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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.
doi:10.1016/j.neuroscience.2012.09.060
PMCID: PMC3544216  PMID: 23041761
ERP; neurovascular coupling; NIRS
2.  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.
doi:10.1016/B978-0-444-53839-0.00015-6
PMCID: PMC3160721  PMID: 21854966
auditory cortex; blood volume; evoked response potential (ERP); hemoglobin; optical; NIRS; quiet sleep
3.  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.
doi:10.1016/j.neuroscience.2008.11.031
PMCID: PMC2706571  PMID: 19154778
Auditory; Rat; Quiet sleep; Slow-wave sleep; Delta
4.  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
5.  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.
doi:10.1111/j.1460-9568.2009.06717.x
PMCID: PMC2688439  PMID: 19473232
Evoked Response Potential; Model; Homeostasis; Optical; Hemodynamic Response
6.  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.
doi:10.1016/j.neuroimage.2007.12.055
PMCID: PMC2373772  PMID: 18272402
7.  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
8.  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.
doi:10.1117/1.2952295
PMCID: PMC2596884  PMID: 19021365
Invertebrate; Imaging; Evoked response; Mayer waves; Photodiode; Coherent

Results 1-8 (8)