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1.  Neurovascular Saturation Thresholds Under High Intensity Auditory Stimulation During Wake 
Neuroscience  2012;227:191-200.
Coupling between neural activity and hemodynamic responses is important in understanding brain function, interpreting brain imaging signals, and assessing pathological conditions. Tissue state is a major factor in neurovascular coupling and may alter the relationship between neural and hemodynamic activity. However, most neurovascular coupling studies are performed under anesthetized or sedated states which may have severe consequences on coupling mechanisms. Our previous studies showed that following prolonged periods of sleep deprivation, evoked hemodynamic responses were muted despite consistent electrical responses, suggesting that sustained neural activity may decrease vascular compliance and limit blood perfusion. To investigate potential perfusion limitations during natural waking conditions, we simultaneously measured evoked response potentials (ERPs) and evoked hemodynamic responses using optical imaging techniques to increasing intensity auditory stimulation. The relationship between evoked hemodynamic responses and integrated ERPs followed a sigmoid relationship where the hemodynamic response approached saturation at lower stimulus intensities than the ERP. If limits in blood perfusion are caused by stretching of the vessel wall, then these results suggest there may be decreased vascular compliance due to sustained neural activity during wake, which could limit vascular responsiveness and local blood perfusion. Conditions that stress cerebral vasculature, such as sleep deprivation and some pathologies (e.g., epilepsy), may further decrease vascular compliance, limit metabolic delivery, and cause tissue trauma. While ERPs and evoked hemodynamic responses provide an indication of the correlated neural activity and metabolic demand, the relationship between these two responses is complex and the different measurement techniques are not directly correlated. Future studies are required to verify these findings and further explore neurovascular coupling during wake by assessing local field potentials, vascular expansion, hemodynamic response localization.
PMCID: PMC3544216  PMID: 23041761
ERP; neurovascular coupling; NIRS
2.  Sleep: A synchrony of cell activity-driven small network states 
The European journal of neuroscience  2013;38(2):2199-2209.
We posit a bottom-up sleep regulatory paradigm in which state changes are initiated within small networks as a consequence of local cell activity. Bottom-up regulatory mechanisms are prevalent throughout nature, occurring in vastly different systems and levels of organization. Synchronization of state without top-down regulation is a fundamental property of large collections of small semi-autonomous entities. We posit that such synchronization mechanisms are sufficient and necessary for whole organism sleep onset. Within brain we posit that small networks of highly interconnected neurons and glia, e.g. cortical columns, are semi-autonomous units oscillating between sleep-like and wake-like states. We review evidence showing that cells, small networks, and regional areas of brain share sleep-like properties with whole animal sleep. A testable hypothesis focused on how sleep is initiated within local networks is presented. We posit that the release of cell activity-dependent molecules, such as ATP and nitric oxide, into the extracellular space initiates state changes within the local networks where they are produced. We review mechanisms of ATP induction of sleep regulatory substances (SRS) and their actions on receptor trafficking. Finally, we provide an example of how such local metabolic and state changes provide mechanistic explanations for clinical conditions such as insomnia.
PMCID: PMC3713192  PMID: 23651209
ATP; cytokine; receptor; cerebral blood flow; brain imaging
3.  Precision rodent whisker stimulator with integrated servo-locked control and displacement measurement 
Journal of neuroscience methods  2010;196(1):20-30.
We developed a high speed voice coil based whisker stimulator that delivers precise deflections of a single whisker or group of whiskers in a repeatable manner. The device is miniature, quiet, and inexpensive to build. Multiple stimulators fit together for independent stimulation of four or more whiskers. The system can be used with animals under anesthesia as well as awake animals with head-restraint, and does not require trimming the whiskers. The system can deliver 1–2 mm deflections in 2 ms resulting in velocities up to 900 mm/s to attain a wide range of evoked responses. Since auditory artifacts can influence behavioral studies using whisker stimulation, we tested potential effects of auditory noise by recording somatosensory evoked potentials (SEP) with varying auditory click levels, and with/without 80 dBa background white noise. We found that auditory clicks as low as 40 dBa significantly influence the SEP. With background white noise, auditory clicks as low as 50 dBa were still detected in components of the SEP. For behavioral studies where animals must learn to respond to whisker stimulation, these sounds must be minimized. Together, the stimulator and data system can be used for psychometric vigilance tasks, mapping of the barrel cortex and other electrophysiological paradigms.
PMCID: PMC3042047  PMID: 21167200
evoked response; voice coil; rodent; vibrissae; auditory
4.  Rat psychomotor vigilance task with fast response times using a conditioned lick behavior 
Behavioural brain research  2010;216(1):229-237.
Investigations into the physiological mechanisms of sleep control require an animal psychomotor vigilance task (PVT) with fast response times (<300ms). Rats provide a good PVT model since whisker stimulation produces a rapid and robust cortical evoked response, and animals can be trained to lick following stimulation. Our prior experiments used deprivation-based approaches to maximize motivation for operant conditioned responses. However, deprivation can influence physiological and neurobehavioral effects. In order to maintain motivation without water deprivation, we conditioned rats for immobilization and head restraint, then trained them to lick for a 10% sucrose solution in response to whisker stimulation. After approximately 8 training sessions, animals produced greater than 80% correct hits to the stimulus. Over the course of training, reaction times became faster and correct hits increased. Performance in the PVT was examined after 3, 6 and 12 hours of sleep deprivation achieved by gentle handling. A significant decrease in percent correct hits occurred following 6 and 12 hours of sleep deprivation and reaction times increased significantly following 12 hours of sleep deprivation. While behaviorally the animals appeared to be awake, we observed significant increases in EEG delta power prior to misses. The rat PVT with fast response times allows investigation of sleep deprivation effects, time on task and pharmacological agents. Fast response times also allow closer parallel studies to ongoing human protocols.
PMCID: PMC2975873  PMID: 20696188
PVT; restraint; conditioned learning; lick; somatosensory cortex; electrophysiology; sleep deprivation; reaction time
5.  Evoked Electrical and Cerebral Vascular Responses Following Sleep Deprivation 
Progress in brain research  2011;193:233-244.
Neuronal activity elicits vascular dilation, delivering additional blood and metabolites to the activated region. With increasing neural activity, vessels stretch and may become less compliant. Most functional imaging studies assume that limits to vascular expansion are not normally reached except under pathological conditions, with the possibility that metabolism could outpace supply. However, we previously demonstrated that evoked hemodynamic responses were larger during quiet sleep when compared to both waking and REM sleep, suggesting that high basal activity during wake may elicit blunted evoked hemodynamic responses due to vascular expansion limits. We hypothesized that extended brain activity through sleep deprivation will further dilate blood vessels, and exacerbate the blunted evoked hemodynamic responses observed during wake, and dampen responses in subsequent sleep. We measured evoked electrical and hemodynamic responses from rats using auditory clicks (0.5 s, 10 Hz, 2–13 s random ISIs) for one hour following 2, 4, or 6 hours of sleep deprivation. Time-of-day matched controls were recorded continuously for 7 hours. Within quiet sleep periods following deprivation, ERP amplitude did not differ; however, the evoked vascular response was smaller with longer sleep deprivation periods. These results suggest that prolonged neural activity periods through sleep deprivation may diminish vascular compliance as indicated by the blunted vascular response. Subsequent sleep may allow vessels to relax, restoring their ability to deliver blood. These results also suggest that severe sleep deprivation or chronic sleep disturbances could push the vasculature to critical limits, leading to metabolic deficit and the potential for tissue trauma.
PMCID: PMC3160721  PMID: 21854966
auditory cortex; blood volume; evoked response potential (ERP); hemoglobin; optical; NIRS; quiet sleep
6.  Mechanisms Underlying State Dependent Surface Evoked Response Patterns 
Neuroscience  2008;159(1):115-126.
Cortical evoked response potentials (ERPs) display a rich set of waveforms that are both context and state dependent. However, the mechanisms that underlie state dependent ERP patterns are unclear. Determining those mechanisms through analysis of single trial ERP waveform signatures may provide insight into the regulation of cortical column state and the roles that sleep plays in cortical function. We implanted rats with EEG and EMG electrodes to record ERPs and to assess sleep/wake states continuously during 1-2s random auditory clicks. Individual cortical auditory ERPs were sorted into one of eight behavioral states, and fell into three categories based on amplitude and latency characteristics. ERPs within waking and rapid eye movement (REM) sleep were predominately low amplitude and short latency. Approximately 50% of ERPs during light quiet sleep (QS1 and QS2) exhibited low amplitude, short latency responses, and the remaining ERPs had high amplitude, long latency responses. This distribution was characteristic of EEG fluctuations during low frequency delta waves. Significantly more individual ERPs showed very low amplitudes during deep quiet sleep (QS3 and QS4), resulting in a lower average ERP. These results support the hypothesis that evoked response amplitudes and waveform patterns follow specific EEG patterns. Since evoked response characteristics distribute differently across states, they could aid our understanding of sleep mechanisms through state related and local neural signaling.
PMCID: PMC2706571  PMID: 19154778
Auditory; Rat; Quiet sleep; Slow-wave sleep; Delta
7.  Conditioned lick behavior and evoked responses using whisker twitches in head restrained rats 
Behavioural brain research  2008;197(1):16-23.
To examine whisker barrel evoked response potentials in chronically implanted rats during behavioral learning with very fast response times, rats must be calm while immobilized with their head restrained. We quantified their behaviors during training with an ethogram and measured each individual animals’ progress over the training period. Once calm under restraint, rats were conditioned to differentiate between a reward and control whisker twitch, then provide a lick response when presented with the correct stimulus, rewarded by a drop of water. Rats produced the correct licking response (after reward whisker twitch), and learned not to lick after a control whisker was twitched. By implementing a high density 64 channel electrocorticogram (ECoG) electrode array, we mapped the barrel field of the somatosensory cortex with high spatial and temporal resolution during conditioned lick behaviors. In agreement with previous reports, we observe a larger evoked response after training, probably related to mechanisms of cortical plasticity.
PMCID: PMC2607480  PMID: 18718491
EEG; ECoG Electrode array; Restraint; Somatosensory cortex; Learning
8.  Characterization of flexible ECoG electrode arrays for chronic recording in awake rats 
Journal of neuroscience methods  2008;173(2):279-285.
We developed a 64 channel flexible polyimide ECoG electrode array and characterized its performance for long term implantation, chronic cortical recording and high resolution mapping of surface evoked potentials in awake rats. To achieve the longest possible recording periods, the flexibility of the electrode array, adhesion between the metals and carrier substrate, and biocompatibility was critical for maintaining the signal integrity. Experimental testing of thin film adhesion was applied to a gold – polyimide system in order to characterize relative interfacial fracture energies for several different adhesion layers, yielding an increase in overall device reliability. We tested several different adhesion techniques including: gold alone without an adhesion layer, titanium-tungsten, tantalum and chromium. We found the titanium-tungsten to be a suitable adhesion layer considering the biocompatibility requirements as well as stability and delamination resistance. While chromium and tantalum produced stronger gold adhesion, concerns over biocompatibility of these materials require further testing. We implanted the polyimide ECoG electrode arrays through a slit made in the skull of rats and recorded cortical surface evoked responses. The arrays performed reliably over a period of at least 100 days and signals compared well with traditional screw electrodes, with better high frequency response characteristics. Since the ultimate goal of chronically implanted electrode arrays is for neural prosthetic devices that need to last many decades, other adhesion layers that would prove safe for implantation may be tested in the same way in order to improve the device reliability.
PMCID: PMC2564809  PMID: 18640155
Surface Evoked Potential; Polyimide; Kapton; Biocompatibility; Device Durability
9.  Physiological Markers of Local Sleep 
The European journal of neuroscience  2009;29(9):1771-1778.
Substantial evidence suggests that brain regions that have been disproportionately used during waking will require a greater intensity and/or duration of subsequent sleep. For example, rats use their whiskers in the dark and their eyes during the light which manifests as a greater magnitude of electroencephalogram (EEG) slow wave activity in the somatosensory and visual cortex during sleep in the corresponding light and dark periods respectively. The parsimonious interpretation of such findings is that sleep is distributed across local brain regions and is use-dependent. The fundamental properties of sleep can also be experimentally defined locally at the level of small neural assemblies such as cortical columns. In this view, sleep is orchestrated, but not fundamentally driven, by central mechanisms. We explore two physiological markers of local, use-dependent sleep, namely, an electrical marker apparent as a change in the size and shape of an electrical evoked response, and a metabolic marker evident as an evoked change in blood volume and oxygenation delivered to activated tissue. Both markers, applied to cortical columns, provide a means to investigate physiological mechanisms for the distributed homeostatic regulation of sleep, and may yield new insights into the consequences of sleep loss and sleep pathologies on waking brain function.
PMCID: PMC2688439  PMID: 19473232
Evoked Response Potential; Model; Homeostasis; Optical; Hemodynamic Response
10.  Action potential propagation imaged with high temporal resolution near-infrared video microscopy and polarized light 
NeuroImage  2008;40(3):1034-1043.
To identify the neural constituents responsible for generating polarized light changes, we created spatially resolved movies of propagating action potentials from stimulated lobster leg nerves using both reflection and transmission imaging modalities. Changes in light polarization are associated with membrane depolarization and provide sub-millisecond temporal resolution. Typically, signals are detected using light transmitted through tissue; however, because we eventually would like to apply polarization techniques in-vivo, reflected light is required. In transmission mode, the optical signal was largest throughout the center of the nerve, suggesting that most of the optical signal arose from the inner nerve bundle. In reflection mode, polarization changes were largest near the edges, suggesting that most of the optical signal arose from the outer sheath. In support of these observations, an optical model of the tissue showed that the outer sheath is more reflective while the inner nerve bundle is more transmissive. In order to apply these techniques in-vivo, we must consider that brain tissue does not have a regular orientation of processes as in the lobster nerve. We tested the effect of randomizing cell orientation by tying the nerve in an overhand knot prior to imaging, producing polarization changes that can be imaged even without regular cell orientations.
PMCID: PMC2373772  PMID: 18272402
Sleep medicine clinics  2007;2(2):161-169.
PMCID: PMC2605347  PMID: 19098992
TNF; IL1; sleep function; brain organization; humoral regulation; sleep homeostasis
12.  In−Vitro and In−Vivo Noise Analysis for Optical Neural Recording 
Journal of biomedical optics  2008;13(4):044038.
Laser diodes (LD) are commonly used for optical neural recordings in chronically recorded animals and humans, primarily due to their brightness and small size. However, noise introduced by LDs may counteract the benefits of brightness when compared to low−noise light emitting diodes (LEDs). To understand noise sources in optical recordings, we systematically compared instrument and physiological noise profiles in two recording paradigms. A better understanding of noise sources will help improve optical recordings and make them more practical with fewer averages. We stimulated lobster nerves and rat cortex, then compared the root mean square (RMS) noise and signal−to−noise ratios (SNRs) of data obtained with LED, superluminescent diode (SLD) and LD illumination for different numbers of averages. The LED data exhibited significantly higher SNRs in fewer averages than LD data in all recordings. In the absence of tissue, LED noise increased linearly with intensity, while LD noise increased sharply in the transition to lasing and settled to noise levels significantly higher than the LED’s, suggesting that speckle noise contributed to the LD’s higher noise and lower SNRs. Our data recommend low coherence and portable light sources for in−vivo chronic neural recording applications.
PMCID: PMC2596884  PMID: 19021365
Invertebrate; Imaging; Evoked response; Mayer waves; Photodiode; Coherent
13.  Optically Teasing Apart Neural Swelling and Depolarization 
Neuroscience  2007;145(3):887-899.
We measured birefringence, 90 degree scattered light, and voltage sensitive dye changes from lobster walking leg nerves. Systematic application of key chemical agents revealed separate cellular mechanisms underlying fast optical signals. Each agent exhibited mixed effects, some having a greater effect on cellular swelling and refractive index, and some altering membrane potential. Birefringence changes were tightly correlated with voltage sensitive dye signals and were perturbed by those agents that altered membrane potential. Signals from light scattered at 90 degrees corroborated the hypothesis that large angle scattering signals arise from changes in the interstitial spaces and were perturbed by those agents that altered cellular swelling and refractive index. We conclude that multiple cellular mechanisms can be exploited to measure rapid optical signals. Since birefringence produces much larger changes than scattering, the use of polarized light might lead to improvements in imaging neural activity with high temporal resolution, especially since birefringence changes corresponded closely to membrane potential.
PMCID: PMC1888560  PMID: 17303339
crustacean; toxin; intrinsic optical imaging; action potential
14.  State Dependent Auditory Evoked Hemodynamic Responses Recorded Optically with Indwelling Photodiodes 
Applied optics  2009;48(10):D121-D129.
Implantable optical technologies provide measurements of cerebral hemodynamic activity from freely behaving animals without movement constraint or anesthesia. In order to study state-dependent neural evoked responses and the consequential hemodynamic response, we simultaneously measured EEG and scattered light changes in chronically implanted rats. Recordings took place under freely behaving conditions, allowing us to compare the evoked responses across wake, sleep, and anesthetized states. The largest evoked electrical and optical responses occurred during quiet sleep compared to wake and REM sleep while isoflurane anesthesia showed a large, late burst of electrical activity synchronized to the stimulus, but an earlier optical response.
PMCID: PMC2707279  PMID: 19340099
Nature reviews. Neuroscience  2008;9(12):910-919.
Sleep is vital to cognitive performance, productivity, health and well-being. Earlier theories of sleep presumed that sleep occurred at the level of the whole organism and that sleep was governed by central control mechanisms. However, evidence now indicates that sleep might be regulated at a more local level within the brain: it seems to be a fundamental property of neuronal networks and is dependent on prior activity within each network. Such local network sleep might be initiated by metabolically driven changes in the production of sleep-regulatory substances. We discuss a mathematical model which illustrates that the sleep-like states of individual cortical columns can be synchronized through humoral and electrical connections, and that whole organism sleep occurs as an emergent property of local network interactions.
PMCID: PMC2586424  PMID: 18985047
16.  Complete Optical Neurophysiology: Toward Optical Stimulation and Recording of Neural Tissue 
Applied optics  2009;48(10):D218-D224.
Direct optical methods to stimulate and record neural activity provide artifact free, non-invasive and non-contact neurophysiological procedures. For stimulation, focused mid-infrared light alters membrane potential and activates individual neural processes. Simultaneous intrinsic scattered light parameters, including birefringence changes, can record neural activity with signals similar to potentiometric dyes. The simultaneous combination of optical stimulation and optical recording techniques provide the potential for powerful tools that may someday remove the need for invasive wires during electrophysiological recordings.
PMCID: PMC2665921  PMID: 19340112
17.  A Network Model for Activity-Dependent Sleep Regulation 
Journal of theoretical biology  2008;253(3):462-468.
We develop and characterize a dynamical network model for activity-dependent sleep regulation. Specifically, in accordance with the activity-dependent theory for sleep, we view organism sleep as emerging from the local sleep states of functional units known as cortical columns; these local sleep states evolve through integration of local activity inputs, loose couplings with neighboring cortical columns, and global regulation (e.g. by the circadian clock). We model these cortical columns as coupled or networked activity-integrators that transition between sleep and waking states based on thresholds on the total activity. The model dynamics for three canonical experiments (which we have studied both through simulation and system-theoretic analysis) match with experimentally-observed characteristics of the cortical-column network. Most notably, assuming connectedness of the network graph, our model predicts the recovery of the columns to a synchronized state upon temporary overstimulation of a single column and/or randomization of the initial sleep and activity-integration states. In analogy with other models for networked oscillators, our model also predicts the possibility for such phenomena as mode-locking.
PMCID: PMC2592512  PMID: 18511082
18.  Discrimination of Auditory Stimuli during Isoflurane Anesthesia 
Comparative medicine  2008;58(5):454-457.
Deep isoflurane anesthesia initiates a burst suppression pattern in which high-amplitude bursts are preceded by periods of nearly silent electroencephalogram. The burst suppression ratio (BSR) is the percentage of suppression (silent electroencephalogram) during the burst suppression pattern and is 1 parameter used to assess anesthesia depth. We investigated cortical burst activity in rats during the burst suppression state. We noted a rapid appearance of bursts and a significant decrease in the BSR during stimulation. The BSR changes were distinctive for the different stimuli applied, and the BSR decreased significantly more when stimulated with a voice familiar to the rat as compared with an unfamiliar voice. These results show that the cortex can show differential sensory responses during deep isoflurane anesthesia.
PMCID: PMC2586896  PMID: 19004371

Results 1-18 (18)