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Sensory processing is distributed among many brain regions that interact via feedforward and feedback signaling. Neuronal oscillations have been shown to mediate intercortical feedforward and feedback interactions. Yet, the macroscopic structure of the multitude of such oscillations remains unclear. Here, we show that simple visual stimuli reliably evoke two traveling waves with spatial wavelengths that cover much of the cerebral hemisphere in awake mice. 30-50 Hz feedforward waves arise in primary visual cortex (V1) and propagate rostrally, while 3-6 Hz feedback waves originate in the association cortex and flow caudally. The phase of the feedback wave modulates the amplitude of the feedforward wave and synchronizes firing between V1 and parietal cortex. Altogether, these results provide direct experimental evidence that visual evoked traveling waves percolate through the cerebral cortex and coordinate neuronal activity across broadly distributed networks mediating visual processing. Processing sensory stimuli requires coordinated activation of neurons broadly distributed across many distant cortical sites, yet it is not clear how this coordination is accomplished in the brain. Here, the authors show that visual stimuli reliably evoke traveling waves of activity that percolate through the cortex and orchestrate neuronal firing across primary visual and association cortices.

The relationship between neuronal activity and computations embodied by it remains an open question. We develop a novel methodology that condenses observed neuronal activity into a quantitatively accurate, simple, and interpretable model and validate it on diverse systems and scales from single neurons in C. elegans to fMRI in humans. The model treats neuronal activity as collections of interlocking 1-dimensional trajectories. Despite their simplicity, these models accurately predict future neuronal activity and future decisions made by human participants. Moreover, the structure formed by interconnected trajectories—a scaffold—is closely related to the computational strategy of the system. We use these scaffolds to compare the computational strategy of primates and artificial systems trained on the same task to identify specific conditions under which the artificial agent learns the same strategy as the primate. The computational strategy extracted using our methodology predicts specific errors on novel stimuli. These results show that our methodology is a powerful tool for studying the relationship between computation and neuronal activity across diverse systems.

Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.

A cardinal feature of consciousness is the maintenance of a stable perceptual world. To accomplish this, sensory information must be faithfully relayed and integrated within the brain. General anesthetic agents reliably and reversibly produce states of unconsciousness. However, despite their ubiquitous use in medicine and science, the mechanisms by which anesthetics induce loss of consciousness remains unknown. Over the past 170 years, researchers have searched for the universal targets that anesthetic agents use to ablate perception (Alkire et al., 2008; Kelz and Mashour, 2019). However, there is not yet a common structural motif, receptor target, or sleep/arousal circuit that all known anesthetics interact with (Alkire et al., 2008; Kelz and Mashour, 2019). It was once postulated that anesthetics may ablate perception by disconnecting the cortex from incoming thalamic signals (Alkire et al., 2000; Alkire and Miller, 2005; White and Alkire, 2003); yet under anesthesia, neurons within primary cortical areas are still able to encode features of sensory stimuli, thereby suggesting sensory information is effectively relayed to the cortex (Hubel and Wiesel, 1962). Thus, it has been recently theorized that anesthetics may hinder the ability for sensory responses to faithfully participate in hierarchal, feedback and integrative circuits at a network level (Lee et al., 2009; Mashour, 2006, 2014). In this dissertation, I investigate this theory by analyzing the spatiotemporal features of visual evoked oscillations over multiple hierarchical cortical areas in awake and anesthetized mice presented with simple visual stimuli and answering a series of motivating questions. Are there consistent neurophysiological substrates to coordinate visual evoked activity across the many cortical regions involved in visual processing in awake mice, who have the ability to perceive stimuli? If so, what is the spatiotemporal structure of this activity pattern, and does it coordinate neural firing in disparate cortical areas? Can we identify patterns that may be related to hierarchical visual processing vs feedback signaling? How do mechanistically distinct anesthetic agents disrupt visual evoked patterns seen in the awake brain? Are there agent specific effects? And finally, can we identify a common mechanism by which all tested anesthetic agents breakdown visual evoked activity? While my research does not test perception per se, findings herein will provide the neurophysiological basis for the integration of visual-evoked activity across cortices during wakefulness, and the breakdown of this coordinated pattern of activity during anesthetic induced states of unconsciousness.

A significant proportion of patients undergoing breast conservation therapy require additional operations to obtain clear margins. The aim of this study was to assess the impact of initial margins and residual carcinoma found on second surgery on the outcomes of breast cancer patients. In this retrospective study, Cox proportional-hazard regression analysis was performed to evaluate data from 437 patients with stage I to IIIA breast cancer who underwent initial breast-conserving surgery between 1994 and 2004. The distant recurrence rate was higher among patients with initial positive margins than among those with initial negative margins (15.5% vs 4.9%; hazard ratio, 3.6; 95% confidence interval 1.5–8.7; P = .003). For patients who had underwent second surgery, the finding of a residual invasive carcinoma was associated with increased risk for distant recurrence (22.8% vs 6.6%; hazard ratio, 3.5; 95% confidence interval, 1.8–7.4; P = .0001). Invasive residual carcinoma found during subsequent surgery after initial compromised margins is an important prognostic marker for distant recurrence.

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness stimuli evoke perceptions; under anesthesia perceptions are abolished; during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perception. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves. These stimulus-evoked waves traverse the cortex and entrain visual and parietal neurons. Under anesthesia and during ketamine-induced dissociation, visual stimuli do not disrupt spontaneous waves. Uniquely in the dissociated state, spontaneous waves traverse the cortex caudally and entrain visual and parietal neurons, akin to stimulus-evoked waves in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling cortical waves emerge in states in which perception can manifest. The awake state is privileged in that this coordination is elicited by specifically by external visual stimuli.

Sensory processing is distributed among many brain regions that interact via feedforward and feedback signaling. It has been hypothesized that neuronal oscillations mediating feedforward and feedback interactions organize into travelling waves. However, stimulus evoked travelling waves of sufficient spatial scale have never been demonstrated directly. Here, we show that simple visual stimuli reliably evoke two traveling waves with spatial wavelengths that cover much of the cerebral hemisphere in awake mice. 30-50Hz feedforward waves arise in primary visual cortex (V1) and propagate rostrally, while 3-6Hz feedback waves originate in the association cortex and flow caudally. The phase of the feedback wave modulates the amplitude of the feedforward wave and synchronizes firing between V1 and parietal cortex. Altogether, these results provide direct experimental evidence that visual evoked travelling waves percolate through the cerebral cortex and coordinate neuronal activity across broadly distributed networks mediating visual processing. Competing Interest Statement The authors have declared no competing interest.