain functions, including learning, memory and plasticity, and are thought to reflect the integrity of underlying thalamocortical circuits. This review aims to provide an overview of the current research investigating sleep spindles in SCZ. After briefly describing the neurophysiological features of sleep spindles, I will discuss alterations in spindle characteristics observed in SCZ, their associations with the clinical symptomatology of these patients and their putative underlying neuronal and molecular mechanisms. I will then discuss the utility of sleep spindle measures as predictors of treatment response and disease progression. Finally, I will highlight future directions for research in this emerging field, including the prospect of utilizing sleep spindles as neurophysiological biomarkers of SCZ.

Aberrant thalamocortical connectivity and shifts between the resting state and task state in patients with schizophrenia.

Prominent pathological hypotheses for schizophrenia include auditory processing deficits and dysconnectivity within cerebral networks. However, most neuroimaging studies have focused on impairments in either resting-state or task-related functional connectivity in patients with schizophrenia. The aims of our study were to examine (1) blood oxygen level-dependent (BOLD) signals during auditory steady-state response (ASSR) tasks, (2) functional connectivity during the resting-state and ASSR tasks and (3) state shifts between the resting-state and ASSR tasks in patients with schizophrenia. To reduce the functional consequences of scanner noise, we employed resting-state and sparse sampling auditory fMRI paradigms in 25 schizophrenia patients and 25 healthy controls. Auditory stimuli were binaural click trains at frequencies of 20, 30, 40 and 80 Hz. Based on the detected ASSR-evoked BOLD signals, we examined the functional connectivity between the thalamus and bilateral auditory cortex during both the resting state and ASSR task state, as well as their alterations. The schizophrenia group exhibited significantly diminished BOLD signals in the bilateral auditory cortex and thalamus during the 80 Hz ASSR task (corrected p < 0.05). We observed a significant inverse relationship between the resting state and ASSR task state in altered functional connectivity within the thalamo-auditory network in schizophrenia patients. Specifically, our findings demonstrated stronger functional connectivity in the resting state (p < 0.004) and reduced functional connectivity during the ASSR task (p = 0.048), which was mediated by abnormal state shifts, within the schizophrenia group. These results highlight the presence of abnormal thalamocortical connectivity associated with deficits in the shift between resting and task states in patients with schizophrenia.

Thalamocortical Dysconnectivity in Treatment-Resistant Depression.

Thalamocortical connectivity is associated with cognitive and affective processing. The role of thalamocortical connectivity in the pathomechanism of treatment-resistant depression (TRD) remains unclear. This study included 48 patients with TRD and 48 healthy individuals. We investigated thalamocortical connectivity by performing resting-state functional MRI with the bilateral thalamus as the seed. In addition, patients with TRD were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS). Compared with the healthy individuals, the patients with TRD exhibited increased functional connectivity (FC) of the thalamus with the insula and superior temporal cortex and reduced the FC of the thalamus with the anterior paracingulate cortex and cerebellum crus II. Our study may support the crucial role of thalamocortical dysconnectivity in the TRD pathomechanism. However, the small sample size may limit the statistical power. A future study with a large sample size of patients with TRD would be required to validate our findings.