Structural Connectivity between Olfactory Tubercle and Ventrolateral Periaqueductal Gray Implicated in Human Feeding Behavior.

The olfactory tubercle (TUB), also called the tubular striatum, receives direct input from the olfactory bulb and, along with the nucleus accumbens, is one of the two principal components of the ventral striatum. As a key component of the reward system, the ventral striatum is involved in feeding behavior, but the vast majority of research on this structure has focused on the nucleus accumbens, leaving the TUB's role in feeding behavior understudied. Given the importance of olfaction in food seeking and consumption, olfactory input to the striatum should be an important contributor to motivated feeding behavior. Yet the TUB is vastly understudied in humans, with very little understanding of its structural organization and connectivity. In this study, we analyzed macrostructural variations between the TUB and the whole brain and explored the relationship between TUB structural pathways and feeding behavior, using body mass index (BMI) as a proxy in females and males. We identified a unique structural covariance between the TUB and the periaqueductal gray (PAG), which has recently been implicated in the suppression of feeding. We further show that the integrity of the white matter tract between the two regions is negatively correlated with BMI. Our findings highlight a potential role for the TUB-PAG pathway in the regulation of feeding behavior in humans.

Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity.

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Unraveling the Link between Olfactory Deficits and Neuropsychiatric Disorders.

Smell loss has caught public attention during the recent COVID-19 pandemic. Research on olfactory function in health and disease gains new momentum. Smell deficits have long been recognized as an early clinical sign associated with neuropsychiatric disorders. Here we review research on the associations between olfactory deficits and neuropathological conditions, focusing on recent progress in four areas: (1) human clinical studies of the correlations between smell deficits and neuropsychiatric disorders; (2) development of olfactory mucosa-derived tissue and cell models for studying the molecular pathologic mechanisms; (3) recent findings in brain imaging studies of structural and functional connectivity changes in olfactory pathways in neuropsychiatric disorders; and (4) application of preclinical animal models to validate and extend the findings from human subjects. Together, these studies have provided strong evidence of the link between the olfactory system and neuropsychiatric disorders, highlighting the relevance of deepening our understanding of the role of the olfactory system in pathophysiological processes. Following the lead of studies reviewed here, future research in this field may open the door to the early detection of neuropsychiatric disorders, personalized treatment approaches, and potential therapeutic interventions through nasal administration techniques, such as nasal brush or nasal spray.

Mapping the Microstructure and Striae of the Human Olfactory Tract with Diffusion MRI.

The human sense of smell plays an important role in appetite and food intake, detecting environmental threats, social interactions, and memory processing. However, little is known about the neural circuity supporting its function. The olfactory tracts project from the olfactory bulb along the base of the frontal cortex, branching into several striae to meet diverse cortical regions. Historically, using diffusion magnetic resonance imaging (dMRI) to reconstruct the human olfactory tracts has been prevented by susceptibility and motion artifacts. Here, we used a dMRI method with readout segmentation of long variable echo-trains (RESOLVE) to minimize image distortions and characterize the human olfactory tracts in vivo We collected high-resolution dMRI data from 25 healthy human participants (12 male and 13 female) and performed probabilistic tractography using constrained spherical deconvolution (CSD). At the individual subject level, we identified the lateral, medial, and intermediate striae with their respective cortical connections to the piriform cortex and amygdala (AMY), olfactory tubercle (OT), and anterior olfactory nucleus (AON). We combined individual results across subjects to create a normalized, probabilistic atlas of the olfactory tracts. We then investigated the relationship between olfactory perceptual scores and measures of white matter integrity, including mean diffusivity (MD). Importantly, we found that olfactory tract MD negatively correlated with odor discrimination performance. In summary, our results provide a detailed characterization of the connectivity of the human olfactory tracts and demonstrate an association between their structural integrity and olfactory perceptual function.SIGNIFICANCE STATEMENT This study provides the first detailed in vivo description of the cortical connectivity of the three olfactory tract striae in the human brain, using diffusion magnetic resonance imaging (dMRI). Additionally, we show that tract microstructure correlates with performance on an odor discrimination task, suggesting a link between the structural integrity of the olfactory tracts and odor perception. Lastly, we generated a normalized probabilistic atlas of the olfactory tracts that may be used in future research to study its integrity in health and disease.

Anticipation-induced delta phase reset improves human olfactory perception.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

Amygdala-stimulation-induced apnea is attention and nasal-breathing dependent.

OBJECTIVE: Evidence suggests that disordered breathing is critically involved in Sudden Unexpected Death in Epilepsy (SUDEP). To that end, evaluating structures that are activated by seizures and can activate brain regions that produce cardiorespiratory changes can further our understanding of the pathophysiology of SUDEP. Past preclinical studies have shown that electrical stimulation of the human amygdala induces apnea, suggesting a role for the amygdala in controlling respiration. In this study, we aimed to both confirm these findings in a larger group of patients with intractable temporal lobe epilepsy (TLE) and also further explore the anatomical and cognitive properties of this effect. METHODS: Seven surgical TLE patients had depth electrodes implanted in the amygdala that were used to deliver electrical stimulation during functional mapping preceding resection. Real-time respiratory monitoring was performed in each patient to confirm apnea. RESULTS: Our data confirm that amygdala stimulation reliably induces apnea (occurring in all 7 patients) and further suggest that apnea can be overcome by instructing the patient to inhale, and can be prevented entirely by breathing through the mouth before electrical stimulation. Finally, stimulation-induced apnea occurred only when stimulating the medial-most amygdalar contacts located in the central nucleus. INTERPRETATION: These findings confirm a functional connection between the amygdala and respiratory control in humans. Moreover, they suggest specific amygdalar nuclei may be critical in mediating this effect and that attentional state is critical to apnea mediated by amygdala activation-perhaps alluding to future development of strategies for the prevention of SUDEP. Ann Neurol 2018;83:460-471.

Automated analysis of breathing waveforms using BreathMetrics: a respiratory signal processing toolbox.

Nasal inhalation is the basis of olfactory perception and drives neural activity in olfactory and limbic brain regions. Therefore, our ability to investigate the neural underpinnings of olfaction and respiration can only be as good as our ability to characterize features of respiratory behavior. However, recordings of natural breathing are inherently nonstationary, nonsinusoidal, and idiosyncratic making feature extraction difficult to automate. The absence of a freely available computational tool for characterizing respiratory behavior is a hindrance to many facets of olfactory and respiratory neuroscience. To solve this problem, we developed BreathMetrics, an open-source tool that automatically extracts the full set of features embedded in human nasal airflow recordings. Here, we rigorously validate BreathMetrics' feature estimation accuracy on multiple nasal airflow datasets, intracranial electrophysiological recordings of human olfactory cortex, and computational simulations of breathing signals. We hope this tool will allow researchers to ask new questions about how respiration relates to body, brain, and behavior.

Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function.

The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2-12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16-0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. SIGNIFICANCE STATEMENT: Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment of local field potential activity in human piriform cortex, amygdala, and hippocampus. These effects diminished when breathing was diverted to the mouth, highlighting the importance of nasal airflow for generating respiratory oscillations. Finally, behavioral data in healthy subjects suggest that breathing phase systematically influences cognitive tasks related to amygdala and hippocampal functions.

Human Amygdala Represents the Complete Spectrum of Subjective Valence.

Although the amygdala is a major locus for hedonic processing, how it encodes valence information is poorly understood. Given the hedonic potency of odor stimuli and the amygdala's anatomical proximity to the peripheral olfactory system, we combined high-resolution fMRI with pattern-based multivariate techniques to examine how valence information is encoded in the amygdala. Ten human subjects underwent fMRI scanning while smelling 9 odorants that systematically varied in perceived valence. Representational similarity analyses showed that amygdala codes the entire dimension of valence, ranging from pleasantness to unpleasantness. This unidimensional representation significantly correlated with self-reported valence ratings but not with intensity ratings. Furthermore, within-trial valence representations evolved over time, prioritizing earlier differentiation of unpleasant stimuli. Together, these findings underscore the idea that both spatial and temporal features uniquely encode pleasant and unpleasant odor valence in the amygdala. The availability of a unidimensional valence code in the amygdala, distributed in both space and time, would create greater flexibility in determining the pleasantness or unpleasantness of stimuli, providing a mechanism by which expectation, context, attention, and learning could influence affective boundaries for guiding behavior. SIGNIFICANCE STATEMENT: Our findings elucidate the mechanisms of affective processing in the amygdala by demonstrating that this brain region represents the entire valence dimension from pleasant to unpleasant. An important implication of this unidimensional valence code is that pleasant and unpleasant valence cannot coexist in the amygdale because overlap of fMRI ensemble patterns for these two valence extremes obscures their unique content. This functional architecture, whereby subjective valence maps onto a pattern continuum between pleasant and unpleasant poles, offers a robust mechanism by which context, expectation, and experience could alter the set-point for valence-based behavior. Finally, identification of spatial and temporal differentiation of valence in amygdala may shed new insights into individual differences in emotional responding, with potential relevance for affective disorders.

Social cognitive regions of human association cortex are selectively connected to the amygdala.

Reasoning about someone's thoughts and intentions - i.e., forming a theory of mind - is an important aspect of social cognition that relies on association areas of the brain that have expanded disproportionately in the human lineage. We recently showed that these association zones comprise parallel distributed networks that, despite occupying adjacent and interdigitated regions, serve dissociable functions. One network is selectively recruited by theory of mind processes. What circuit properties differentiate these parallel networks? Here, we show that social cognitive association areas are intrinsically and selectively connected to regions of the anterior medial temporal lobe that are implicated in emotional learning and social behaviors, including the amygdala at or near the basolateral complex and medial nucleus. The results suggest that social cognitive functions emerge through coordinated activity between amygdala circuits and a distributed association network, and indicate the medial nucleus may play an important role in social cognition in humans.

Calming effect of Clinically Designed Improvisatory Music for patients admitted to the epilepsy monitoring unit during the COVID-19 pandemic: a pilot study.

Background: Epilepsy monitoring requires simulating seizure-inducing conditions which frequently causes discomfort to epilepsy monitoring unit (EMU) patients. COVID-19 hospital restrictions added another layer of stress during hospital admissions. The purpose of this pilot study was to provide evidence that live virtual Clinically Designed Improvisatory Music (CDIM) brings relief to EMU patients for their psychological distress. Methods: Five persons with epilepsy (PWEs) in the EMU during the COVID-19 lockdown participated in the study (average age ± SD = 30.2 ± 6 years). Continuous electroencephalogram (EEG) and electrocardiogram (EKG) were obtained before, during, and after live virtual CDIM. CDIM consisted of 40 minutes of calming music played by a certified clinical music practitioner (CMP) on viola. Post-intervention surveys assessed patients' emotional state on a 1-10 Likert scale. Alpha/beta power spectral density ratio was calculated for each subject across the brain and was evaluated using one-way repeated analysis of variance, comparing 20 minutes before, during, and 20 minutes after CDIM. Post-hoc analysis was performed using paired t-test at the whole brain level and regions with peak changes. Results: Patients reported enhanced emotional state (9 ± 1.26), decrease in tension (9.6 ± 0.49), decreased restlessness (8.6 ± 0.80), increased pleasure (9.2 ± 0.98), and likelihood to recommend (10 ± 0) on a 10-point Likert scale. Based on one-way repeated analysis of variance, alpha/beta ratio increased at whole-brain analysis (F3,12 = 5.01, P = 0.018) with a peak in midline (F3,12 = 6.63, P = 0.0068 for Cz) and anterior medial frontal region (F3,12 = 6.45, P = 0.0076 for Fz) during CDIM and showed a trend to remain increased post-intervention. Conclusion: In this pilot study, we found positive effects of CDIM as reported by patients, and an increased alpha/beta ratio with meaningful electroencephalographic correlates due to the calming effects in response to CDIM. Our study provides proof of concept that live virtual CDIM offered demonstrable comfort with biologic correlations for patients admitted in the EMU during the COVID-19 pandemic.

High-precision mapping reveals the structure of odor coding in the human brain.

Odor perception is inherently subjective. Previous work has shown that odorous molecules evoke distributed activity patterns in olfactory cortices, but how these patterns map on to subjective odor percepts remains unclear. In the present study, we collected neuroimaging responses to 160 odors from 3 individual subjects (18 h per subject) to probe the neural coding scheme underlying idiosyncratic odor perception. We found that activity in the orbitofrontal cortex (OFC) represents the fine-grained perceptual identity of odors over and above coarsely defined percepts, whereas this difference is less pronounced in the piriform cortex (PirC) and amygdala. Furthermore, the implementation of perceptual encoding models enabled us to predict olfactory functional magnetic resonance imaging responses to new odors, revealing that the dimensionality of the encoded perceptual spaces increases from the PirC to the OFC. Whereas encoding of lower-order dimensions generalizes across subjects, encoding of higher-order dimensions is idiosyncratic. These results provide new insights into cortical mechanisms of odor coding and suggest that subjective olfactory percepts reside in the OFC.

High-Frequency Oscillations in Tumor-Related Epilepsy.

INTRODUCTION: To define the patient characteristics, tumor characteristics, and clinical course of patients with primary brain tumors with high-frequency oscillations (HFOs) recorded on electrocorticography. Furthermore, we evaluated whether the presence of HFOs portends a greater risk of postoperative tumor-related epilepsy and whether the resection of HFO-generating tissue reduces likelihood of postoperative tumor-related epilepsy. METHODS: This was a retrospective study of 35 patients undergoing awake craniotomy for tumor resection, all of whom underwent intraoperative electrocorticography. Electrocorticography data were reviewed to assess the presence of HFOs and determine their contact locations. The data were analyzed to determine whether HFO-generating tissue was included in the resection and relationship to postoperative seizure outcome. RESULTS: Seventeen patients (48.5%) were found to have HFOs. Very few patients (4 of 35, 11.4%) had sharp waves. Patients with and without HFOs did not significantly differ in demographics, presentation, tumor characteristics, or tumor molecular genetics. A history of seizures prior to resection was not associated with the presence of HFOs ( P = 0.62), although when patients had seizures during the same hospitalization as the resection, HFOs were more likely to be present ( P = 0.045). Extent of HFO resection was not associated with the likelihood of postoperative seizure freedom. CONCLUSIONS: Approximately half (48.5%) of patients undergoing resection for a primary brain tumor had HFOs. Although HFO resection was not shown to lead to improved seizure freedom, this study was limited by a small sample size, and further investigation into HFO resection and patient outcomes in this population is warranted.

Quantity of SARS-CoV-2 RNA copies exhaled per minute during natural breathing over the course of COVID-19 infection.

SARS-CoV-2 is spread through exhaled breath of infected individuals. A fundamental question in understanding transmission of SARS-CoV-2 is how much virus an individual is exhaling into the environment while they breathe, over the course of their infection. Research on viral load dynamics during COVID-19 infection has focused on internal swab specimens, which provide a measure of viral loads inside the respiratory tract, but not on breath. Therefore, the dynamics of viral shedding on exhaled breath over the course of infection are poorly understood. Here, we collected exhaled breath specimens from COVID-19 patients and used RTq-PCR to show that numbers of exhaled SARS-CoV-2 RNA copies during COVID-19 infection do not decrease significantly until day 8 from symptom-onset. COVID-19-positive participants exhaled an average of 80 SARS-CoV-2 viral RNA copies per minute during the first 8 days of infection, with significant variability both between and within individuals, including spikes over 800 copies a minute in some patients. After day 8, there was a steep drop to levels nearing the limit of detection, persisting for up to 20 days. We further found that levels of exhaled viral RNA increased with self-rated symptom-severity, though individual variation was high. Levels of exhaled viral RNA did not differ across age, sex, time of day, vaccination status or viral variant. Our data provide a fine-grained, direct measure of the number of SARS-CoV-2 viral copies exhaled per minute during natural breathing-including 312 breath specimens collected multiple times daily over the course of infection-in order to fill an important gap in our understanding of the time course of exhaled viral loads in COVID-19.

Impact of intraoperative direct cortical stimulation dynamics on perioperative seizures and afterdischarge frequency in patients undergoing awake craniotomy.

OBJECTIVE: Intraoperative stimulation is used as a crucial adjunct in neurosurgical oncology, allowing for greater extent of resection while minimizing morbidity. However, limited data exist regarding the impact of cortical stimulation on the frequency of perioperative seizures in these patients. METHODS: A retrospective chart review of patients undergoing awake craniotomy with electrocorticography data by a single surgeon at the authors' institution between 2013 and 2020 was conducted. Eighty-three patients were identified, and electrocorticography, stimulation, and afterdischarge (AD)/seizure data were collected and analyzed. Stimulation characteristics (number, amplitude, density [stimulations per minute], composite score [amplitude × density], total and average stimulation duration, and number of positive stimulation sites) were analyzed for association with intraoperative seizures (ISs), ADs, and postoperative clinical seizures. RESULTS: Total stimulation duration (p = 0.005), average stimulation duration (p = 0.010), and number of stimulations (p = 0.020) were found to significantly impact AD incidence. A total stimulation duration of more than 145 seconds (p = 0.04) and more than 60 total stimulations (p = 0.03) resulted in significantly higher rates of ADs. The total number of positive stimulation sites was associated with increased IS (p = 0.048). Lesions located within the insula (p = 0.027) were associated with increased incidence of ADs. Patients undergoing repeat awake craniotomy were more likely to experience IS (p = 0.013). Preoperative antiepileptic drug use, seizure history, and number of prior resections of any type showed no impact on the outcomes considered. The charge transferred to the cortex per second during mapping was significantly higher in the 10 seconds leading to AD than at any other time point examined in patients experiencing ADs, and was significantly higher than any time point in patients not experiencing ADs or ISs. Although the rate of transfer for patients experiencing ISs was highest in the 10 seconds prior to the seizure, it was not significantly different from those who did not experience an AD or IS. CONCLUSIONS: The data suggest that intraoperative cortical stimulation is a safe and effective technique in maximizing extent of resection while minimizing neurological morbidity in patients undergoing awake craniotomies, and that surgeons may avoid ADs and ISs by minimizing duration and total number of stimulations and by decreasing the overall charge transferred to the cortex during mapping procedures.

Identification of human gustatory cortex by activation likelihood estimation.

Over the last two decades, neuroimaging methods have identified a variety of taste-responsive brain regions. Their precise location, however, remains in dispute. For example, taste stimulation activates areas throughout the insula and overlying operculum, but identification of subregions has been inconsistent. Furthermore, literature reviews and summaries of gustatory brain activations tend to reiterate rather than resolve this ambiguity. Here, we used a new meta-analytic method [activation likelihood estimation (ALE)] to obtain a probability map of the location of gustatory brain activation across 15 studies. The map of activation likelihood values can also serve as a source of independent coordinates for future region-of-interest analyses. We observed significant cortical activation probabilities in: bilateral anterior insula and overlying frontal operculum, bilateral mid dorsal insula and overlying Rolandic operculum, and bilateral posterior insula/parietal operculum/postcentral gyrus, left lateral orbitofrontal cortex (OFC), right medial OFC, pregenual anterior cingulate cortex (prACC) and right mediodorsal thalamus. This analysis confirms the involvement of multiple cortical areas within insula and overlying operculum in gustatory processing and provides a functional "taste map" which can be used as an inclusive mask in the data analyses of future studies. In light of this new analysis, we discuss human central processing of gustatory stimuli and identify topics where increased research effort is warranted.

Human Primary Olfactory Amygdala Subregions Form Distinct Functional Networks, Suggesting Distinct Olfactory Functions.

Three subregions of the amygdala receive monosynaptic projections from the olfactory bulb, making them part of the primary olfactory cortex. These primary olfactory areas are located at the anterior-medial aspect of the amygdala and include the medial amygdala (MeA), cortical amygdala (CoA), and the periamygdaloid complex (PAC). The vast majority of research on the amygdala has focused on the larger basolateral and basomedial subregions, which are known to be involved in implicit learning, threat responses, and emotion. Fewer studies have focused on the MeA, CoA, and PAC, with most conducted in rodents. Therefore, our understanding of the functions of these amygdala subregions is limited, particularly in humans. Here, we first conducted a review of existing literature on the MeA, CoA, and PAC. We then used resting-state fMRI and unbiased k-means clustering techniques to show that the anatomical boundaries of human MeA, CoA, and PAC accurately parcellate based on their whole-brain resting connectivity patterns alone, suggesting that their functional networks are distinct, relative both to each other and to the amygdala subregions that do not receive input from the olfactory bulb. Finally, considering that distinct functional networks are suggestive of distinct functions, we examined the whole-brain resting network of each subregion and speculated on potential roles that each region may play in olfactory processing. Based on these analyses, we speculate that the MeA could potentially be involved in the generation of rapid motor responses to olfactory stimuli (including fight/flight), particularly in approach/avoid contexts. The CoA could potentially be involved in olfactory-related reward processing, including learning and memory of approach/avoid responses. The PAC could potentially be involved in the multisensory integration of olfactory information with other sensory systems. These speculations can be used to form the basis of future studies aimed at clarifying the olfactory functions of these under-studied primary olfactory areas.

HFOApp: A MATLAB Graphical User Interface for High-Frequency Oscillation Marking.

Epilepsy affects 3.4 million people in the United States, and, despite the availability of numerous antiepileptic drugs, 36% of patients have uncontrollable seizures, which severely impact quality of life. High-frequency oscillations (HFOs) are a potential biomarker of epileptogenic tissue that could be useful in surgical planning. As a result, research into the efficacy of HFOs as a clinical tool has increased over the last 2 decades. However, detection and identification of these transient rhythms in intracranial electroencephalographic recordings remain time-consuming and challenging. Although automated detection algorithms have been developed, their results are widely inconsistent, reducing reliability. Thus, manual marking of HFOs remains the gold standard, and manual review of automated results is required. However, manual marking and review are time consuming and can still produce variable results because of their subjective nature and the limitations in functionality of existing open-source software. Our goal was to develop a new software with broad application that improves on existing open-source HFO detection applications in usability, speed, and accuracy. Here, we present HFOApp: a free, open-source, easy-to-use MATLAB-based graphical user interface for HFO marking. This toolbox offers a high degree of intuitive and ergonomic usability and integrates interactive automation-assist options with manual marking, significantly reducing the time needed for review and manual marking of recordings, while increasing inter-rater reliability. The toolbox also features simultaneous multichannel detection and marking. HFOApp was designed as an easy-to-use toolbox for clinicians and researchers to quickly and accurately mark, quantify, and characterize HFOs within electrophysiological datasets.

Human hippocampal connectivity is stronger in olfaction than other sensory systems.

During mammalian evolution, primate neocortex expanded, shifting hippocampal functional networks away from primary sensory cortices, towards association cortices. Reflecting this rerouting, human resting hippocampal functional networks preferentially include higher association cortices, while those in rodents retained primary sensory cortices. Research on human visual, auditory and somatosensory systems shows evidence of this rerouting. Olfaction, however, is unique among sensory systems in its relative structural conservation throughout mammalian evolution, and it is unknown whether human primary olfactory cortex was subject to the same rerouting. We combined functional neuroimaging and intracranial electrophysiology to directly compare hippocampal functional networks across human sensory systems. We show that human primary olfactory cortex-including the anterior olfactory nucleus, olfactory tubercle and piriform cortex-has stronger functional connectivity with hippocampal networks at rest, compared to other sensory systems. This suggests that unlike other sensory systems, olfactory-hippocampal connectivity may have been retained in mammalian evolution. We further show that olfactory-hippocampal connectivity oscillates with nasal breathing. Our findings suggest olfaction might provide insight into how memory and cognition depend on hippocampal interactions.

Epileptogenesis-induced changes of hippocampal-piriform connectivity.

OBJECTIVE: Tissue remodeling has been described in brain circuits that are involved in the generation and propagation of epileptic seizures. Human and animal studies suggest that the anterior piriform cortex (aPC) is crucial for seizure expression in focal epilepsies. Here, we investigate the effect of kainic-acid (KA)-induced seizures on the effective connectivity of the aPC with bilateral hippocampal CA3 regions using cerebro-cerebral evoked potentials (CCEPs). METHODS: Adult male Sprague-Dawley rats were implanted with a tripolar electrode in the left aPC for stimulation and recording, and with unipolar recording electrodes in bilateral CA3 regions. Single pulse stimulations were given to the aPC and CCEPs were averaged before KA injections and after the emergence of spontaneous recurrent seizures (SRS). Similar recordings at equivalent time intervals were obtained from animals that received saline injections instead of KA (controls). RESULTS: In the experimental group, the percentage change of increased amplitude of the contralateral (but not ipsilateral) CA3 CCEPs between pre-KA injection and after the emergence of SRS was significantly greater than in controls. No significant single-pulse-induced spectral change responses were observed in either epileptic or control rats when comparing pre- and post-stimulus time intervals. Also, we found no correlation between seizure frequency and the extent of amplitude changes in the CCEPs. CONCLUSIONS: In the KA model, epileptogenesis results in plastic changes that manifest as an amplification of evoked potential amplitudes recorded in the contralateral hippocampus in response to single-pulse stimulation of the aPC. These results suggest epileptogenesis-induced facilitation of interhemispheric connectivity between the aPC and the hippocampus. Since the amplitude increase of the contralateral CCEP is a possible in vivo biomarker of epilepsy, any intervention (e.g. neuromodulatory) that can reverse this phenomenon may hold a potential antiepileptic efficacy.