Biology subjects

Palaniyappan, L.

Publications and source records attributed to Palaniyappan, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Dissociable Anterior and Posterior Beta-Burst Dynamics Track Thought Disorder in Schizophrenia

BackgroundThought disorder in schizophrenia reflects disrupted internal model maintenance in predictive processing. Beta oscillations have been proposed to index top-down predictive signalling, but prior resting-state studies have focused on spectral power, overlooking transient burst dynamics that enable the stabilization and reinstatement of internal representations, especially in the default mode network (DMN). MethodsResting-state MEG was acquired from 25 patients (7 females) with schizophrenia and 25 matched controls (8 females) between May 2024 and October 2025. Beta bursts (15-30 Hz) were extracted from source-localized cortical time series, and burst rate, duration, power, and inter-regional synchrony were quantified. Associations with computationally-derived semantic and syntactic speech features were assessed using principal-component regression within patients. ResultsConventional beta power did not differ between groups after correction. In contrast, beta-burst dynamics showed significant group-by-anterior-posterior-position interactions for burst rate (p = 0.018), power (p = 0.0014) and duration (p < 0.001). Within the DMN, patients showed shorter inferior parietal burst duration (t(46.0) = -2.74, FDR-p = 0.0343) and increased burst synchrony within left prefrontal cortex (t(31.0) = 2.81, FDR-p = 0.0343) and between prefrontal cortices (t(29.8) = 2.73, FDR-p = 0.0423). Within patients, burst components predicted speech organization (R{superscript 2} = 0.47, F(3,19) = 5.66, p = 0.006), driven by the inferior parietal burst-duration component ({beta} = -0.55, p = 0.0036), but did not predict overall clinical severity. LimitationsThe modest patient sample, short resting-state recording, cross-sectional design, and lack of laminar specificity limit causal and mechanistic inference; burst-speech associations require replication. ConclusionSchizophrenia was associated with dissociable anterior and posterior beta-burst abnormalities that tracked objective speech markers of thought disorder. These findings suggest impaired hierarchical coordination of predictive beta signalling as a candidate mechanism linking intrinsic network dysfunction to disorganized thought.

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bioRxiv2026

Tetradic Dynamics of Dyadic Sensorimotor Coordination: A Multiscale EEG Hyperscanning Study

HighlightsO_LILeader-follower roles structure dyadic coordination mechanisms C_LIO_LIMirroring yields a robust Follower reaction time advantage C_LIO_LITonic-phasic analyses reveal scale-dependent condition asymmetry C_LIO_LIPhasic dynamics resolve into Leader anticipation and Follower post-response inhibition C_LIO_LIIntegrated information decomposition reveals a role-specific inter-brain predictive architecture C_LI How do leader and follower roles shape the brain mechanisms that support coordinated action between people? This question has direct therapeutic relevance for conditions such as schizophrenia and autism spectrum disorder, where the capacity for reciprocal social coordination is a defining vulnerability. Here, we propose a tetradic framework and examine sensorimotor coordination in 16 healthy adult pairs using simultaneous dual-brain EEG hyperscanning, a 2x2 within-subject design crossing Role (Leader/Follower) and Condition (Mirroring/Matching). Mirroring required resonance with a partners movement; Matching required its controlled transformation. This contrast was designed to dissociate automatic from controlled coordination processes across roles. Behaviourally, Mirroring produced a reaction-time advantage that was selective to Followers, a finding replicated in a combined cohort, and consistent with role-dependent attention-inhibition gating. At the neural level, sustained (tonic) activity was dominated by Matching-related frontoparietal engagement regardless of role, while time-resolved (phasic) activity revealed a Mirroring-dominant reorganization that differentiated into role-specific patterns: anticipatory gating in Leaders and post-response inhibitory rebound in Followers. Information-theoretic decomposition of inter-brain coupling identified a Leader-specific predictive signal in medial prefrontal and cingulate cortices, a Follower-specific adaptive signal across sensorimotor and temporal regions, and a shared redundancy scaffold in orbitofrontal and insular cortices. These findings characterize tetradic coordination within dyads as a multiscale, role-asymmetric architecture in which top-down predictive control and bottom-up adaptive regulation are functionally dissociable. The tetradic framework provides an organizing scaffold for this dissociation, and the role-specific signatures it reveals offer candidate biomarkers for clinical populations in whom interpersonal coordination is disrupted.

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bioRxiv2026

Distributed neurophysiological dynamics link perception, action, and language in schizophrenia

Schizophrenia is characterized by disturbances in both perception and expression that profoundly impair social functioning, yet these domains are typically studied in isolation. Predictive processing theories suggest that such symptoms may arise from abnormal updating of internal models, but the neural mechanisms linking perceptual and expressive dysfunction remain unclear. Using magnetoencephalography during multisensory perception and motor tasks, we tested whether beta-band activity (15-30 Hz), a neural signal implicated in predictive control, provides a shared substrate across domains. Compared to healthy individuals, patients with schizophrenia showed attenuated event-related modulation of beta activity, including weaker beta suppression during sensory processing and delayed or reduced post-movement beta rebound. These abnormalities were associated with a widened audiovisual temporal binding window, indicating atypical multisensory integration. Multivariate analyses further revealed that reduced beta modulation across sensory and motor systems covaried with impoverished semantic diversity, simplified syntactic structure in natural speech, and greater clinical symptom burden. Notably, beta abnormalities emerged as distributed latent patterns spanning sensory, motor, and frontotemporal regions. Together, these findings identify diminished event-related beta modulation as a common neural signature linking disrupted multisensory integration, action monitoring, and language organization in schizophrenia. We situate perceptual and expressive impairments within a unified framework of predictive dysfunction and advance a mechanistically grounded account that highlights beta dynamics as a promising target for future mechanistic and translational studies in psychosis. Significance StatementSchizophrenia disrupts both how people perceive the world and how they express their thoughts, yet these symptoms are usually studied separately. Using magnetoencephalography during multisensory and motor tasks, we identify a shared neural mechanism linking these domains: reduced event-related modulation of beta-band (15-30 Hz) activity, a signal implicated in predictive control. Compared to healthy individuals, patients showed diminished beta changes during sensory processing and movement completion, suggesting reduced flexibility in updating internal models. Importantly, this neural pattern covaried with abnormal audiovisual binding, disorganized natural speech, and greater clinical severity. These findings reveal distributed beta modulation as a cross-domain neural marker of predictive dysfunction, offering a unified framework for understanding perceptual and expressive disturbances in schizophrenia.

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bioRxiv2026

Plasma proteomics reveal heterogeneous subtypes of depression linked to inflammation and aging

The clinical heterogeneity of depression has defied biological classification, limiting personalized treatment. Previous neuroimaging- or symptom-based subtyping of depression failed to clarify the underlying pathoetiology, while plasma proteins which integrates signals from multiple organ systems, offers a promising way to define biologically grounded subtypes. Using plasma proteomics from 2,127 incident depression cases in a cohort of 53000 individuals, we identified three biologically distinct subtypes differing in inflammation, aging, and metabolic profiles. The most prevalent subtype ( inflammation/ageing) was characterized by aging-related inflammation, poorest prognosis with hippocampal atrophy and highest suicide risk, mediated by age-related amygdala atrophy; this subtype had highest anhedonia burden. A distinct inflammation/energy dysregulation group had metabolic pathway enrichment with high inflammation and lifestyle risk factors (smoking) but no ageing trend, predominantly physical/psychomotor symptoms and decreased thalamic volume. In contrast, the inflammation-resilient group had the lowest inflammatory proteomic loading, lowest depression severity, more resilient lifestyle and increased hippocampal volume. These proteomic signatures, detectable years before symptom onset, enable risk stratification and suggest subtype-specific targeted physical and lifestyle interventions.

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bioRxiv2025

Subanesthetic Ketamine Disrupts Predictive Signaling in the Prefrontal Cortex

Corollary discharge (CD) signals allow the brain to predict and suppress the sensory consequences of its own actions, providing stability to perception and thought. Disruption of these predictive mechanisms has long been hypothesized to contribute to the disorganization of experience in schizophrenia, yet direct circuit-level evidence has been lacking. Here, we show that ketamine, a dissociative N-methyl-D-aspartate receptor (NMDAR) antagonist, at subanesthetic doses, selectively disrupts CD signaling in the lateral prefrontal cortex (LPFC)--a region thought to be the seed of mental representations and one of the most affected areas in schizophrenia. We recorded activity from 1,342 neurons in LPFC areas 8a and 9/46 of macaques performing a visuospatial working-memory task in a virtual environment, before and after subanesthetic ketamine administration. Ketamine impaired performance and increased overall firing rates but markedly suppressed saccade-related responses carrying CD signals. This led to decreased discriminability of eye movement signals. This finding links two major ideas in neuroscience research: the role of disrupted glutamate signaling and the failure of the brains predictive models. It provides evidence for how these mechanisms may interact in the prefrontal cortex to disturb the sense of reality.

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bioRxiv2024

Converging effects of cannabis and psychosis on the dopamine system: A longitudinal neuromelanin-sensitive MRI study in cannabis use disorder and first episode schizophrenia.

ImportanceDespite evidence that individuals who use cannabis early in life are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in both conditions, the mechanism linking the two conditions remains unclear. ObjectiveTo use neuromelanin-sensitive MRI (neuromelanin-MRI), a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in cannabis use and psychosis and whether this alteration can be observed in cannabis users whether or not they have a diagnosis of first-episode schizophrenia. Design, Setting, and ParticipantsThis longitudinal observational study recruited participants from 2019 to 2023 from an early intervention service for psychosis in London, Ontario, Canada. The sample consisted of 25 participants with cannabis use disorder (CUD) and 36 participants without CUD (nCUD), of which 28 had first-episode schizophrenia (FES). One-year follow-up was completed for 12 CUD and 25 nCUD participants. Main Outcomes and MeasuresNeuromelanin-MRI contrast within the substantia nigra (SN) and within a subregion previously linked to psychosis severity (a priori psychosis region of interest) and diagnoses of schizophrenia-spectrum disorder and cannabis use disorder derived from the Structured Clinical Interview for DSM-5. Linear mixed effects analyses were performed relating neuromelanin-MRI contrast to clinical measures. ResultsWe found that CUD was associated with elevated neuromelanin-MRI signal in a cluster of ventral SN voxels (387 of 2060 SN voxels, pcorrected=0.027, permutation test). Furthermore, CUD was associated with elevated neuromelanin-MRI signal in an SN subregion previously documented to have elevated signal in relation to untreated psychotic symptoms (t92 =2.12, p=0.037). In contrast, FES was not associated with a significant alteration in neuromelanin-MRI signal (241 SN voxels had elevated signal, pcorrected=0.094). Conclusions and RelevanceThese findings suggest that elevated dopamine function in a critical SN subregion may contribute to the risk of psychosis in people with CUD. Thus, cannabis affects the long-suspected final common pathway for the clinical expression of psychotic symptoms. Imaging the dopamine system with neuromelanin-MRI may index long-term dopamine turnover. Key PointsO_ST_ABSQuestionC_ST_ABSIs the same midbrain dopamine pathway impacted by cannabis as in psychosis? FindingsCannabis use disorder participants had elevated neuromelanin-MRI signal in a cluster of ventral substantia nigra voxels and in a subregion previously documented to have elevated signal in relation to untreated psychotic symptoms. MeaningIncreased dopamine functioning in the ventral substantia nigra may contribute to the risk of psychosis in people with cannabis use disorders.

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bioRxiv2024

Neurite Density and Free Water in the Gray and White Matter of Early Psychosis Patients

Diffusion weighted imaging has been frequently used to characterize the white matter in patients with schizophrenia, but the most commonly used model, diffusion tensor imaging (DTI), is not specific to the histological nature of microstructural changes. This is particularly true in the more complex grey matter tissue. Furthermore, DTI changes have not been consistently reported in early schizophrenia populations, but this does not exclude more subtle changes that may not affect the model fit. Recently developed biophysical models of diffusion, such as the neurite orientation dispersion and density imaging (NODDI) model, may overcome these issues by quantifying specific tissue subcompartments, capturing diffusion profiles characteristic of intra-neurite, extra-neurite, and free water space. We applied the NODDI model to early schizophrenia patients (n=54) and healthy controls (n=51) from the Human Connectome Project - Early Psychosis dataset, investigating both the grey and white matter. We observed a diffuse, increased free water fraction throughout the grey matter, especially in the left insula, though there were not notable changes in the white matter. The spatial variation in the grey matter free water was not fully explained by the partial volume effects from the cerebrospinal fluid, indicating a role for tissue edema. The role of vasogenic processes in early stages of psychosis that may precede white matter anomalies documented in later disease stages warrant further investigation.

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bioRxiv2024

Stable White Matter Structure in the First Three Years after Psychosis Onset

BackgroundWhite matter alterations observed using diffusion weighted imaging have become a hallmark of chronic schizophrenia, but it is unclear when these changes arise over the course of the disease. Nearly all studies thus far have been cross-sectional, so despite their large sample sizes, they cannot determine if changes accumulate as a degenerative process, or if patients with pre-existing white matter damage are predisposed to more chronic forms of schizophrenia. MethodsWe examined 160 scans comprising two years of annual follow-up data from n=42 controls and n=28 schizophrenia patients recruited in the first two years since their diagnosis, totalling two to three scans per subject. We additionally examined six-month follow-up data obtained from an ultra-high field (7 Tesla) scanner (n=68 scans; n=19 first-episode schizophrenia patients; n=15 controls) as a validation dataset. A longitudinal model was used to compare the trajectory of diffusion tenor parameters between patients and controls. Positive and negative symptom scores were correlated with diffusion parameters using ROI- and clustering-based approaches. ResultsWe failed to observe any longitudinal differences in any diffusion tensor imaging parameters between patients and controls in either dataset. We did, however, observe consistent associations between white matter alterations and negative symptoms in both datasets. ConclusionsWhite matter does not appear susceptible to schizophrenia-linked degeneration in the early stages of disease, but pre-existing pathology may be linked to disease severity.

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bioRxiv2024

GPT-3 reveals selective insensitivity to global vs. local linguistic context in speech produced by treatment-naive patients with positive thought disorder

BackgroundEarly psychopathologists proposed that certain features of positive thought disorder, the disorganized language output produced by some people with schizophrenia, suggest an insensitivity to global, relative to local, discourse context. This idea has received support from carefully controlled psycholinguistic studies in language comprehension. In language production, researchers have so far remained reliant on subjective qualitative rating scales to assess and understand speech disorganization. Now, however, recent advances in large language models mean that it is possible to quantify sensitivity to global and local context objectively by probing lexical probability (the predictability of a word given its preceding context) during natural language production. MethodsFor each word in speech produced by 60 first-episode psychosis patients and 35 healthy, demographically-matched controls, we extracted lexical probabilities from GPT-3 based on contexts that ranged from very local-- a single preceding word: P(Wn | Wn-1)--to global-- up to 50 preceding words: P(Wn|Wn-50, Wn-49, ..., Wn-1). ResultsWe show, for the first time, that disorganized speech is characterized by disproportionate insensitivity to global, versus local, linguistic context. Critically, this global-versus-local insensitivity selectively predicted clinical ratings of positive thought disorder, above and beyond overall symptom severity. There was no evidence of a relationship with negative thought disorder (impoverishment). ConclusionsWe provide an automated, interpretable measure that can potentially be used to quantify speech disorganization in schizophrenia. Our findings directly link the clinical phenomenology of thought disorder to neurocognitive constructs that are grounded in psycholinguistic theory and neurobiology.

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bioRxiv2023

Changes in the structure of spontaneous speech predict the disruption of hierarchical brain organization in first-episode psychosis

Psychosis implicates changes across a broad range of cognitive functions. These functions are cortically organized in the form of a hierarchy ranging from primary sensorimotor (unimodal) to higher-order association cortices, which involve functions such as language (transmodal). Language has long been documented as undergoing structural changes in psychosis. We hypothesized that these changes as revealed in spontaneous speech patterns may act as readouts of alterations in the configuration of this unimodal-to-transmodal axis of cortical organization in psychosis. Results from 29 patients with first-episodic psychosis (FEP) and 29 controls scanned with 7T resting-state fMRI confirmed a compression of the cortical hierarchy in FEP, which affected metrics of the hierarchical distance between the sensorimotor and default mode networks, and of the hierarchical organization within the semantic network. These organizational changes were predicted by graphs representing semantic and syntactic associations between meaningful units in speech produced during picture descriptions. These findings unite psychosis, language, and the cortical hierarchy in a single conceptual scheme, which helps to situate language within the neurocognition of psychosis and opens the clinical prospect for mental dysfunction to become computationally measurable in spontaneous speech.

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bioRxiv2023

A multistage, dual voxel study of glutamate in the anterior cingulate cortex in schizophrenia supports a primary pyramidal dysfunction model of disorganization

BackgroundSchizophrenia is an illness where glutamatergic dysfunction in the anterior cingulate cortex (ACC) has been long suspected; Recent in vivo evidence (Adams et al. 2022) has implicated pyramidal dysfunction (reduced glutamate tone) as the primary pathophysiology contributing to subtle features, with a secondary disinhibition effect (higher glutamate tone) resulting in the later emergence of prominent clinical symptoms. We investigate if genetic high risk (GHR) for schizophrenia reduces glutamatergic tone in ACC when compared to the states of clinical high risk (CHR) and first episode schizophrenia (FES) where symptoms are already prominent. MethodsWe recruited 302 individuals across multiple stages of psychosis (CHR, n=63; GHR, n=76; FES, n=96) and healthy controls (n=67) and obtained proton magnetic resonance spectroscopy of glutamate from perigenual ACC (pACC) and dorsal ACC (dACC) using 3-Tesla scanner. ResultsGHR had lower Glu compared to CHR while CHR had higher Glu compared to FES and HC. Higher disorganization burden, but not any other symptom domain, was predicted by lower levels of Glu in the GHR group (dACC and pACC) and in the CHR group (pACC only). ConclusionsThe reduction in glutamatergic tone in GHR supports the case for a pyramidal dysfunction contributing to higher disorganization, indicating disorganization to be the core domain in the pathophysiology of schizophrenia. Higher glutamate (likely due to disinhibition) is apparent when psychotic symptoms are raising to be prominent (CHR), though at the full-blown stage of psychosis, the relationship between glutamate and symptoms ceases to be a simple linear one.

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bioRxiv2022

Neural sequences in primate prefrontal cortex encode working memory in naturalistic environments

Working memory is the ability to briefly remember and manipulate information after it becomes unavailable to the senses. The mechanisms supporting working memory coding in the primate brain remain controversial. Here we demonstrate that microcircuits in layers 2/3 of the primate lateral prefrontal cortex dynamically represent memory content in a naturalistic task through sequential activation of single neurons. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of macaque monkeys during a naturalistic visuospatial working memory task set in a virtual environment. We found that the sequential activation of single neurons encoded trajectories to target locations held in working memory. Neural sequences were not a mere successive activation of cells with memory fields at specific spatial locations, but an abstract representation of the subjects trajectory to the target. Neural sequences were less correlated to target trajectories during perception and were not found during working memory tasks lacking the spatiotemporal structure of the naturalistic task. Finally, ketamine administration distorted neural sequences, selectively decreasing working memory performance. Our results indicate that neurons in the lateral prefrontal cortex causally encode working memory in naturalistic conditions via complex and temporally precise activation patterns.

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bioRxiv2022

Stable working memory and perceptual representations in macaque lateral prefrontal cortex during naturalistic vision in virtual environments

Primates use perceptual and mnemonic visuospatial representations to perform everyday functions. Neurons in the lateral prefrontal cortex (LPFC) have been shown to encode both of these representations during tasks where eye movements are strictly controlled and visual stimuli are reduced in complexity. This raises the question of whether perceptual and mnemonic representations encoded by LPFC neurons remain robust during naturalistic vision -- in the presence of a rich visual scenery and during eye movements. Here we investigate this issue by training macaque monkeys to perform working memory and perception tasks in a visually complex virtual environment that requires navigation using a joystick and allows for free visual exploration of the scene. We recorded the activity of 3950 neurons in the LPFC (areas 8a and 9/46) of two rhesus macaques using multi-electrode arrays, and measured eye movements using video tracking. We found that navigation trajectories to target locations and eye movement behavior differed between the perception and working memory tasks suggesting that animals employed different behavioral strategies. Single neurons were tuned to target location during cue encoding and working memory delay and neural ensemble activity was predictive of the animals behavior. Neural decoding of target location was stable throughout the working memory delay epoch. However, neural representations of similar target locations differed between the working memory and perception tasks. These findings indicate that during naturalistic vision, LPFC neurons maintain robust and distinct neural codes for mnemonic and perceptual visuospatial representations. Significance StatementWe show that LPFC neurons encode working memory and perceptual representations during a naturalistic task set in a virtual environment. We show that despite eye movement and complex visual input, neurons maintain robust working memory representations of space which are distinct from neuronal representations for perception. We further provide novel insight on the use of virtual environments to construct behavioral tasks for electrophysiological experiments.

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bioRxiv2021

Evaluating test-retest reliability and sex/age-related effects on temporal clustering coefficient of dynamic functional brain networks

The multilayer dynamic network model has been proposed as an effective method to understand how the brain functions dynamically. Specially, derived from the definition of clustering coefficient in static networks, the temporal clustering coefficient provides a direct measure of topological stability of dynamic brain networks and shows potential in predicting altered brain functions in both normal and pathological conditions. However, test-retest reliability and demographic-related effects on this measure remain to be evaluated. Using a publicly available dataset from the Human Connectome Project consisting of 337 young healthy adults (157 males/180 females; 22 to 37 years old), the present study investigated: (1) the test-retest reliability of temporal clustering coefficient across four repeated resting-state functional magnetic resonance imaging scans as measured by intraclass correlation coefficient (ICC); and (2) sex- and age-related effects on temporal clustering coefficient. The results showed that (1) the temporal clustering coefficient had overall moderate test-retest reliability (ICC > 0.40 over a wide range of densities) at both global and subnetwork levels; (2) female subjects showed significantly higher temporal clustering coefficient than males at both global and subnetwork levels, in particular within the default-mode and subcortical regions; (3) temporal clustering coefficient of the subcortical subnetwork was negatively correlated with age in young adults. Our findings suggest that temporal clustering coefficient is a reliable and reproducible approach for the identification of individual differences in brain function, and provide evidence for sex and age effects on human brain dynamic connectome.

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bioRxiv2021

Myelin imaging of the basal forebrain in first-episode psychosis

Cholinergic dysfunction has been implicated in the pathophysiology of psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis ([~] 31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used Magnetic Resonance Spectroscopy (1H-MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n=85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 and 1H-MRS-based dorsal anterior cingulate choline in healthy controls, while this relationship was disrupted in FEP. Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia and other psychiatric disorders such as depression.

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bioRxiv2020

Naturalistic coding of working memory in primate prefrontal cortex

The primate lateral prefrontal cortex (LPFC) is considered fundamental for temporarily maintaining and manipulating mental representations that serve behavior, a cognitive function known as working memory1. Studies in non-human primates have shown that LPFC lesions impair working memory2 and that LPFC neuronal activity encodes working memory representations3. However, such studies have used simple displays and constrained gaze while subjects held information in working memory3, which put into question their ethological validity4,5. Currently, it remains unclear whether LPFC microcircuits can support working memory function during natural behavior. We tested macaque monkeys in a working memory navigation task in a life-like virtual environment while their gaze was unconstrained. We show that LPFC neuronal populations robustly encode working memory representations in these conditions. Furthermore, low doses of the NMDA receptor antagonist, ketamine, impaired working memory performance while sparing perceptual and motor skills. Ketamine decreased the firing of narrow spiking inhibitory interneurons and increased the firing of broad spiking cells reducing population decoding accuracy for remembered locations. Our results show that primate LPFC generates robust neural codes for working memory in naturalistic settings and that such codes rely upon a fine balance between the activation of excitatory and inhibitory neurons.

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bioRxiv2019

Altered cortical gyrification in adults who were born very preterm and its associations with cognition and mental health

BackgroundThe last trimester of pregnancy is a critical period for the establishment of cortical gyrification and altered folding patterns have been reported following very preterm birth (< 33 weeks of gestation) in childhood and adolescence. However, research is scant on the persistence of such alterations in adulthood and their associations with cognitive and psychiatric outcomes. MethodsWe studied 79 very-preterm adults and 81 age-matched full-term controls. T1-weighted images were used to measure local gyrification index (LGI), indicating the degree of folding across multiple vertices of the reconstructed cortical surface. Group and group-sex LGI differences were assessed using per-vertex adjustment for cortical thickness and overall intracranial volume. Within-group correlations were also computed between LGI and functional outcomes, including general intelligence (IQ) and psychopathology. ResultsVery preterm adults had significantly reduced LGI in extensive cortical regions encompassing the frontal, anterior temporal and occipito-parietal lobes. Alterations in lateral fronto-temporal-parietal and medial occipito-parietal regions were present in both males and females, although males reported more extensive alterations. In both very preterm adults and controls, higher LGI was associated with higher IQ and lower psychopathology scores, with the spatial distribution of these associations substantially differing between the two groups. ConclusionsVery preterm adults brains are characterized by significant and widespread local hypogyria and these abnormalities might be implicated in cognitive and psychiatric outcomes. Gyrification reflects an early developmental process and provides a fingerprint for very preterm birth.

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bioRxiv2019

Deviant cortical sulcation related to schizophrenia, but not cognitive deficits, likely predate brain development in the second trimester.

ObjectivesAberrant cortical development, inferred from cortical folding measures, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the approximate timing of the prenatal insult linked to schizophrenia as well as the cognitive impairment seen in this illness. MethodsAnatomical T1 MRI scans from a publicly available dataset of 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth. 5 major primary sulci that are invariable, representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, intraparietal sulcus and inferior frontal sulcus) with formation representing distinct developmental periods were chosen. Sulcal depth was measured using BrainVISA software. ResultsA repeated measure Analysis of Variance with 5 sulci and 2 hemispheres as within-subject factors and gender, age and intracranial volume as covariates revealed a significant effect of diagnosis (F[1,134]=14.8, p=0.0002). Control subjects had had deeper superior temporal (left t=3.2, p=0.002; right t=2.8, p=0.006), right inferior frontal (t=2.7, p=0.007) and left calcarine (t=2.2, p=0.03) sulci. A deeper superior frontal sulcus predicted better overall cognitive scores (F[1,54]=8.7, p=0.005) among patients. ConclusionOur results suggest that the gestational cortical disruption underlying schizophrenia is likely to predate, if not, coincide with the appearance of calcarine sulcus (early 2nd trimester) and affects frontal, temporal and occipital lobes. Nevertheless, the burden of cognitive deficits may relate specifically to aberrant superior frontal development occurring in late 2nd trimester.

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