Donoghue, and Emery N. Brown. A point process framework for relating neural spiking activity to spiking history, neural ensemble, and extrinsic covariate effects. J Neurophysiol 93: 1074 -1089, 2005. First published September 8, 2004 doi:10.1152/jn.00697.2004. Multiple factors simultaneously affect the spiking activity of individual neurons. Determining the effects and relative importance of these factors is a challenging problem in neurophysiology. We propose a statistical framework based on the point process likelihood function to relate a neuron's spiking probability to three typical covariates: the neuron's own spiking history, concurrent ensemble activity, and extrinsic covariates such as stimuli or behavior. The framework uses parametric models of the conditional intensity function to define a neuron's spiking probability in terms of the covariates. The discrete time likelihood function for point processes is used to carry out model fitting and model analysis. We show that, by modeling the logarithm of the conditional intensity function as a linear combination of functions of the covariates, the discrete time point process likelihood function is readily analyzed in the generalized linear model (GLM) framework. We illustrate our approach for both GLM and non-GLM likelihood functions using simulated data and multivariate single-unit activity data simultaneously recorded from the motor cortex of a monkey performing a visuomotor pursuit-tracking task. The point process framework provides a flexible, computationally efficient approach for maximum likelihood estimation, goodness-of-fit assessment, residual analysis, model selection, and neural decoding. The framework thus allows for the formulation and analysis of point process models of neural spiking activity that readily capture the simultaneous effects of multiple covariates and enables the assessment of their relative importance.

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma and cellular pathologies is unclear. Here, we show reduced behaviorally-driven gamma before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease (AD). Optogenetically driving FS-PV-interneurons at gamma (40 Hz), but not other frequencies, reduced levels of amyloid-β (A β)1-40 and A β1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia and histological analysis confirmed increased microglia co-localization with A β. Subsequently, we designed a non-invasive 40 Hz light-flickering paradigm that reduced A β1-40 and A β1-42 levels in visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate AD-associated pathology.

In the united states, nearly 60,000 patients per day receive general anesthesia for surgery. 1 General anesthesia is a drug-induced, reversible condition that includes specific behavioral and physiological traits -unconsciousness, amnesia, analgesia, and akinesia -with concomitant stability of the autonomic, cardiovascular, respiratory, and thermoregulatory systems. 2 General anesthesia produces distinct patterns on the electroencephalogram (EEG), the most common of which is a progressive increase in low-frequency, high-amplitude activity as the level of general anesthesia deepens 3,4 (Fig. 1). How anesthetic drugs induce and maintain the behavioral states of general anesthesia is an important question in medicine and neuroscience. 6 Substantial insights can be gained by considering the relationship of general anesthesia to sleep and to coma.Humans spend approximately one third of their lives asleep. Sleep, a state of decreased arousal that is actively generated by nuclei in the hypothalamus, brain stem, and basal forebrain, is crucial for the maintenance of health. 7,8 Normal human sleep cycles between two states -rapid-eye-movement (REM) sleep and non-REM sleep -at approximately 90-minute intervals. REM sleep is characterized by rapid eye movements, dreaming, irregularities of respiration and heart rate, penile and clitoral erection, and airway and skeletal-muscle hypotonia. 7 In REM sleep, the EEG shows active high-frequency, lowamplitude rhythms (Fig. 1). Non-REM sleep has three distinct EEG stages, with higheramplitude, lower-frequency rhythms accompanied by waxing and waning muscle tone, decreased body temperature, and decreased heart rate.Coma is a state of profound unresponsiveness, usually the result of a severe brain injury. 9 Comatose patients typically lie with eyes closed and cannot be roused to respond appropriately to vigorous stimulation. A comatose patient may grimace, move limbs, and have stereotypical withdrawal responses to painful stimuli yet make no localizing responses or discrete defensive movements. As the coma deepens, the patient's responsiveness even to painful stimuli may diminish or disappear. Although the patterns of EEG activity observed in comatose patients depend on the extent of the brain injury, they frequently resemble the high-amplitude, low-frequency activity seen in patients under general anesthesia 10 (Fig. 1). General anesthesia is, in fact, a reversible drug-induced coma. Nevertheless, anesthesiologists refer to it as "sleep" to avoid disquieting patients. Unfortunately, anesthesiologists also use the word "sleep" in technical descriptions to refer to Copyright © 2010 CLINICAL SIGNS AND EEG PAT TERNS OF UNCONSCIOUSNESS INDUCED BY GENER AL ANESTHESIAThe clinical signs and EEG patterns of general anesthesia-induced unconsciousness can be described in relation to the three periods in which they appear: induction, maintenance, and emergence. INDUCTION PERIODBefore induction, the patient has a normal, active EEG, with prominent alpha activity (10 Hz) when the eyes are clo...

Significance Anesthesiologists reversibly manipulate the brain function of nearly 60,000 patients each day, but brain-state monitoring is not an accepted practice in anesthesia care because markers that reliably track changes in level of consciousness under general anesthesia have yet to be identified. We found specific behavioral and electrophysiological changes that mark the transition between consciousness and unconsciousness induced by propofol, one of the most commonly used anesthetic drugs. Our results provide insights into the mechanisms of propofol-induced unconsciousness and establish EEG signatures of this brain state that could be used to monitor the brain activity of patients receiving general anesthesia.

Regulation of circadian period in humans was thought to differ from that of other species, with the period of the activity rhythm reported to range from 13 to 65 hours (median 25.2 hours) and the period of the body temperature rhythm reported to average 25 hours in adulthood, and to shorten with age. However, those observations were based on studies of humans exposed to light levels sufficient to confound circadian period estimation. Precise estimation of the periods of the endogenous circadian rhythms of melatonin, core body temperature, and cortisol in healthy young and older individuals living in carefully controlled lighting conditions has now revealed that the intrinsic period of the human circadian pacemaker averages 24.18 hours in both age groups, with a tight distribution consistent with other species. These findings have important implications for understanding the pathophysiology of disrupted sleep in older people.

Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non‐linear relationship to illuminance. The dose‐response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty‐three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase‐delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose‐response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase‐delaying response achieved in response to a single episode of evening bright light (≈9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of ≈100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences.

The widely used electroencephalogram-based indices for depth-of-anesthesia monitoring assume that the same index value defines the same level of unconsciousness for all anesthetics. In contrast, we show that different anesthetics act at different molecular targets and neural circuits to produce distinct brain states that are readily visible in the electroencephalogram. We present a two-part review to educate anesthesiologists on use of the unprocessed electroencephalogram and its spectrogram to track the brain states of patients receiving anesthesia care. Here in Part I, we review the biophysics of the electroencephalogram, and the neurophysiology of the electroencephalogram signatures of three intravenous anesthetics: propofol, dexmedetomidine and ketamine; and four inhaled anesthetics: sevoflurane, isoflurane, desflurane and nitrous oxide. Later in Part II, we discuss patient management using these electroencephalogram signatures. Use of these electroencephalogram signatures suggests a neurophysiologically-based paradigm for brain-state monitoring of patients receiving anesthesia care.