Thalamocortical Connections Research Articles

Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients-both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged and normalized the visual2 and somatomotor network connections, and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p = 2e-10, Hedges' g = 1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, anxiety, or demographics. It had moderate test-retest reliability (ICC = 0.62) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC = 0.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

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.

Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway

Abnormalities in thalamocortical crosstalk can lead to neuropsychiatric disorders. Variants in CACNA1G, which encodes the α1G subunit of the thalamus-enriched T-type calcium channel, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit consequences of these genetic variants in humans remain unknown. Here, we developed a human assembloid model of the thalamocortical pathway to dissect the contribution of genetic variants in T-type calcium channels. We discovered that the M1531V CACNA1G variant associated with seizures led to changes in T-type currents in thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in assembloids. By contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant axonal projections. These results illustrate the utility of multi-cellular systems for interrogating human genetic disease risk variants at both cellular and circuit level.

Abnormal thalamocortical network dynamics in patients with migraine and its relationship with electroacupuncture treatment response.

Acupuncture is an effective and safe alternative treatment to prevent and treat migraine, but its central analgesic mechanism remains poorly understood. It is believed that the dysfunction of the thalamocortical connectivity network is an important contributor to migraine pathophysiology. This study aimed to investigate the abnormal thalamocortical network dynamics in patients with migraine without aura (MWoA) before and after an 8-week electroacupuncture treatment. A total of 143 patients with MWoA and 100 healthy controls (HC) were included, and resting-state functional magnetic resonance imaging (fMRI) data were acquired. Dynamic functional network connectivity (dFNC) was calculated for each subject. The modulation effect of electroacupuncture on clinical outcomes of migraine, dFNC, and their association were investigated. In our results, dFNC matrices were classified into two clusters (brain states). As compared with the HC, patients with MWoA had a higher proportion of brain states with a strong thalamocortical between-network connection, implying an abnormal balance of the network organization across dFNC brain states. Correlation analysis showed that this abnormality was associated with summarized clinical measurements of migraine. A total of 60 patients were willing to receive an 8-week electroacupuncture treatment, and 24 responders had 50% changes in headache frequency. In electroacupuncture responders, electroacupuncture could change the abnormal thalamocortical connectivities towards a pattern more similar to that of HC. Our findings suggested that electroacupuncture could relieve the symptoms of migraine and has the potential capacity to regulate the abnormal function of the thalamocortical circuits.

REM sleep remains paradoxical: sub-states determined by thalamo-cortical and cortico-cortical functional connectivity.

During paradoxical sleep (PS, aka REM sleep) the cerebral cortex displays rapid electroencephalographic activity similar to that of wakefulness, whereas in the posterior associative thalamus, rapid activity is interrupted by frequent periods of slow-wave (delta) oscillations at 2-3Hz, thereby dissociating the intrinsic frequency in thalamus and cortex. Here we studied the functional consequences of such a dissociation using intrathalamic and intracortical recordings in 21 epileptic patients, applying coherence analysis to examine changes in functional connectivity between the posterior thalamus (mainly medial pulvinar) and six cortical functional networks, and also between each cortical network with respect to the others. Periods of slow-wave thalamic activity ('delta PS') were more prevalent than phases of 'rapid PS,' and the delta/rapid thalamic alternance did not overlap with the classical tonic/phasic dichotomy based on rapid eye movements. Thalamo-cortical and cortico-cortical functional connectivity significantly decreased during delta PS, relative to both rapid PS periods and to wakefulness. The fact that delta thalamic activity and low thalamo-cortical binding coincided with a suppression of cortico-cortical connectivity supports a crucial role for the posterior associative thalamus, and particularly the medial pulvinar, in ensuring trans-thalamic communication between distant cortical areas. Disruption of such a trans-thalamic communication during delta PS compromises the functional binding between cortical areas, and consequently might contribute to the alteration of perceptual experiences commonly reported during dreams. KEY POINTS: During paradoxical, or REM, sleep (PS), rapid thalamic activity is interrupted by frequent periods of slow delta waves at 2-3Hz. During these periods of thalamic delta activity there was a drastic drop of functional connectivity between associative thalamus and cortex, and also among different cortical networks. The delta/rapid alternance did not overlap with the classically defined 'tonic/phasic' periods and therefore suggests a distinct dichotomy of functional states in PS. Recurrent decrease in thalamo-cortical and cortico-cortical functional connectivity during PS may compromise the spatio-temporal binding between cortical areas, which in turn could hinder the formation of coherent mental content during dreams.

Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients- both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged and normalized the visual2 and somatomotor network connections, and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p=2e-10, Hedges' g=1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, anxiety, or demographics. It had moderate test-retest reliability (ICC=.61) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC=.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

Restoring transient connectivity during development improves dysfunctions in fragile X mice.

Early-generated circuits are critical for the maturation of cortical network activity and the formation of excitation/inhibition (E/I) balance. This process involves the maturation of specific populations of inhibitory neurons. While parvalbumin (PV)-expressing neurons have been associated with E/I impairments observed in neurodevelopmental disorders, somatostatin-expressing (SST) neurons have recently been shown to regulate PV neuron maturation by controlling neural dynamics in the developing cortex. SST neurons receive transient connections from the sensory thalamus, yet the implications of transient connectivity in neurodevelopmental disorders remain unknown. Here, we show that thalamocortical connectivity to SST neurons is persistent rather than transient in a mouse model of Fragile X syndrome. We were able to restore the transient dynamics using chemogenetics, which led to the recovery of fragile X-associated dysfunctions in circuit maturation and sensory-dependent behavior. Overall, our findings unveil the role of early transient dynamics in controlling downstream maturation of sensory functions.

Patterns of the left thalamus embedding into the connectome associated with reading skills in children with reading disabilities

Abstract We examined how the connectivity structure of left thalamus, especially thalamo-cortical connections, are reflected in children’s reading performance. Diffusion-weighted MRI at 3T and a series of reading measures were collected from 64 children ages from 8 to 14 years, 33 girls and 31 boys. The topological properties of the left thalamus were computed based on the whole-brain white matter network and a hub-attached reading network, and correlated with reading scores. Significant correlations between topological metrics of the left thalamus and reading scores were observed only in the hub-attached reading network. Two efficiency measures were negatively correlated with rapid automatized naming. Transmission cost was positively correlated with phonemic decoding, and this correlation was independent of efficiency scores. A validation analysis using an independent dataset replicated most of the findings, except for the correlation between local efficiency of the thalamus and rapid automatized naming. Our result highlights the role of the left thalamus and thalamo-cortical network in understanding the neurocognitive bases of skilled reading and dyslexia in children.

Neuromodulation using transcranial focused ultrasonography in neonates with perinatal hypoxic-ischemic encephalopathy

Perinatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy, accounting for over half of all cases and the consequences of HIE can be devastating, making it one of the most severe perinatal complications. Therapeutic hypothermia has been shown to offer neuroprotection by reducing metabolic demand and slowing the cascade of injury processes. However, despite its benefits, therapeutic hypothermia has only modestly improved neurodevelopmental outcomes, indicating a major need for additional therapeutic approaches. Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive brain stimulation technique for focally modulating specific brain regions that has recently drawn attention for its potential to modulate brain activity and promote neuroplasticity. The capacity of TUS to induce neuroplasticity through specific sonication parameters has been demonstrated in adult patients. Leveraging TUS to enhance functional connectivity and inhibit GABAergic systems within the injured thalami holds promise for inducing neuroplasticity in neonates with HIE. We hypothesize that enhancing thalamocortical functional connectivity and reducing local GABA levels through the use of TUS could potentially improve neurodevelopmental outcomes in neonates with HIE who have sustained thalamic injury and aim to test this hypothesis. Testing of the hypothesis will be conducted with a comprehensive assessment of safety and feasibility in neonates through a Phase I study, followed by further clinical studies to evaluate efficacy.

Transcranial focused ultrasound modulates visual thalamus in a nonhuman primate model.

The thalamus plays a pivotal role as a neural hub, integrating and distributing visual information to cortical regions responsible for visual processing. Transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation technology, enabling modulation of neural circuits with high spatial precision. This study investigates the tFUS neuromodulation at visual thalamus and characterizes the resultant effects on interconnected visual areas in a nonhuman primate model. Experiments were conducted on a rhesus macaque trained in a visual fixation task, combining tFUS stimulation with simultaneous scalp electroencephalography (EEG) and intracranial recordings from area V4, a region closely linked to the thalamus. Ultrasound was delivered through a 128-element random array ultrasound transducer operating at 700 kHz, with the focus steered onto the pulvinar of the thalamus based on neuroanatomical atlas and individual brain model. EEG source imaging revealed localized tFUS-induced activities in the thalamus, midbrain, and visual cortical regions. Critically, tFUS stimulation of the pulvinar can elicit robust neural responses in V4 without visual input, manifested as significant modulations in local field potentials, elevated alpha and gamma power, corroborating the functional thalamocortical connectivity. Furthermore, the tFUS neuromodulatory effects on visually-evoked V4 activities were region-specific within the thalamus and dependent on ultrasound pulse repetition frequency. This work provides direct electrophysiological evidence demonstrating the capability of tFUS in modulating the visual thalamus and its functional impact on interconnected cortical regions in a large mammalian model, paving the way for potential investigations for tFUS treating visual, sensory, and cognitive impairments.

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.

Imaging of the superficial white matter in health and disease

Abstract The superficial white matter, the layer of white matter immediately deep to the cortical grey matter, is a highly complex, heterogeneous tissue region comprising dense meshes of neural fibres, a robust population of interstitial neurons, and ongoing glial activity and myelination. It originates from the histologically distinct, developmentally vital subplate in the foetal brain, maintains thalamo-cortical connections throughout adult life, and is a necessary passage for all axons passing between the grey and white matter. Despite these features, the superficial white matter is among the most poorly understood regions of the brain, in part due to its complex makeup and the resulting difficulty of its study. In this review, we present our current knowledge of superficial white matter (SWM) anatomy, development, and response to disease. We discuss the unique challenges encountered in the neuroimaging of this region, including the lack of standard definition and the non-specificity of neuroimaging markers amplified by the complexity of the tissue. We discuss recent innovations and offer potential pathways forward.

Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression.

Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916.

Repeat traumatic brain injury exacerbates acute thalamic hyperconnectivity in humans.

Repeated mild traumatic brain injury is of growing interest regarding public and sporting safety and is thought to have greater adverse or cumulative neurological effects when compared with single injury. While epidemiological links between repeated traumatic brain injury and outcome have been investigated in humans, exploration of its mechanistic substrates has been largely undertaken in animal models. We compared acute neurological effects of repeat mild traumatic brain injury (n = 21) to that of single injury (n = 21) and healthy controls (n = 76) using resting-state functional MRI and quantified thalamic functional connectivity, given previous identification of its prognostic potential in human mild traumatic brain injury and rodent repeat mild traumatic brain injury. Acute thalamocortical functional connectivity showed a rank-based trend of increasing connectivity with number of injuries, at local and global scales of investigation. Thus, history of as few as two previous injuries can induce a vulnerable neural environment of exacerbated hyperconnectivity, in otherwise healthy individuals from non-specialist populations. These results further establish thalamocortical functional connectivity as a scalable marker of acute injury and long-term neural dysfunction following mild traumatic brain injury.

Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development

During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian “fire together, wire together” precept. However, select connections, essential for circuit development, are transient. They are effectively connected early in development, but strongly diminish during maturation. The mechanisms by which transient connectivity recedes are unknown. To investigate this process, we characterize transient thalamocortical inputs, which depress onto somatostatin inhibitory interneurons during development, by employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies in mice. We demonstrate that in contrast to typical activity-dependent mechanisms, transient thalamocortical connectivity onto somatostatin interneurons is non-canonical and involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules in particular, supports the elimination of this connectivity. Remarkably, we found that this process impacts the development of normal exploratory behaviors of adult mice.

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.

Increased Thalamocortical Functional Connectivity on Discontinuation of Treatment in Painful Diabetic Peripheral Neuropathy.

Altered functional connectivity has been demonstrated in key brain regions involved in pain processing in painful diabetic peripheral neuropathy (Painful-DPN). However, the impact of neuropathic pain treatment on functional connectivity has not been investigated. Sixteen participants underwent resting state functional MRI (rs-fMRI) when optimally treated for neuropathic pain during their involvement in the OPTION-DM trial and 1-week following withdrawal of treatment. On discontinuation of pain treatment, there was a rise in functional connectivity between the left thalamus and primary somatosensory cortex (S1) and the left thalamus and insular cortex, key brain regions that are involved in cerebral processing of pain. The changes in functional connectivity between scans also correlated with measures of pain (baseline pain severity and neuropathy pain symptom inventory). Moreover, when participants were stratified into higher and lower than average baseline pain sub-groups, the change in thalamic-S1 cortical functional connectivity between scans was significantly greater in those with high baseline pain compared with the lower baseline pain group. This study shows that thalamo-cortical functional connectivity has the potential to act as an objective biomarker for neuropathic pain in diabetes for use in clinical pain trials.

A Reconsideration of the Core and Matrix Classification of Thalamocortical Projections.

In 1998, Jones suggested a classification of thalamocortical projections into core and matrix divisions (Jones, 1998). In this classification, core projections are specific, topographical, innervate middle cortical layers, and serve to transmit specific information to the cortex for further analysis; matrix projections, in contrast, are diffuse, much less topographic, innervate upper layers, especially Layer 1, and serve a more global, modulatory function, such as affecting levels of arousal. This classification has proven especially influential in studies of thalamocortical relationships. Whereas it may be the case that a clear subset of thalamocortical connections fit the core motif, since they are specific, topographic, and innervate middle layers, we argue that there is no clear evidence for any single class that encompasses the remainder of thalamocortical connections as is claimed for matrix. Instead, there is great morphological variation in connections made by thalamocortical projections fitting neither a core nor matrix classification. We thus conclude that the core/matrix classification should be abandoned, because its application is not helpful in providing insights into thalamocortical interactions and can even be misleading. As one example of the latter, recent suggestions indicate that core projections are equivalent to first-order thalamic relays (i.e., those that relay subcortical information to the cortex) and matrix to higher-order relays (i.e., those that relay information from one cortical area to another), but available evidence does not support this relationship. All of this points to a need to replace the core/matrix grouping with a more complete classification of thalamocortical projections.

A shifting role of thalamocortical connectivity in the emergence of cortical functional organization.

The cortical patterning principle has been a long-standing question in neuroscience, yet how this translates to macroscale functional specialization in the human brain remains largely unknown. Here we examine age-dependent differences in resting-state thalamocortical connectivity to investigate its role in the emergence of large-scale functional networks during early life, using a primarily cross-sectional but also longitudinal approach. We show that thalamocortical connectivity during infancy reflects an early differentiation of sensorimotor networks and genetically influenced axonal projection. This pattern changes in childhood, when connectivity is established with the salience network, while decoupling externally and internally oriented functional systems. A developmental simulation using generative network models corroborated these findings, demonstrating that thalamic connectivity contributes to developing key features of the mature brain, such as functional segregation and the sensory-association axis, especially across 12-18 years of age. Our study suggests that the thalamus plays an important role in functional specialization during development, with potential implications for studying conditions with compromised internal and external processing.

Genetic Implication of Specific Glutamatergic Neurons of the Prefrontal Cortex in the Pathophysiology of Schizophrenia

BackgroundThe prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. Here, we combined high-resolution single-nuclei RNA sequencing data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder. MethodsGene expression specificity values were calculated from a single-nuclei RNA sequencing dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood. Enrichment of schizophrenia common variant liability and burden of rare protein-truncating coding variants were tested in genes with high expression specificity for each cell type. We also explored schizophrenia common variant associations in relation to gene expression across the developmental trajectory of implicated neurons. ResultsCommon risk variation for schizophrenia was prominently enriched in genes with high expression specificity for a population of mature layer 4 glutamatergic neurons emerging in infancy. Common variant liability to schizophrenia increased along the developmental trajectory of this neuronal population. Fine-mapped genes at schizophrenia genome-wide association study risk loci had significantly higher expression specificity than other genes in these neurons and in a population of layer 5/6 glutamatergic neurons. People with schizophrenia had a higher rate of rare protein-truncating coding variants in genes expressed by cells of the PFC than control individuals, but no cell population was significantly enriched above this background rate. ConclusionsWe identified a population of layer 4 glutamatergic PFC neurons likely to be particularly affected by common variant genetic risk for schizophrenia, which may contribute to disturbances in thalamocortical connectivity in the condition.