Biology subjects

Hamm, J. P.

Publications and source records attributed to Hamm, J. P..

13 recordsLinked to original sources

bioRxiv2026

A dominant frontoparietal beta oscillatory brain state in the days after psilocybin and 5-MeO-DMT

Background. Serotonergic psychedelics show promise for treating psychiatric disorders, with symptom improvements lasting for weeks after a single dose. Clarifying the neural basis of these effects would benefit from an identification of empirical biomarkers of such lasting shifts in brain function. Resting state EEG offers a rapid (<5 minute), low-cost window into functional brain networks. However, connectivity is not static, but cycles between recurring semi-stable patterns that vary across frequency bands. Here we employed a dynamic function connectivity (dFC) framework to identify frequency-specific connectivity states and examine how they change in the weeks following psychedelic use. Methods. We collected resting-state EEG from individuals who had used one of two serotonergic psychedelic subclasses within the prior three weeks, psilocybin/LSD (typical; n=14) or 5-MeO-DMT (atypical; n=12), and age- and sex-matched controls (n=16). Frequency-band-specific spatial connectivity states (phase-lag index) were estimated across the full sample (5 per band). Groups were compared on proportion and dwell-time (per state) and state-to-state transitions. Results. A right frontoparietally-distributed beta synchrony state was dominant after both typical and atypical psychedelics use (proportion/dwell-time). This effect correlated with the number of days since using psychedelics. A globally-distributed theta-band state was prominent in recent users of typical psychedelics but occurred less often in atypical users. In contrast, neural entropy (Lempel-Ziv complexity; known to increase acutely during psychedelic dosing) was not altered in recent users of either subclass. Conclusion. These results reveal a beta-band signature of altered neural dynamics in the week following a psychedelic dose, consistent with a relaxation of brain network hierarchy after psychedelics.

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bioRxiv2026

A Key Regulator of Dendritic Morphology in Supragranular Neocortex Impacts Mismatch Negativity

BackgroundCytoskeletal structure and neuronal function are heavily intertwined, and altered pyramidal neuron morphology (e.g., reduced dendritic arbors) has been consistently identified in the neocortex of individuals with psychiatric disorders. A missense mutation in Kalrn (Kalrn-PT) enhances activation of RhoA, a cytoskeletal regulator, and leads to adolescent-onset dendritic regression in supragranular auditory cortex. To investigate the relationship between this spatiotemporally altered cytoskeletal structure and psychiatric-relevant dysfunction, we examine the functional impacts of this genetic mutation, focusing on mismatch negativity - a common biomarker of altered sensory integration that matures across adolescence. MethodsIn Kalrn-PT and littermate wild-type mice, pyramidal dendritic morphology was assessed across primary visual cortex (V1) layers using Golgi staining (n=172 neurons/26 mice). Local field potentials (LFPs) and neuronal spiking were recorded during a visual oddball sequence (n=25 mice). Deviance detection - the rodent neural analogue of mismatch negativity - was analyzed across V1 layers. ResultsKalrn-PT mice exhibit reductions in V1 dendritic length specific to layer 2/3, mirroring observations in post-mortem samples from people with psychiatric disorders. Deviance detection was reduced in LFPs from Kalrn-PT mice and absent in layer 2/3 neurons, despite typical feature selectivity and firing rates. These deficits were accompanied by reduced functional connectivity between visual and frontal areas. ConclusionsThese results highlight alterations in higher-level sensory cortical integration in Kalrn-PT mice and demonstrate that adolescent-onset, disease-relevant structural and functional phenotypes can be linked by a common upstream effector. Further, these alterations appear restricted to supragranular layers, demonstrating an outsized role for Kalrn, particularly longer isoforms, in superficial neocortex.

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bioRxiv2026

Global context rapidly shapes sensory responses in V1

Context modulates sensory processing in the cerebral cortex by suppressing responses to expected stimuli and enhancing responses to unexpected ones. Recent proposals argue that early sensory areas such as primary visual cortex (V1) are shaped only by local context, including recent stimulus history, whereas modulation by global context, such as learned temporal structure, is present exclusively in higher cortical areas. This view is incompatible with predictive coding theories. To directly dissociate local and global contextual influences, we used a global/local oddball paradigm in which mice viewed five-item sequences. Across conditions, sequence structure was held constant while stimulus identity and predictability were selectively manipulated, allowing the isolation of response modulations due to local deviance, global expectation, and stimulus repetition independently. In the canonical sequence (AAAA-B), B is locally deviant but globally predictable. Using two-photon calcium imaging and LFP recordings in mouse V1, we found that global predictability abolished context modulation: responses to B were equivalent to those evoked by a random sequence control (e.g., CDEAB). This effect emerged rapidly, after only <10 sequence repetitions, demonstrating fast learning of global structure. When the stimulus was globally deviant, either by replacing B with a novel stimulus (AAAA-C) or by presenting B unpredictably in a standard oddball paradigm, V1 exhibited robust response enhancement. These effects required feedback from anterior cingulate area (ACa), establishing a causal role for higher cortical circuits in conveying global predictions to V1. Strikingly, when an additional A replaced B (AAAA-A), responses were strongly suppressed despite global deviance, indicating that stimulus-specific adaptation may constrain the expression of global prediction error signals in early sensory cortex. HighlightsGlobal context rapidly modulates neural responses in V1 Global deviations, but not predictable local deviants, elicit enhanced responses Downstream brain region ACa is necessary for global context modulation in V1 Standard oddball paradigms involve higher-order contextual modulation

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bioRxiv2026

Cortical deviance detection represents a canonical difference signal

Context modulates neural processing of sensory stimuli. Neural responses are suppressed to stimuli that are typical in their context and augmented to stimuli that deviate from their context. The latter has been conceptualized as a "prediction error", which can serve to enhance the salience, direct attention, or support learning about behaviorally relevant events. Predictive coding theories posit that prediction errors act to signal the difference between internal predictions and actual sensory input, yet most paradigms simultaneously alter both predictions and input, so cannot test for a true difference signal. Increased neural responses to deviants could, instead, encode generalized surprise or augmented bottom-up signaling. Here we compare neural responses to auditory stimuli across oddball paradigm variants. We found that responses of putative excitatory neurons in primary auditory cortex (A1) to auditory deviants contain frequency change information and a memory trace of contextual information. Interestingly, in a fixed-deviant oddball paradigm where predictions are altered but deviant input remains constant, neural response patterns encoded standard-to-deviant frequency difference. These results support the interpretation that A1 deviance detection can be interpreted as a sensory prediction error that represents the difference between prediction and sensory input, a corollary of the predictive coding framework.

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bioRxiv2025

Mismatch negativity develops in adolescence and independently of microglia

Higher brain functions and cognition undergo a critical period of development during adolescence, when psychiatric disorders such as schizophrenia typically onset. Understanding how developmental processes during adolescence interact with schizophrenia pathophysiology and risk remains a central goal in psychiatry. Here we show that a well-established biomarker of schizophrenia, mismatch negativity, matures during adolescence in mouse primary visual cortex, along with a strengthening of fronto-visual functional connectivity. Because microglia are implicated in schizophrenia risk and disease states, we further investigated what role microglia may play in the development of mismatch responses under physiological conditions. We found that microglial depletion with PLX5622 in adolescence arrests the development of resting oscillations in frontal areas, but does not affect the development of deviance detection, other signatures of visual context processing, or prefrontal-visual functional connectivity. Our findings suggest (a) a key component of mismatch negativity develops in adolescence, a period of vulnerability to schizophrenia, and (b) the development underlying this component does not require robust microglia activity, clarifying the developmental role of microglia in higher order visual processing.

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bioRxiv2025

Duet model of predictive coding unifies diverse neuroscienceexperimental protocols

The brain continuously generates predictions about the external world. When stimulus X is presented repeatedly, the brain predicts that the next one is also X. A deviant stimulus Y elicits a stronger sensory response than the baseline, reflecting the amplification of an unexpected stimulus. Here, we introduce the duet predictive coding model, a minimal and biologically plausible framework in which neurons encode both positive and negative prediction errors. This model reproduces neural responses observed in vision and audition across diverse predictive coding paradigms, particularly omission. Our proposed circuit mechanism predicts (1) neurons tuned to negative prediction errors in the oddball paradigm, supported by experimental evidence in mice; (2) the magnitude of unexpected responses quantitatively depends on the dissimilarity between standard and deviant stimuli and diminishes with increasing interstimulus interval. Our findings suggest that the brains deviance detection relies on dual-error computation, offering a unifying explanation across seemingly disparate experimental protocols.

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bioRxiv2024

A lasting impact of serotonergic psychedelics on visual processing and behavior

Serotonergic psychedelics (e.g., psilocybin, LSD) have potential to treat psychiatric disorders, with therapeutic effects lasting days to weeks after a single dose. Prominent theories suggest that psychedelics have a lasting effect on hierarchical brain circuits, reducing top-down influence on information processing to facilitate an unbiased, bottom-up reassessment of the world, but direct and concrete evidence for such an effect is lacking. Here we directly tested this hypothesis in both humans and mice, assessing predictive processing in the fronto-visual system in the days after a single psychedelic exposure. Individuals who recently (<3 weeks) used 5-HT2AReceptor agonist psychedelics (psilocybin, LSD) were assessed via electroencephalography (EEG) and electrooculography recordings during a saccadic prediction task and compared to age- and sex-matched non-users. Compared to non-users, recent psychedelic users produced fewer fast saccades and less suppression of EEG delta/theta power to predictively presented stimuli, pointing to a disruption of predictive processing. These changes correlated with time since psychedelic use and were replicated in a second cohort taking a different serotonergic psychedelic (5-MeO-DMT). Direct recordings of primary visual cortex (V1) in mice administered psilocybin (1 mg/kg) evinced a similar loss of predictive suppression 24-hrs after the dose. This coincided with weakened top-down modulation of V1 from anterior cingulate area (ACa), a subregion of medial prefrontal cortex, along with clear spine growth in ACa neurons that project to V1. These results suggest that psychedelic-induced neural plasticity serves to reorganize feedback circuits in the cortex and relax top-down influence on bottom-up sensory processing - an effect that persists beyond the acute exposure period and may underlie a therapeutic window.

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bioRxiv2023

Spatiotemporal dynamics across visual cortical laminae support a predictive coding framework for interpreting mismatch responses

AbstractContext modulates neocortical processing of sensory data. Unexpected visual stimuli elicit large responses in primary visual cortex (V1) -- a phenomenon known as deviance detection (DD) at the neural level, or "mismatch negativity" (MMN) when measured with EEG. It remains unclear how visual DD/MMN signals emerge across cortical layers, in temporal relation to the onset of deviant stimuli, and with respect to brain oscillations. Here we employed a visual "oddball" sequence - a classic paradigm for studying aberrant DD/MMN in neuropsychiatric populations - and recorded local field potentials in V1 of awake mice with 16-channel multielectrode arrays. Multiunit activity and current source density profiles showed that while basic adaptation to redundant stimuli was present early (50ms) in layer 4 responses, DD emerged later (150-230ms) in supragranular layers (L2/3). This DD signal coincided with increased delta/theta (2-7Hz) and high-gamma (70-80Hz) oscillations in L2/3 and decreased beta oscillations (26-36hz) in L1. These results clarify the neocortical dynamics elicited during an oddball paradigm at a microcircuit level. They are consistent with a predictive coding framework, which posits that predictive suppression is present in cortical feed-back circuits, which synapse in L1, while "prediction errors" engage cortical feed-forward processing streams, which emanate from L2/3.

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bioRxiv2023

Multimodal mismatch responses in associative but not primary visual cortex evidence hierarchical predictive coding in cortical networks

A key function of the mammalian neocortex is to process sensory data in the context of current and past stimuli. Primary sensory cortices, such as V1, respond weakly to stimuli that typical in their context but strongly to novel stimuli, an effect known as "deviance detection". How deviance detection occurs in associative cortical regions that are downstream of V1 is not well-understood. Here we investigated parietal associative area (PTLp) responses to auditory, visual, and audio-visual mismatches with two-photon calcium imaging and local field potential recordings. We employed basic unisensory auditory and visual oddball paradigms as well as a novel multisensory oddball paradigm, involving typical parings (VaAc or VbAd) presented at p=.88 with rare "deviant" pairings (e.g. VaAd or VbAc) presented at p=.12. We found that PTLp displayed robust deviance detection responses to auditory-visual mismatches, both in individual neurons and in population theta and gamma-band oscillations. In contrast, V1 neurons displayed deviance detection only to visual deviants in a unisensory context, but not to auditory or auditory-visual mismatches. Taken together, these results accord with a predictive processing framework for cortical responses, wherein modality specific prediction errors (i.e. deviance detection responses) are computed in functionally specified cortical areas and feed-forward to update higher brain regions.

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bioRxiv2023

A frontosensory circuit for visual context processing is synchronous in the theta/alpha band

Visual processing is strongly influenced by context. Stimuli that deviate from contextual regularities elicit augmented responses in primary visual cortex (V1). These heightened responses, known as "deviance detection," require both inhibition local to V1 and top-down modulation from higher areas of cortex. Here we investigated the spatiotemporal mechanisms by which these circuit elements interact to support deviance detection. Local field potential recordings in mice in anterior cingulate area (ACa) and V1 during a visual oddball paradigm showed that interregional synchrony peaks in the theta/alpha band (6-12 Hz). Two-photon imaging in V1 revealed that mainly pyramidal neurons exhibited deviance detection, while vasointestinal peptide-positive interneurons (VIPs) increased activity and somatostatin-positive interneurons (SSTs) decreased activity (adapted) to redundant stimuli (prior to deviants). Optogenetic drive of ACa-V1 inputs at 6-12 Hz activated V1-VIPs but inhibited V1-SSTs, mirroring the dynamics present during the oddball paradigm. Chemogenetic inhibition of VIP interneurons disrupted ACa-V1 synchrony and deviance detection responses in V1. These results outline spatiotemporal and interneuron-specific mechanisms of top-down modulation that support visual context processing.

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bioRxiv2018

Cortical subnetworks encode context of a visual stimulus

Cortical processing of sensory events is significantly influenced by context. For instance, a repetitive or redundant visual stimulus elicits attenuated cortical responses, but if the same stimulus is unexpected or \"deviant\", responses are augmented. This contextual modulation of sensory processing is likely a fundamental function of neural circuits, yet an understanding of how it is computed is still missing. Using holographic two-photon calcium imaging in awake animals, here we identify three distinct, spatially intermixed ensembles of neurons in mouse primary visual cortex which differentially respond to the same stimulus under separate contexts, including a subnetwork which selectively responds to deviant events. These non-overlapping ensembles are distributed across layers 2-5, though deviance detection is more common in superficial layers. Contextual preferences likely arise locally since they are not present in bottom up inputs from the thalamus or top-down inputs from prefrontal cortex. The functional parcellation of cortical circuits into independent ensembles that encode stimulus context provides a circuit basis underlying cortically based perception of novel or redundant stimuli, a key deficit in many psychiatric disorders.\n\nOne Sentence SummaryVisual cortex represents deviant and redundant stimuli with separate subnetworks.

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bioRxiv2018

Seizures start as silent microseizures by neuronal ensembles

Understanding seizure formation and spread remains a critical goal of epilepsy research. While many studies have documented seizure spread, it remains mysterious how they start. We used fast in-vivo two-photon calcium imaging to reconstruct, at cellular resolution, the dynamics of focal cortical seizures as they emerge in epileptic foci (intrafocal), and subsequently propagate (extrafocal). We find that seizures start as intrafocal coactivation of small numbers of neurons (ensembles), which are electrographically silent. These silent \"microseizures\" expand saltatorily until they break into neighboring cortex, where they progress smoothly and first become detectable by LFP. Surprisingly, we find spatially heterogeneous calcium dynamics of local PV interneuron sub-populations, which rules out a simple role of inhibitory neurons during seizures. We propose a two-step model for the circuit mechanisms of focal seizures, where neuronal ensembles first generate a silent microseizure, followed by widespread neural activation in a travelling wave, which is then detected electrophysiologically.

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bioRxiv2018

Human sensory Long-Term Potentiation (LTP) predicts visual memory performance and is modulated by the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism

BackgroundLong-Term Potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory, and to gain additional insight into variations in memory function and memory decline. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to BDNF Val66Met; a single nucleotide polymorphism implicated in memory function.\n\nMethods28 participants (15 female) were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP-like enhancements of the visually-evoked response, and a test of visual memory.\n\nResultsThe magnitude of LTP 40 minutes after induction was predictive of long-term memory performance. Additionally, the BDNF Met allele was associated with both reduced LTP and reduced memory performance.\n\nConclusionsThe current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.

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