Perception results from the interplay of sensory input and prior knowledge. Despite behavioral evidence that long-term priors powerfully shape perception, the neural mechanisms underlying these ...interactions remain poorly understood. We obtained direct cortical recordings in neurosurgical patients as they viewed ambiguous images that elicit constant perceptual switching. We observe top-down influences from the temporal to occipital cortex, during the preferred percept that is congruent with the long-term prior. By contrast, stronger feedforward drive is observed during the non-preferred percept, consistent with a prediction error signal. A computational model based on hierarchical predictive coding and attractor networks reproduces all key experimental findings. These results suggest a pattern of large-scale information flow change underlying long-term priors' influence on perception and provide constraints on theories about long-term priors' influence on perception.
Departing from traditional linguistic models, advances in deep learning have resulted in a new type of predictive (autoregressive) deep language models (DLMs). Using a self-supervised next-word ...prediction task, these models generate appropriate linguistic responses in a given context. In the current study, nine participants listened to a 30-min podcast while their brain responses were recorded using electrocorticography (ECoG). We provide empirical evidence that the human brain and autoregressive DLMs share three fundamental computational principles as they process the same natural narrative: (1) both are engaged in continuous next-word prediction before word onset; (2) both match their pre-onset predictions to the incoming word to calculate post-onset surprise; (3) both rely on contextual embeddings to represent words in natural contexts. Together, our findings suggest that autoregressive DLMs provide a new and biologically feasible computational framework for studying the neural basis of language.
Humans form lasting memories of stimuli that were only encountered once. This naturally occurs when listening to a story, however it remains unclear how and when memories are stored and retrieved ...during story-listening. Here, we first confirm in behavioral experiments that participants can learn about the structure of a story after a single exposure and are able to recall upcoming words when the story is presented again. We then track mnemonic information in high frequency activity (70-200 Hz) as patients undergoing electrocorticographic recordings listen twice to the same story. We demonstrate predictive recall of upcoming information through neural responses in auditory processing regions. This neural measure correlates with behavioral measures of event segmentation and learning. Event boundaries are linked to information flow from cortex to hippocampus. When listening for a second time, information flow from hippocampus to cortex precedes moments of predictive recall. These results provide insight on a fine-grained temporal scale into how episodic memory encoding and retrieval work under naturalistic conditions.
The relationship between conscious experience and brain activity has intrigued scientists and philosophers for centuries. In the last decades, several theories have suggested different accounts for ...these relationships. These theories have developed in parallel, with little to no cross-talk among them. To advance research on consciousness, we established an adversarial collaboration between proponents of two of the major theories in the field, Global Neuronal Workspace and Integrated Information Theory. Together, we devised and preregistered two experiments that test contrasting predictions of these theories concerning the location and timing of correlates of visual consciousness, which have been endorsed by the theories' proponents. Predicted outcomes should either support, refute, or challenge these theories. Six theory-impartial laboratories will follow the study protocol specified here, using three complementary methods: Functional Magnetic Resonance Imaging (fMRI), Magneto-Electroencephalography (M-EEG), and intracranial electroencephalography (iEEG). The study protocol will include built-in replications, both between labs and within datasets. Through this ambitious undertaking, we hope to provide decisive evidence in favor or against the two theories and clarify the footprints of conscious visual perception in the human brain, while also providing an innovative model of large-scale, collaborative, and open science practice.
Tuberous sclerosis complex (TSC) and some focal cortical dysplasias (FCDs) are associated with dysfunctional mTOR signaling, resulting in increased cell growth and ribosomal S6 protein ...phosphorylation (phospho-S6). mTOR inhibitors can reduce TSC tumor growth and seizure frequency, and preclinical FCD studies indicate seizure suppression. This pilot study evaluated safety of mTOR inhibitor everolimus in treatment resistant (failure of >2 anti-seizure medications) TSC and FCD patients undergoing surgical resection and to assess mTOR signaling and molecular pathways.
We evaluated everolimus in 14 treatment resistant epilepsy patients undergoing surgical resection (4.5 mg/m2 daily for 7 days; n = 4 Active, mean age 18.3 years, range 4-26; n = 10, Control, mean age 13.1, range 3-45). Everolimus was well tolerated. Mean plasma everolimus in Active participants were in target range (12.4 ng/ml). Brain phospho-S6 was similar in Active and Control participants with a lower trend in Active participants, with Ser235/236 1.19-fold (p = 0.67) and Ser240/244 1.15-fold lower (p = 0.66). Histologically, Ser235/236 was 1.56-fold (p = 0.37) and Ser240/244 was 5.55-fold lower (p = 0.22). Brain proteomics identified 11 proteins at <15% false discovery rate associated with coagulation system (p = 1.45x10-9) and acute phase response (p = 1.23x10-6) activation. A weighted gene correlation network analysis (WGCNA) of brain proteomics and phospho-S6 identified 5 significant modules. Higher phospho-S6 correlated negatively with cellular respiration and synaptic transmission and positively with organophosphate metabolic process, nuclear mRNA catabolic process, and neuron ensheathment. Brain metabolomics identified 14 increased features in Active participants, including N-acetylaspartylglutamic acid. Plasma proteomics and cytokine analyses revealed no differences.
Short-term everolimus before epilepsy surgery in TSC and FCD resulted in no adverse events and trending lower mTOR signaling (phospho-S6). Future studies should evaluate implications of our findings, including coagulation system activation and everolimus efficacy in FCD, in larger studies with long-term treatment to better understand molecular and clinical effects.
ClinicalTrials.gov NCT02451696.
Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from ...humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.
•At the molecular level MTLE is characterized by gene expression changes in the hippocampus.•Up-regulation of glia genes and down-regulation of neuronal genes was seen in the hippocampus.•small RNAs reflect disease state more robustly then mRNAs.•let-7b-3p and let-7c-3p maybe be key regulators of multiple pathways involved in MTLE pathology.
Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10-22% and subclinical epileptiform abnormalities occur in 22-54%. Cognitive ...deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy.
We evaluated control (
= 8), severe AD (
= 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases (
= 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level.
Proteomics identified 2,459 proteins in the choroid plexus. At a 5% false discovery rate (FDR), 616 proteins were differentially expressed in AD vs. control, 1 protein in epilepsy vs. control, and 438 proteins in AD vs. epilepsy. There was more variability in the epilepsy group across syndromes. The top 20 signaling pathways associated with differentially expressed proteins in AD vs. control included cell metabolism pathways; activated fatty acid beta-oxidation (
= 2.00 x 10
, z = 3.00), and inhibited glycolysis (
= 1.00 x 10
, z = -3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system (
= 5.62 x 10
, z = 2.00), and pathogen-induced cytokine storm (
= 2.19 x 10
, z = 3.61). Of the 617 altered proteins in AD and epilepsy vs. controls, 497 (81%) were positively correlated (
< 0.0001,
= 0.27).
We found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.
Contextual embeddings, derived from deep language models (DLMs), provide a continuous vectorial representation of language. This embedding space differs fundamentally from the symbolic ...representations posited by traditional psycholinguistics. We hypothesize that language areas in the human brain, similar to DLMs, rely on a continuous embedding space to represent language. To test this hypothesis, we densely record the neural activity patterns in the inferior frontal gyrus (IFG) of three participants using dense intracranial arrays while they listened to a 30-minute podcast. From these fine-grained spatiotemporal neural recordings, we derive a continuous vectorial representation for each word (i.e., a brain embedding) in each patient. Using stringent zero-shot mapping we demonstrate that brain embeddings in the IFG and the DLM contextual embedding space have common geometric patterns. The common geometric patterns allow us to predict the brain embedding in IFG of a given left-out word based solely on its geometrical relationship to other non-overlapping words in the podcast. Furthermore, we show that contextual embeddings capture the geometry of IFG embeddings better than static word embeddings. The continuous brain embedding space exposes a vector-based neural code for natural language processing in the human brain.
Human neuroimaging studies suggest that localization and identification of relevant auditory objects are accomplished via parallel parietal-to-lateral-prefrontal "where" and ...anterior-temporal-toinferior-frontal "what" pathways, respectively. Using combined hemodynamic (functional MRI) and electromagnetic (magnetoencephalography) measurements, we investigated whether such dual pathways exist already in the human nonprimary auditory cortex, as suggested by animal models, and whether selective attention facilitates sound localization and identification by modulating these pathways in a feature-specific fashion. We found a double dissociation in response adaptation to sound pairs with phonetic vs. spatial sound changes, demonstrating that the human nonprimary auditory cortex indeed processes speech-sound identity and location in parallel anterior "what" (in anterolateral Heschl's gyrus, anterior superior temporal gyrus, and posterior planum polare) and posterior "where" (in planum temporale and posterior superior temporal gyrus) pathways as early as ≈70-150 ms from stimulus onset. Our data further show that the "where" pathway is activated ≈30 ms earlier than the "what" pathway, possibly enabling the brain to use top-down spatial information in auditory object perception. Notably, selectively attending to phonetic content modulated response adaptation in the "what" pathway, whereas attending to sound location produced analogous effects in the "where" pathway. This finding suggests that selectiveattention effects are feature-specific in the human nonprimary auditory cortex and that they arise from enhanced tuning of receptive fields of task-relevant neuronal populations.
In reverberant environments, acoustic reflections interfere with the direct sound arriving at a listener's ears, distorting the spatial cues for sound localization. Yet, human listeners have little ...difficulty localizing sounds in most settings. Because reverberant energy builds up over time, the source location is represented relatively faithfully during the early portion of a sound, but this representation becomes increasingly degraded later in the stimulus. We show that the directional sensitivity of single neurons in the auditory midbrain of anesthetized cats follows a similar time course, although onset dominance in temporal response patterns results in more robust directional sensitivity than expected, suggesting a simple mechanism for improving directional sensitivity in reverberation. In parallel behavioral experiments, we demonstrate that human lateralization judgments are consistent with predictions from a population rate model decoding the observed midbrain responses, suggesting a subcortical origin for robust sound localization in reverberant environments.
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