Control of working memory by phase-amplitude coupling of human hippocampal neurons.

Retaining information in working memory is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference1,2. However, how cognitive control regulates working memory storage is unclear. Here we show 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 their working memory. In the hippocampus, TG-PAC was indicative of working memory load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. The spike timing of these PAC neurons was coordinated with frontal theta activity when cognitive control demand was high. By introducing noise correlations with persistently active neurons in the hippocampus, PAC neurons shaped the geometry of the population code. This led to higher-fidelity representations of working memory content that were associated with improved behaviour. Our results support a multicomponent architecture of working memory1,2, with frontal control managing maintenance of working memory content in storage-related areas3-5. Within this framework, hippocampal TG-PAC integrates cognitive control and working memory storage across brain areas, thereby suggesting a potential mechanism for top-down control over sensory-driven processes.

Intrinsic neural diversity quenches the dynamic volatility of 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 (resilience). To better understand the relationship between excitability heterogeneity (variability in excitability within a population of neurons) and resilience, we analyzed both analytically and numerically a nonlinear sparse neural network with balanced excitatory and inhibitory connections evolving over long time scales. Homogeneous networks demonstrated increases in excitability, and strong firing rate correlations-signs of instability-in response to a slowly varying modulatory fluctuation. Excitability heterogeneity tuned network stability in a context-dependent way by restraining responses to modulatory challenges and limiting firing rate correlations, while enriching dynamics during states of low modulatory drive. Excitability heterogeneity was found to implement a homeostatic control mechanism enhancing network resilience to changes in population size, connection probability, strength and variability of synaptic weights, by quenching the volatility (i.e., its susceptibility to critical transitions) of its dynamics. Together, these results highlight the fundamental role played by cell-to-cell heterogeneity in the robustness of brain function in the face of change.

In-silico EEG biomarkers of reduced inhibition in human cortical microcircuits in depression.

Reduced cortical inhibition by somatostatin-expressing (SST) interneurons has been strongly associated with treatment-resistant depression. However, due to technical limitations it is impossible to establish experimentally in humans whether the effects of reduced SST interneuron inhibition on microcircuit activity have signatures detectable in clinically-relevant brain signals such as electroencephalography (EEG). To overcome these limitations, we simulated resting-state activity and EEG using detailed models of human cortical microcircuits with normal (healthy) or reduced SST interneuron inhibition (depression), and found that depression microcircuits exhibited increased theta, alpha and low beta power (4-16 Hz). The changes in depression involved a combination of an aperiodic broadband and periodic theta components. We then demonstrated the specificity of the EEG signatures of reduced SST interneuron inhibition by showing they were distinct from those corresponding to reduced parvalbumin-expressing (PV) interneuron inhibition. Our study thus links SST interneuron inhibition level to distinct features in EEG simulated from detailed human microcircuits, which can serve to better identify mechanistic subtypes of depression using EEG, and non-invasively monitor modulation of cortical inhibition.

Age-dependent increased sag amplitude 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 multielectrode recordings from human brain slices of different ages. Our results thus report changes in human pyramidal neuron input integration properties and provide fundamental insights into the neuronal mechanisms of altered cortical excitability and resting-state activity in human aging.

Evaluating the Current State of Epilepsy Care in the Province of Ontario.

There are numerous challenges pertaining to epilepsy care across Ontario, including Epilepsy Monitoring Unit (EMU) bed pressures, surgical access and community supports. We sampled the current clinical, community and operational state of Ontario epilepsy centres and community epilepsy agencies post COVID-19 pandemic. A 44-item survey was distributed to all 11 district and regional adult and paediatric Ontario epilepsy centres. Qualitative responses were collected from community epilepsy agencies. Results revealed ongoing gaps in epilepsy care across Ontario, with EMU bed pressures and labour shortages being limiting factors. A clinical network advising the Ontario Ministry of Health will improve access to epilepsy care.

Diversity-induced trivialization and resilience of neural dynamics.

Heterogeneity is omnipresent across all living systems. Diversity enriches the dynamical repertoire of these systems but remains challenging to reconcile with their manifest robustness and dynamical persistence over time, a fundamental feature called resilience. To better understand the mechanism underlying resilience in neural circuits, we considered a nonlinear network model, extracting the relationship between excitability heterogeneity and resilience. To measure resilience, we quantified the number of stationary states of this network, and how they are affected by various control parameters. We analyzed both analytically and numerically gradient and non-gradient systems modeled as non-linear sparse neural networks evolving over long time scales. Our analysis shows that neuronal heterogeneity quenches the number of stationary states while decreasing the susceptibility to bifurcations: a phenomenon known as trivialization. Heterogeneity was found to implement a homeostatic control mechanism enhancing network resilience to changes in network size and connection probability by quenching the system's dynamic volatility.

Beamforming Seizures from the Temporal Lobe Using Magnetoencephalography.

BACKGROUND: Surgical treatment of drug-resistant temporal lobe epilepsy (TLE) depends on proper identification of the seizure onset zone (SOZ) and differentiation of mesial, temporolimbic seizure onsets from temporal neocortical seizure onsets. Noninvasive source imaging using electroencephalography (EEG) and magnetoencephalography (MEG) can provide accurate information on interictal spike localization; however, EEG and MEG have low sensitivity for epileptiform activity restricted to deep temporolimbic structures. Moreover, in mesial temporal lobe epilepsy (MTLE), interictal spikes frequently arise in neocortical foci distant from the SOZ, rendering interictal spike localization potentially misleading for presurgical planning. METHODS: In this study, we used two different beamformer techniques applied to the MEG signal of ictal events acquired during EEG-MEG recordings in six patients with TLE (three neocortical, three MTLE) in whom the ictal source localization results could be compared to ground truth SOZ localizations determined from intracranial EEG and/or clinical, neuroimaging, and postsurgical outcome evidence. RESULTS: Beamformer analysis proved to be highly accurate in all cases and was able to identify focal SOZs in mesial, temporolimbic structures. In three patients, interictal spikes were absent, too complex for dipole modeling, or localized to anterolateral temporal neocortex distant to a mesial temporal SOZ, and thus unhelpful in presurgical investigation. CONCLUSIONS: MEG beamformer source reconstruction is suitable for analysis of ictal events in TLE and can complement or supersede the traditional analysis of interictal spikes. The method outlined is applicable to any type of epileptiform event, expanding the information value of MEG and broadening its utility for presurgical recording in epilepsy.

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 reactivation of our original perceptual dynamics? 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 less reliable and less temporally precise responses in prefrontal and temporoparietal cortex; these higher-order representations, which were sensitive to sentence semantics, were shared across perception and rehearsal of the same sentence. The mental rehearsal of natural speech involves the transformation of stimulus-locked speech representations in sensorimotor and premotor cortex, combined with diffuse reactivation of higher-order semantic representations.

Optical phased array neural probes for beam-steering in brain tissue.

Implantable silicon neural probes with integrated nanophotonic waveguides can deliver patterned dynamic illumination into brain tissue at depth. Here, we introduce neural probes with integrated optical phased arrays and demonstrate optical beam steering in vitro. Beam formation in brain tissue is simulated and characterized. The probes are used for optogenetic stimulation and calcium imaging.

Volitional control of individual neurons in the human brain.

Brain-machine interfaces allow neuroscientists to causally link specific neural activity patterns to a particular behaviour. Thus, in addition to their current clinical applications, brain-machine interfaces can also be used as a tool to investigate neural mechanisms of learning and plasticity in the brain. Decades of research using such brain-machine interfaces have shown that animals (non-human primates and rodents) can be operantly conditioned to self-regulate neural activity in various motor-related structures of the brain. Here, we ask whether the human brain, a complex interconnected structure of over 80 billion neurons, can learn to control itself at the most elemental scale-a single neuron. We used the unique opportunity to record single units in 11 individuals with epilepsy to explore whether the firing rate of a single (direct) neuron in limbic and other memory-related brain structures can be brought under volitional control. To do this, we developed a visual neurofeedback task in which participants were trained to move a block on a screen by modulating the activity of an arbitrarily selected neuron from their brain. Remarkably, participants were able to volitionally modulate the firing rate of the direct neuron in these previously uninvestigated structures. We found that a subset of participants (learners), were able to improve their performance within a single training session. Successful learning was characterized by (i) highly specific modulation of the direct neuron (demonstrated by significantly increased firing rates and burst frequency); (ii) a simultaneous decorrelation of the activity of the direct neuron from the neighbouring neurons; and (iii) robust phase-locking of the direct neuron to local alpha/beta-frequency oscillations, which may provide some insights in to the potential neural mechanisms that facilitate this type of learning. Volitional control of neuronal activity in mnemonic structures may provide new ways of probing the function and plasticity of human memory without exogenous stimulation. Furthermore, self-regulation of neural activity in these brain regions may provide an avenue for the development of novel neuroprosthetics for the treatment of neurological conditions that are commonly associated with pathological activity in these brain structures, such as medically refractory epilepsy.

Modeling Reveals Human-Rodent Differences in H-Current Kinetics Influencing Resonance in Cortical Layer 5 Neurons.

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 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.

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

Single-neuron correlate of epilepsy-related cognitive deficits in visual recognition memory in right mesial temporal lobe.

OBJECTIVE: Impaired memory is a common comorbidity of refractory temporal lobe epilepsy (TLE) and often perceived by patients as more problematic than the seizures themselves. The objective of this study is to understand what the relationship of these behavioral impairments is to the underlying pathophysiology, as there are currently no treatments for these deficits, and it remains unknown what circuits are affected. METHODS: We recorded single neurons in the medial temporal lobes (MTLs) of 62 patients (37 with refractory TLE) who performed a visual recognition memory task to characterize the relationship between behavior, tuning, and anatomical location of memory selective and visually selective neurons. RESULTS: Subjects with a seizure onset zone (SOZ) in the right but not left MTL demonstrated impaired ability to recollect as indicated by the degree of asymmetry of the receiver operating characteristic curve. Of the 1973 recorded neurons, 159 were memory selective (MS) and 366 were visually selective (VS) category cells. The responses of MS neurons located within right but not left MTL SOZs were impaired during high-confidence retrieval trials, mirroring the behavioral deficit seen both in our task and in standardized neuropsychological tests. In contrast, responses of VS neurons were unimpaired in both left and right MTL SOZs. Our findings show that neuronal dysfunction within SOZs in the MTL was specific to a functional cell type and behavior, whereas other cell types respond normally even within the SOZ. We show behavioral metrics that detect right MTL SOZ-related deficits and identify a neuronal correlate of this impairment. SIGNIFICANCE: Together, these findings show that single-cell responses can be used to assess the causal effects of local circuit disruption by an SOZ in the MTL, and establish a neural correlate of cognitive impairment due to epilepsy that can be used as a biomarker to assess the efficacy of novel treatments.

EEG phase synchronization during semantic unification relates to individual differences in children's vocabulary skill.

As we listen to speech, our ability to understand what was said requires us to retrieve and bind together individual word meanings into a coherent discourse representation. This so-called semantic unification is a fundamental cognitive skill, and its development relies on the integration of neural activity throughout widely distributed functional brain networks. In this proof-of-concept study, we examine, for the first time, how these functional brain networks develop in children. Twenty-six children (ages 4-17) listened to well-formed sentences and sentences containing a semantic violation, while EEG was recorded. Children with stronger vocabulary showed N400 effects that were more concentrated to centroparietal electrodes and greater EEG phase synchrony (phase lag index; PLI) between right centroparietal and bilateral frontocentral electrodes in the delta frequency band (1-3 Hz) 1.27-1.53 s after listening to well-formed sentences compared to sentences containing a semantic violation. These effects related specifically to individual differences in receptive vocabulary, perhaps pointing to greater recruitment of functional brain networks important for top-down semantic unification with development. Less skilled children showed greater delta phase synchrony for violation sentences 3.41-3.64 s after critical word onset. This later effect was partly driven by individual differences in nonverbal reasoning, perhaps pointing to non-verbal compensatory processing to extract meaning from speech in children with less developed vocabulary. We suggest that functional brain network communication, as measured by momentary changes in the phase synchrony of EEG oscillations, develops throughout the school years to support language comprehension in different ways depending on children's verbal and nonverbal skill levels.

Music in epilepsy: Predicting the effects of the unpredictable.

Epilepsy is the most common serious neurological disorder in the world. Despite medical and surgical treatment, many individuals continue to have seizures, suggesting adjunctive management strategies are required. Promising effects of daily listening to Mozart K.448 on reducing seizure frequency in individuals with epilepsy have been demonstrated. In our recent randomized control study, we reported the positive effect of daily listening to Mozart K.448 on reducing seizures compared to daily listening to a control piece with an identical power spectrum to the Mozart piece yet devoid of rhythmic structure. Despite the promising effect of listening to Mozart K.448 on reducing seizure in individuals with epilepsy, the mechanism(s) underlying such an effect is largely unknown. In this paper, we specifically review how auditory stimulation alters brain dynamics, in addition to computational approaches to define the structural features of classical music, to then propose a plausible mechanism for the underlying anti-convulsant effects of listening to Mozart K.448. We review the evidence demonstrating that some Mozart pieces in addition to compositions from other composers such as Joplin contain less predictable rhythmic structure in comparison with other composers such as Beethoven. We propose through both entrainment and 1/f resonance mechanisms that listening to musical pieces containing the least predictable rhythmic structure, might reduce the self similarity of brain activity which in turn modulates low frequency power, situating the brain in a more "noise like" state and away from brain dynamics that can lead to seizures.

Differential Generation of Saccade, Fixation, and Image-Onset Event-Related Potentials in the Human Mesial Temporal Lobe.

Event-related potentials (ERPs) are a commonly used electrophysiological signature for studying mesial temporal lobe (MTL) function during visual memory tasks. 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 provide MTL structures with salient visual information, perhaps they both engage similar neural mechanisms. To explore this question, we used intracranial electroencephalographic data from the MTLs of 11 patients with medically refractory epilepsy who participated in a visual search task. We characterized the electrophysiological responses of MTL structures to saccades, fixations, and image-onset. We demonstrated that the image-onset response is an evoked/additive response with a low-frequency power increase. 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 termination (fixation), suggesting it is likely the MTL response to a corollary discharge, rather than a response to visual stimulation. We discuss the distinct mechanistic underpinnings of these responses which shed light on the underlying neural circuitry involved in visual memory processing.

Severe Intraoperative Orbital Venous Congestion during Resection of a Frontal Meningioma Presenting with Post-operative Vision Loss and Ophthalmoplegia: A Case Report.

We describe a unique case of a middle-aged man who noticed complete vision loss in the right eye after awaking from resection of a large right-sided frontal meningioma. Visual acuity was hand motions, and there were multiple signs of right orbital venous congestion. Magnetic resonance imaging and venography (MRI/V) of the brain and orbits demonstrated expected post-operative findings with no evidence of cavernous sinus thrombosis or fistula. Empiric treatment with intravenous antibiotics and intravenous methylprednisolone were ineffective. Immediate post-operative computerised tomography (CT) images were re-reviewed and revealed right restricted diffusion of the entire intraorbital right optic nerve. Discussion with the neurosurgical team revealed that during craniotomy, a prominent diploic venous plexus in the frontal bone adjacent to the meningioma was identified and coagulated with bone wax. Review of pre-operative imaging revealed large diploid flow voids in the right frontal bone, corresponding to the intraoperative findings. This prominent venous plexus appeared to drain from the meningioma posteriorly into the vein of Labbe. A second pathway drained anteriorly through the right angular vein into the orbit. We hypothesise that the posterior outflow pathway was coagulated intraoperatively, causing redirection of all venous outflow from the meningioma into the right orbit through the anterior pathway. This resulted in significant orbital hypertension with manifest signs and symptoms. Furthermore, sudden rise in intraorbital pressure led to infarction of the optic nerve, leaving the patient with hand motions vision. We suggest that pre-operative vascular imaging should be performed in patients with large meningiomas, as pre-operative embolisation of venous outflow channels may prevent severe post-operative complications.

Brief activation of GABAergic interneurons initiates the transition to ictal events through post-inhibitory rebound excitation.

Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like ("ictal") event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.

Theta-gamma coordination between anterior cingulate and prefrontal cortex indexes correct attention shifts.

Anterior cingulate and lateral prefrontal cortex (ACC/PFC) are believed to coordinate activity to flexibly prioritize the processing of goal-relevant over irrelevant information. This between-area coordination may be realized by common low-frequency excitability changes synchronizing segregated high-frequency activations. We tested this coordination hypothesis by recording in macaque ACC/PFC during the covert utilization of attention cues. We found robust increases of 5-10 Hz (theta) to 35-55 Hz (gamma) phase-amplitude correlation between ACC and PFC during successful attention shifts but not before errors. Cortical sites providing theta phases (i) showed a prominent cue-induced phase reset, (ii) were more likely in ACC than PFC, and (iii) hosted neurons with burst firing events that synchronized to distant gamma activity. These findings suggest that interareal theta-gamma correlations could follow mechanistically from a cue-triggered reactivation of rule memory that synchronizes theta across ACC/PFC.

Predictive coding: A contemporary view on the burden of normality and forced normalization in individuals undergoing epilepsy surgery.

Following epilepsy surgery, a good psychosocial outcome is not necessarily contingent on a good seizure outcome. Increasingly, it is believed that "successful" surgery is a combination of both an acceptable and expected seizure status as well as the individual's perception of improvements in quality of life (QOL). The factors that create this optimal outcome remain an ongoing area of research in the epilepsy community. That being said, there have been some major breakthroughs in observing and understanding poor outcomes seen in a subset of postoperative patients with epilepsy. Characteristics of burden of normality and forced normalization are two phenomena that have been evident in cases of poor postoperative outcomes. In this review, we provide a summary of research and concepts used to explain these poor QOL outcomes for a seemingly successful surgery and suggest a contemporary view in understanding the mechanism of forced normalization through understanding the brain as a predictive organ. Using such a predictive coding model together with recommendations of other studies, we suggest the crucial need for a preoperative intervention addressing patient predictions and expectations to optimize on the benefits achievable through epilepsy surgery.