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Valiante, T. A.

Publications and source records attributed to Valiante, T. A..

36 records · Page 2Linked to original sources

Abstract representations emerge in human hippocampal neurons during inference behavior

Humans have the remarkable cognitive capacity to rapidly adapt to changing environments. Central to this capacity is the ability to form high-level, abstract representations that take advantage of regularities in the world to support generalization1. However, little is known about how these representations are encoded in populations of neurons, how they emerge through learning, and how they relate to behavior2,3. Here we characterized the representational geometry of populations of neurons (single-units) recorded in the hippocampus, amygdala, medial frontal cortex, and ventral temporal cortex of neurosurgical patients who are performing an inferential reasoning task. We find that only the neural representations formed in the hippocampus simultaneously encode multiple task variables in an abstract, or disentangled, format. This representational geometry is uniquely observed after patients learn to perform inference, and consisted of disentangled directly observable and discovered latent task variables. Interestingly, learning to perform inference by trial and error or through verbal instructions led to the formation of hippocampal representations with similar geometric properties. The observed relation between representational format and inference behavior suggests that abstract/disentangled representational geometries are important for complex cognition.

neuroscience↗

Hippocampal Theta Phase Precession Supports Memory Formation and Retrieval of Naturalistic Experience in Humans

Linking different experiences together is a key aspect of episodic memory. A potential neural mechanism for linking sequential events over time is phase precession, which causes neurons to fire progressively earlier in time relative to theta-frequency local field potential oscillations. However, no direct link between phase precession and behaviorally assessed memory encoding or retrieval success has been established. We recorded the activity of single neurons and local field potentials in the human medial temporal lobe (MTL) while participants encoded and retrieved memories of movie clips. Transient brief theta bouts and theta phase precession were observed following cognitive boundaries during movie watching as well as following stimulus onset during memory retrieval. Phase precession was dynamic, with different neurons exhibiting phase precession in different task periods. The strength of phase precession provided information about memory encoding and retrieval success that was not available in firing rates, thereby linking the temporal code established by phase precession to behaviorally assessed memory strength. These data reveal phase precession during non spatial memory in humans and provide direct neural evidence for a functional role of phase precession in episodic memory.

neuroscience↗

Control of working memory maintenance by theta-gamma phase amplitude coupling of human hippocampal neurons

Retaining information in working memory (WM) is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference. How cognitive control regulates WM storage, however, remains unknown. We hypothesized that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in WM. In the hippocampus, TG-PAC was indicative of WM load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. These PAC neurons were more strongly coordinated with frontal theta activity when cognitive control demand was high, and they introduced information-enhancing and behaviorally relevant noise correlations with persistently active neurons in the hippocampus. We show that TG-PAC integrates cognitive control and WM storage to improve the fidelity of WM representations and facilitate behavior.

neuroscience↗

In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of 5 subunit-containing GABAA receptor (5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of 5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of 5-PAM on tonic inhibition as measured in human neurons, and tested in silico 5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that 5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an 5-PAM dose response and identified simulated EEG biomarker candidates. Our results serve to de-risk and facilitate 5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.

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Hyperpolarization-activated cation channels shape the spiking frequency preference of human cortical layer 5 pyramidal neurons

Discerning the contribution of specific ionic currents to complex neuronal dynamics is a difficult, but important, task. This challenge is exacerbated in the human setting, although the widely-characterized uniqueness of the human brain as compared to preclinical models necessitates the direct study of human neurons. Neuronal spiking frequency preference is of particular interest given its role in rhythm generation and signal transmission in cortical circuits. Here, we combine the frequency-dependent gain (FDG), a measure of spiking frequency preference, and novel in silico analyses to dissect the contributions of individual ionic currents to key FDG features of human L5 neurons. We confirm that a contemporary model of such a neuron, primarily constrained to capture subthreshold activity driven by the hyperpolarization-activated cyclic nucleotide gated (h-) current, replicates key features of the in vitro FDG both with and without h-current activity. With the model confirmed as a viable approximation of the biophysical features of interest, we applied new analysis techniques to quantify the activity of each modeled ionic current in the moments prior to spiking, revealing unique dynamics of the h-current. These findings motivated patch-clamp recordings in analogous rodent neurons to characterize their FDG, which confirmed that a biophysically-detailed model of these neurons captures key inter-species differences in the FDG. These differences are correlated with distinct contributions of the h-current to neuronal activity. Together, this interdisciplinary and multi-species study provides new insights directly relating the dynamics of the h-current to neuronal spiking frequency preference in human L5 neurons. Significance StatementUnderstanding the contributions of individual ionic currents to neuronal activity is vital, considering the established role of ion channel modifications in neuropsychiatric conditions. We combine in vitro characterization of the spiking frequency preference of human L5 cortical pyramidal neurons via the frequency-dependent gain (FDG) with new analyses of a biophysically-detailed computational model of such a neuron to delineate the connection between the dynamics of the hyperpolarization-activated cyclic nucleotide gated (h-) current prior to spiking and key properties of the FDG. By further determining that both these FDG properties and h-current dynamics are distinct in analogous rodent neurons, we provide convincing evidence for the key role of the h-current in the frequency preference of human L5 cortical neurons.

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All-optical interrogation of excitability during seizure propagation reveals high local inhibition amidst baseline excitability

Seizures are classically described as an epiphenomenon of hyperexcitability and hypersynchronicity across brain regions. However, this view is insufficient to explain the complex, dynamic evolution of focal-onset seizures in the brain. Recent studies have proposed mechanisms involving an evolution of excitability driven specifically by a spatiotemporally progressing seizure wavefront. These mechanisms attempt to align the abnormal propagation of neural activity with well-known neurobiological parameters, such as excitation-inhibition balance and neuronal connectivity patterns. We describe a direct test of these mechanisms by performing real-time, in vivo investigations of excitability in the acutely epileptic state and during seizure propagation. We used all-optical interrogation to test single-neuronal and local-circuit excitability in the epileptic brain. We demonstrate a surprising paradox during the acutely epileptic state, wherein the brain becomes susceptible to large synchronous inputs, yet single-cell excitability is largely maintained at baseline levels. At a finer scale, excitability of neurons at the single-cell level is related to their distance from the seizure wavefront. Local circuit excitability is increased in the distal penumbra but, crucially, we find inhibition in close proximity to the seizure wavefront. This is in contrast with previously suggested notions of widespread inhibition outside the direct area of action during a focal-onset seizure. These experimental results provide the first direct, in vivo evidence for the precise spatial scale over which single-cell excitability dynamics evolve during seizure propagation, providing support for local inhibitory restraint of seizure propagation.

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Neural diversity quenches the dynamic volatility of balanced neural networks

Heterogeneity is the norm in biology. The brain is no different: neuronal cell-types are myriad, reflected through their cellular morphology, type, excitability, connectivity motifs and ion channel distributions. While this biophysical diversity enriches neural systems dynamical repertoire, it remains challenging to reconcile with the robustness and persistence of brain function over time. To better understand the relationship between heterogeneity and resilience, we analyzed both analytically and numerically a non-linear sparse neural network with balanced excitatory and inhibitory connections evolving over long time scales. We examined how neural diversity expressed as excitability heterogeneity in this network influences its dynamic volatility (i.e., its susceptibility to critical transitions). We exposed this network to slowly-varying modulatory fluctuations, continuously interrogating its stability and resilience. Our results show that excitability heterogeneity implements a homeostatic control mechanism tuning network stability in a context-dependent way. Such diversity was also found to enhance network resilience, quenching the volatility of its dynamics, effectively making the system independent of changes in many control parameters, such as population size, connection probability, strength and variability of synaptic weights as well as modulatory drive. Taken together, these results highlight the fundamental role played by cell-type heterogeneity in the robustness of brain function in the face of change. Significance StatementContemporary research has identified widespread cell-to-cell intrinsic diversity in the brain, manifest through variations in biophysical features such as neuronal excitability. A natural question that arises from this phenomenon is what functional role, if any, this heterogeneity might serve. Combining computational and mathematical techniques, this interdisciplinary research shows that intrinsic cell-to-cell diversity, far from mere developmental noise, represents a homeostatic control mechanism, promoting the resilience of neuronal circuits. These results highlight the importance of diversity in the robustness and persistence of brain function over time and in the face of change.

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Age-dependent increased sag current in human pyramidal neurons dampens baseline cortical activity

Aging involves various neurobiological changes, although their effect on brain function in humans remains poorly understood. The growing availability of human neuronal and circuit data provides opportunities for uncovering age-dependent changes of brain networks and for constraining models to predict consequences on brain activity. Here we found increased sag voltage amplitude in human middle temporal gyrus layer 5 pyramidal neurons from older subjects, and captured this effect in biophysical models of younger and older pyramidal neurons. We used these models to simulate detailed layer 5 microcircuits and found lower baseline firing in older pyramidal neuron microcircuits, with minimal effect on response. We then validated the predicted reduced baseline firing using extracellular multi-electrode recordings from human brain slices of different ages. Our results thus report changes in human pyramidal neuron input integration properties and provide fundamental insights on the neuronal mechanisms of altered cortical excitability and resting state activity in human aging.

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A corollary discharge mediates saccade related inhibition of single units in mnemonic structures of the human brain

Despite the critical link between visual exploration and memory, little is known about how single-unit activity (SUA) in the human mesial temporal lobe (MTL) is modulated by saccadic eye movements (SEMs). Here we characterize SEM associated SUA modulations, unit-by-unit, and contrast them to image onset, and to occipital lobe SUA. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies SEMs, inhibiting/exciting a unique population of broad/narrow spiking units, respectively, before and during SEMs, and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking SUA to event-related potentials (ERPs), which are directionally modulated following SEMs, we recontextualize the ERP associated with SEM as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded SEM-related ERP in the human brain.

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Resilience through diversity: Loss of neuronal heterogeneity in epileptogenic human tissue renders neural networks more susceptible to sudden changes in synchrony

A myriad of pathological changes associated with epilepsy can be recast as decreases in cell and circuit heterogeneity. We thus propose recontextualizing epileptogenesis as a process where reduction in cellular heterogeneity in part, renders neural circuits less resilient to seizure. By comparing patch clamp recordings from human layer 5 (L5) cortical pyramidal neurons from epileptogenic and non-epileptogenic tissue, we demonstrate significantly decreased biophysical heterogeneity in seizure generating areas. Implemented computationally, this renders model neural circuits prone to sudden transitions into synchronous states with increased firing activity, paralleling ictogenesis. This computational work also explains the surprising finding of significantly decreased excitability in the population activation functions of neurons from epileptogenic tissue. Finally, mathematical analyses reveal a unique bifurcation structure arising only with low heterogeneity and associated with seizure-like dynamics. Taken together, this work provides experimental, computational, and mathematical support for the theory that ictogenic dynamics accompany a reduction in biophysical heterogeneity.

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Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

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Cognitive boundary signals in the human medial temporal lobe shape episodic memory representation

While experience unfolds continuously, memories are organized as a set of discrete events that bind together the "where", "when", and "what" of episodic memory. This segmentation of continuous experience is thought to be facilitated by the detection of salient environmental or cognitive events. However, the underlying neural mechanisms and how such segmentation shapes episodic memory representations remain unclear. We recorded from single neurons in the human medial temporal lobe while subjects watched videos with different types of embedded boundaries and were subsequently evaluated for memories of the video contents. Here we show neurons that signal the presence of cognitive boundaries between subevents from the same episode and neurons that detect the abstract separation between different episodes. The firing rate and spike timing of these boundary-responsive neurons were predictive of later memory retrieval accuracy. At the population level, abrupt neural state changes following boundaries predicted enhanced memory strength but impaired order memory, capturing the behavioral tradeoff subjects exhibited when recalling episodic content versus temporal order. Successful retrieval was associated with reinstatement of the neural state present following boundaries, indicating that boundaries structure memory search. These findings reveal a neuronal substrate for detecting cognitive boundaries and show that cognitive boundary signals facilitate the mnemonic organization of continuous experience as a set of discrete episodic events.

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Implantable photonic neural probes for light-sheet fluorescence brain imaging

SignificanceLight-sheet fluorescence microscopy is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. Here, we demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. AimMass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. ApproachWe develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200 mm diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed and in vitro mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. ResultsThe probes had 5 to 10 addressable sheets and average sheet thicknesses < 16 m for propagation distances up to 300 m in free space. Imaging areas were as large as {approx} 240 m x 490 m in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. ConclusionsThe neural probes can lead to new variants of light-sheet fluorescence microscopy for deep brain imaging and experiments in freely-moving animals.

bioengineering↗

Volitional Control of Individual Neurons in the Human Brain

Can the human brain, a complex interconnected structure of over 80 billion neurons learn to control itself at the most elemental scale - a single neuron. We directly linked the firing rate of a single (direct) neuron to the position of a box on a screen, which participants tried to control. Remarkably, all subjects upregulated the firing rate of the direct neuron in memory structures of their brain. Learning was accompanied by improved performance over trials, simultaneous decorrelation of the direct neuron to local neurons, and direct neuron to beta frequency oscillation phase-locking. Such previously unexplored neuroprosthetic skill learning within memory related brain structures, and associated beta frequency phase-locking implicates the ventral striatum. Our demonstration that humans can volitionally control neuronal activity in mnemonic structures, may provide new ways of probing the function and plasticity of human memory without exogenous stimulation.

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Inter-species h-current differences influence resonant properties in a novel human cortical layer 5 neuron model

While our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically-detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound (PIR) spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.

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Sag currents are a major contributor to human pyramidal cell intrinsic differences across cortical layers and between individuals

In the human neocortex coherent interlaminar theta oscillations are driven by deep cortical layers, suggesting neurons in these layers exhibit distinct electrophysiological properties. To characterize this potential distinctiveness, we use in vitro whole-cell recordings from cortical layers 2 and 3 (L2&3), layer 3c (L3c) and layer 5 (L5) of the human cortex. Across all layers we observe notable heterogeneity, indicating human cortical pyramidal neurons are an electrophysiologically diverse population. L5 pyramidal cells are the most excitable of these neurons and exhibit the most prominent sag current (abolished by blockade of the hyperpolarization activated cation current, Ih). While subthreshold resonance is more common in L3c and L5, we rarely observe this resonance at frequencies greater than 2Hz. However, the frequency dependent gain of L5 neurons reveals they are most adept at tracking both delta and theta frequency inputs, a unique feature that may indirectly be important for the generation of cortical theta oscillations.

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Differential generation of saccade, fixation and image onset event-related potentials in the human mesial temporal lobe

The electrophysiological signatures of encoding and retrieval recorded from mesial temporal lobe (MTL) structures are observed as event related potentials (ERPs) during visual memory tasks. The waveforms of the ERPs associated with the onset of visual stimuli (image-onset) and eye movements (saccades and fixations) provide insights into the mechanisms of their generation. We hypothesized that since eye movements and image-onset (common methods of stimulus presentation when testing memory) provide MTL structures with salient visual information, that perhaps they both engage similar neural mechanisms. To explore this question, we used intracranial electroencephalographic (iEEG) data from the MTLs of 11 patients with medically refractory epilepsy who participated in a visual search task. We sought to characterize electrophysiological responses of MTL structures to saccades, fixations and image onset. We demonstrate that the image-onset response is an evoked/additive response with a low-frequency power increase and post-stimulus phase clustering. In contrast, ERPs following eye movements appeared to arise from phase resetting of higher frequencies than the image onset ERP. Intriguingly, this reset was associated with saccade onset and not saccade termination (fixation), suggesting it is likely the MTL response to a corollary discharge, rather than a response to visual stimulation - in stark contrast to the image onset response. The distinct mechanistic underpinnings of these two ERP may help guide future development of visual memory tasks.

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Transformation of Speech Sequences in Human Sensorimotor Circuits

After we listen to a series of words, we can silently replay them in our mind. Does this mental replay involve a re-activation of our original perceptual representations? We recorded electrocorticographic (ECoG) activity across the lateral cerebral cortex as people heard and then mentally rehearsed spoken sentences. For each region, we tested whether silent rehearsal of sentences involved reactivation of sentence-specific representations established during perception or transformation to a distinct representation. In sensorimotor and premotor cortex, we observed reliable and temporally precise responses to speech; these patterns transformed to distinct sentence-specific representations during mental rehearsal. In contrast, we observed slower and less reliable responses in prefrontal and temporoparietal cortex; these higher-order representations, which were sensitive to sentence semantics, were shared across perception and rehearsal. The mental rehearsal of natural speech involves the transformation of time-resolved speech representations in sensorimotor and premotor cortex, combined with diffuse reactivation of higher-order semantic representations.\n\nConflict of interestThe authors declare no competing financial interests.

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