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Hyperexcitability of brain circuits is a common feature of autism spectrum disorders (ASDs). Genetic deletion of a chromatin-binding protein, retinoic acid induced 1 ( RAI1 ), causes Smith-Magenis syndrome (SMS). SMS is a syndromic ASD associated with intellectual disability, autistic features, maladaptive behaviors, overt seizures, and abnormal electroencephalogram (EEG) patterns. The molecular and neural mechanisms underlying abnormal brain activity in SMS remain unclear. Here we show that panneural Rai1 deletions in mice result in increased seizure susceptibility and prolonged hippocampal seizure duration in vivo and increased dentate gyrus population spikes ex vivo. Brain-wide mapping of neuronal activity pinpointed selective cell types within the limbic system, including the hippocampal dentate gyrus granule cells (dGCs) that are hyperactivated by chemoconvulsant administration or sensory experience in Rai1 -deficient brains. Deletion of Rai1 from glutamatergic neurons, but not from gamma-aminobutyric acidergic (GABAergic) neurons, was responsible for increased seizure susceptibility. Deleting Rai1 from the Emx1 Cre -lineage glutamatergic neurons resulted in abnormal dGC properties, including increased excitatory synaptic transmission and increased intrinsic excitability. Our work uncovers the mechanism of neuronal hyperexcitability in SMS by identifying Rai1 as a negative regulator of dGC intrinsic and synaptic excitability.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning., (Published by Elsevier Inc.)

Intrinsically photosensitive retinal ganglion cells (ipRGCs) combine direct photosensitivity through melanopsin with synaptically mediated drive from classical photoreceptors through bipolar-cell input. Here, we sought to provide a fuller description of the least understood ipRGC type, the M5 cell, and discovered a distinctive functional characteristic-chromatic opponency (ultraviolet excitatory, green inhibitory). Serial electron microscopic reconstructions revealed that M5 cells receive selective UV-opsin drive from Type 9 cone bipolar cells but also mixed cone signals from bipolar Types 6, 7, and 8. Recordings suggest that both excitation and inhibition are driven by the ON channel and that chromatic opponency results from M-cone-driven surround inhibition mediated by wide-field spiking GABAergic amacrine cells. We show that M5 cells send axons to the dLGN and are thus positioned to provide chromatic signals to visual cortex. These findings underscore that melanopsin's influence extends beyond unconscious reflex functions to encompass cortical vision, perhaps including the perception of color., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Thalamic oscillators contribute to both normal rhythms associated with sleep and anesthesia and abnormal, hypersynchronous oscillations that manifest behaviorally as absence seizures. In this review, we highlight new findings that refine thalamic contributions to cortical rhythms and suggest that thalamic oscillators may be subject to both local and global control. We describe endogenous thalamic mechanisms that limit network synchrony and discuss how these protective brakes might be restored to prevent absence seizures. Finally, we describe how intrinsic and circuit-level specializations among thalamocortical loops may determine their involvement in widespread oscillations and render subsets of thalamic nuclei especially vulnerable to pathological synchrony., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Temporary circuits amplify spontaneous activity in the visual system of neonatal rats., Competing Interests: The authors declare that no competing interests exist.

The photopigment melanopsin confers photosensitivity upon a minority of retinal output neurons. These intrinsically photosensitive retinal ganglion cells (ipRGCs) are more diverse than once believed, comprising five morphologically distinct types, M1 through M5. Here, in mouse retina, we provide the first in-depth characterization of M4 cells, including their structure, function, and central projections. M4 cells apparently correspond to ON α cells of earlier reports, and are easily distinguished from other ipRGCs by their very large somata. Their dendritic arbors are more radiate and highly branched than those of M1, M2, or M3 cells. The melanopsin-based intrinsic photocurrents of M4 cells are smaller than those of M1 and M2 cells, presumably because melanopsin is more weakly expressed; we can detect it immunohistochemically only with strong amplification. Like M2 cells, M4 cells exhibit robust, sustained, synaptically driven ON responses and dendritic stratification in the ON sublamina of the inner plexiform layer. However, their stratification patterns are subtly different, with M4 dendrites positioned just distal to those of M2 cells and just proximal to the ON cholinergic band. M4 receptive fields are large, with an ON center, antagonistic OFF surround and nonlinear spatial summation. Their synaptically driven photoresponses lack direction selectivity and show higher ultraviolet sensitivity in the ventral retina than in the dorsal retina, echoing the topographic gradient in S- and M-cone opsin expression. M4 cells are readily labeled by retrograde transport from the dorsal lateral geniculate nucleus and thus likely contribute to the pattern vision that persists in mice lacking functional rods and cones.

Electrical impedance myography (EIM) is a non-invasive, painless technique for the evaluation of neuromuscular disease, and here we evaluate its potential application in spinal muscular atrophy (SMA). Twenty-one SMA patients and 18 healthy children underwent EIM of biceps brachii and tibialis anterior using a commercially available impedance device. Hand-held dynamometry and ultrasound assessment of subcutaneous fat thickness were also performed. All EIM parameters differed significantly between both SMA patients and normal subjects and between type 2 and type 3 SMA patients. In addition, EIM had an accuracy level as high as 93% for correctly categorizing patients as type 2 or type 3. Multiple regression analyses confirmed a strong association between EIM and dynamometry. These results confirm that EIM can accurately categorize patients with SMA. Because EIM requires no patient effort and is rapid to apply, it may serve a useful role in future SMA clinical trials.

Primary Objective: To create a system for the acquisition of multi-angle, multifrequency muscle impedance data., Research Design: Device development and preliminary testing., Methods and Procedures: The system presented here employs an interrogating signal composed of multiple tones with frequencies between 10 kHz and 300 kHz. The use of a composite signal makes possible measurement of impedance at multiple frequencies simultaneously. In addition, this system takes impedance measurements at multiple orientations with respect to the muscle fibres by means of an electronically reconfigurable electrode array. The required measurement time is reduced by taking advantage of muscle's linearity with respect to the flow of electrical current., Main Outcomes and Results: The system was tested in normal subjects, a patient with amyotrophic lateral sclerosis, and one with inclusion body myositis; unique impedance signatures were identified the two patients., Conclusions: Early data suggest that this system is capable of high-quality data collection and may detect changes in neuromuscular disease; study of additional normal subjects and patients with a variety of neuromuscular diseases is warranted.

Background: Patient complaints of excessively warm or cold feet are common in medical practice. Such symptoms can be caused by underlying vascular or neurologic disease, and measurement of foot temperature during daily activity and sleep could provide a deeper understanding of their actual thermal basis., Methods: We used a Thermochron iButton to assess surface foot temperature variation and its relationship to ambient temperature during the day with activity and at night during sleep in 39 healthy individuals aged 18 to 65 years in a temperate region of the United States. We simultaneously used actigraphy to record leg movement., Results: We identified a mean +/- SD awake temperature of 30.6 degrees +/- 2.6 degrees C and asleep temperature of 34.0 degrees +/- 1.8 degrees C, with values reaching as low as 15.9 degrees C in the winter and as high as 37.5 degrees C in the summer. Foot temperature was found to be independent of foot movement or sex; however, there was, as expected, a strong association between foot temperature and ambient temperature (r = .59, P < .001). Several measures of foot temperature variation demonstrated a significant or near-significant reduction with increasing age, including the Euclidean distance (r = -.38, P = .02) for awake periods and the variance (r = -.30, P = .06) during sleep., Conclusions: These results provide data on the normal variation of foot temperature in individuals living in a temperate climate and demonstrate the potential use of Thermochron iButton technology in clinical contexts, including the evaluation of patients with excessively warm or cold feet.

Localized impedance methods can provide useful approaches for assessing neuromuscular disease. The mechanism of these impedance changes remains, however, uncertain. In order to begin to understand the relation of muscle pathology to surface impedance values, 8 immature rats, 12 mature rats and 8 mature rats that had undergone sciatic crush were killed. Measurement was made on tissue from the gastrocnemius muscle from each animal in an impedance cell, and the conductivity and relative permittivity of the tissue were calculated in both the longitudinal and transverse directions for frequencies of 2 kHz to 1 MHz. In addition, quantitative histological analysis was performed on the tissue. Significant elevations in transverse conductivity and transverse relative permittivity were found with animal growth, but longitudinal values showed no difference. After sciatic crush, both transverse and longitudinal conductivity increased significantly, with no change in the relative permittivity in either direction. The frequency dependence of the values also changed after nerve injury. In the healthy animals, there was a strong linear relation between measured conductivity and relative permittivity with cell area, but not for the sciatic crush animals. These results provide a first step toward developing a comprehensive understanding of how the electrical properties of muscle alter in neuromuscular disease states.

Unlabelled: Tarulli AW, Duggal N, Esper GJ, Garmirian LP, Fogerson PM, Lin CH, Rutkove SB. Electrical impedance myography in the assessment of disuse atrophy., Objective: To quantify disuse atrophy using electrical impedance myography (EIM), a noninvasive technique that we have used successfully to study neurogenic and myopathic atrophy., Design: We performed EIM of the tibialis anterior of subjects with disuse atrophy secondary to cast immobilization and in their contralateral normal leg. Subjects were studied shortly after cast removal and again several weeks to months after the cast was removed and normal mobility was restored., Setting: Outpatient neurology and orthopedic practices at a tertiary care medical center., Participants: Otherwise healthy subjects (N=10) with unilateral leg fracture., Interventions: Not applicable., Main Outcome Measures: Resistance, reactance, and phase measured at 50kHz., Results: The main EIM outcome parameter, phase at 50kHz, was lower in the immobilized leg in 9 of 10 cases. Additionally, when normal mobility was restored, the phase of the casted leg increased relative to its initial measurement in all 10 cases, while it increased inconsistently in the contralateral leg., Conclusions: EIM may be a powerful tool for the assessment of disuse atrophy.

Objective: To determine how thermoregulation of the feet is affected by diabetes and diabetic polyneuropathy in both wakefulness and sleep., Research Design and Methods: Normal subjects, diabetic subjects without neuropathy, diabetic subjects with small-fiber diabetic polyneuropathy, and those with advanced diabetic polyneuropathy were categorized based on neurological examination, nerve conduction studies, and quantitative sensory testing. Subjects underwent foot temperature monitoring using an iButton device attached to the foot and a second iButton for recording of ambient temperature. Socks and footwear were standardized, and subjects maintained an activity diary. Data were collected over a 32-h period and analyzed., Results: A total of 39 normal subjects, 28 patients with diabetes but without diabetic polyneuropathy, 14 patients with isolated small-fiber diabetic polyneuropathy, and 27 patients with more advanced diabetic polyneuropathy participated. No consistent differences in foot temperature regulation between the four groups were identified during wakefulness. During sleep, however, multiple metrics revealed significant abnormalities in the diabetic patients. These included reduced mean foot temperature (P < 0.001), reduced maximal temperature (P < 0.001), increased rate of cooling (P < 0.001), as well as increased frequency of variation (P = 0.005), supporting that patients with diabetic polyneuropathy and even those with only diabetes but no diabetic polyneuropathy have impaired nocturnal thermoregulation., Conclusions: Nocturnal foot thermoregulation is impaired in patients with diabetes and diabetic polyneuropathy. Because neurons are highly temperature sensitive and because foot warming is part of the normal biology of sleep onset and maintenance, these findings suggest new potentially treatable mechanisms of diabetes-associated nocturnal pain and sleep disturbance.

Objectives: To assess changes in electrical impedance myography (EIM) parameters in amyotrophic lateral sclerosis (ALS)., Methods: Ten patients with ALS and a cohort of normal subjects underwent EIM testing of tibialis anterior. Montages using voltage and current electrodes placed at a distance (far) and in close proximity (near) were compared. The EIM parameters, resistance (R), reactance (X), and phase (theta) in the patients with ALS, were compared with normal values., Results: theta measured at 50 kHz using the near montage was most sensitive to the presence of ALS, with 9 of 10 patients with ALS having smaller theta values than the calculated lower limit of normal. theta using the far montage and X using both the near and far montages were also sensitive to disease, whereas R did not seem to be useful., Conclusion: EIM is sensitive to muscle abnormalities in ALS, with theta measured with near montages providing the best results.

Electrical impedance myography (EIM) is a method for non-invasively and quantitatively assessing muscle health, in which the major outcome parameter, phase (theta), decreases in diseased states. In order to create a set of normal reference values, we performed 50-kHZ EIM in 5 muscles of 87 healthy individuals, using theta as the major outcome variable. Because the distributions of data were mostly skewed, logarithmic transformations were performed, and the resulting data were fitted to quadratic functions. The lower limit of normal was set by plotting the lower 95% confidence interval of the curve for each muscle and then identifying age-specific reference values. We found that the distribution of data was similar to that for other neurophysiologic parameters. The lower limit of normal was easily defined, and relatively few values fell below the proposed lower limit. By using commercially available bioimpedance devices, these values will allow other investigators to explore the application of 50-kHZ EIM in clinical neuromuscular disease research.