Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength-sensitive cone photoreceptors in daylight. Recently a parallel, non-rod, non-cone photoreceptive pathway, arising from a population of retinal ganglion cells, was discovered in nocturnal rodents. These ganglion cells express the putative photopigment melanopsin and by signalling gross changes in light intensity serve the subconscious, 'non-image-forming' functions of circadian photoentrainment and pupil constriction. Here we show an anatomically distinct population of 'giant', melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field. The intrinsic, rod and (L + M) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based colour opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, in the diurnal trichromatic primate, 'non-image-forming' and conventional 'image-forming' retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.

The long-term goal of this research is to understand how retinal ganglion cells that express the photopigment melanopsin, also known as OPN4, contribute to vision in humans and other primates. Here we report the results of anatomical studies using our polyclonal antibody specifically against human melanopsin that confirm and extend previous descriptions of melanopsin cells in primates. In macaque and human retina, two distinct populations of melanopsin cells were distinguished based on dendritic stratification in either the inner or outer portion of the inner plexiform layer (IPL) . Variation in dendritic field size and cell density with eccentricity was confirmed, and dendritic spines, a new feature of melanopsin cells, were described. The spines were the sites of input from DB6 diffuse bipolar cell axon terminals to the inner stratifying type of melanopsin cells. The outer stratifying melanopsin type received inputs from DB6 bipolar cells via the DB6 cell’s bistratified outer axonal processes. Outer stratifying melanopsin cells also received inputs from axon terminals of dopaminergic amacrine cells. On the outer stratifying melanopsin cells, ribbon synapses from bipolar cells and conventional synapses from amacrine cells were identified in electron-microscopic immunolabeling experiments. Both inner and outer stratifying melanopsin cell types were retrogradely labeled following tracer injection in the lateral geniculate nucleus (LGN). In addition, a method for targeting melanopsin cells for intracellular injection using their intrinsic fluorescence was developed. This technique was used to demonstrate that melanopsin cells were tracer-coupled to amacrine cells and would be applicable to electrophysiological experiments in the future.

The assessment of physical activity in healthy populations and in those with chronic diseases is challenging. The aim of this systematic review was to identify whether available activity monitors (AM) have been appropriately validated for use in assessing physical activity in these groups. Following a systematic literature search we found 134 papers meeting the inclusion criteria; 40 conducted in a field setting (validation against doubly labelled water), 86 in a laboratory setting (validation against a metabolic cart, metabolic chamber) and 8 in a field and laboratory setting. Correlation coefficients between AM outcomes and energy expenditure (EE) by the criterion method (doubly labelled water and metabolic cart/chamber) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted. Random-effects meta-analyses were performed to pool the results across studies where possible. Types of devices were compared using meta-regression analyses. Most validation studies had been performed in healthy adults (n = 118), with few carried out in patients with chronic diseases (n = 16). For total EE, correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices. For active EE, correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices. Uniaxial devices tended to underestimate TEE (−12.07 (95%CI; -18.28 to −5.85) %) compared to triaxial (−6.85 (95%CI; -18.20 to 4.49) %, p = 0.37) and were statistically significantly less accurate than multisensor devices (−3.64 (95%CI; -8.97 to 1.70) %, p<0.001). TEE was underestimated during slow walking speeds in 69% of the lab validation studies compared to 37%, 30% and 37% of the studies during intermediate, fast walking speed and running, respectively. The high level of heterogeneity in the validation studies is only partly explained by the type of activity monitor and the activity monitor outcome. Triaxial and multisensor devices tend to be more valid monitors. Since activity monitors are less accurate at slow walking speeds and information about validated activity monitors in chronic disease populations is lacking, proper validation studies in these populations are needed prior to their inclusion in clinical trials.

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In non-mammalian vertebrates, retinal bipolar cells show center-surround receptive field organization. In mammals, recordings from bipolar cells are rare and have not revealed a clear surround. Here we report center-surround receptive fields of identified cone bipolar cells in the macaque monkey retina. In the peripheral retina, cone bipolar cell nuclei were labeled in vitro with diamidino-phenylindole (DAPI), targeted for recording under microscopic control, and anatomically identified by intracellular staining. Identified cells included 'diffuse' bipolar cells, which contact multiple cones, and 'midget' bipolar cells, which contact a single cone. Responses to flickering spots and annuli revealed a clear surround: both hyperpolarizing (OFF) and depolarizing (ON) cells responded with reversed polarity to annular stimuli. Center and surround dimensions were calculated for 12 bipolar cells from the spatial frequency response to drifting, sinusoidal luminance modulated gratings. The frequency response was bandpass and well fit by a difference of Gaussians receptive field model. Center diameters were all two to three times larger than known dendritic tree diameters for both diffuse and midget bipolar cells in the retinal periphery. In one instance intracellular staining revealed tracer spread between a recorded cell and its nearest neighbors, suggesting that homotypic electrical coupling may contribute to receptive field center size. Surrounds were around ten times larger in diameter than centers and in most cases the ratio of center to surround strength was approximately 1. We suggest that the center-surround receptive fields of the major primate ganglion cell types are established at the bipolar cell, probably by the circuitry of the outer retina.

In the primate retina the small bistratified, "blue-yellow" color-opponent ganglion cell receives parallel ON-depolarizing and OFFhyperpolarizing inputs from short (S)-wavelength sensitive and combined long (L)-and middle (M)-wavelength sensitive cone photoreceptors, respectively. However, the synaptic pathways that create S versus LM cone-opponent receptive field structure remain controversial. Here, we show in the macaque monkey retina in vitro that at photopic light levels, when an identified rod input is excluded, the small bistratified cell displays a spatially coextensive receptive field in which the S-ON-input is in spatial, temporal, and chromatic balance with the LM-OFF-input. ON pathway block with L-AP-4, the mGluR6 receptor agonist, abolished the S-ON response but spared the LM-OFF response. The isolated LM component showed a center-surround receptive field structure consistent with an input from OFFcenter, ON-surround "diffuse" cone bipolar cells. Increasing retinal buffering capacity with HEPES attenuated the LM-ON surround component, consistent with a non-GABAergic outer retina feedback mechanism for the bipolar surround. The GABAa/c receptor antagonist picrotoxin and the glycine receptor antagonist strychnine did not affect chromatic balance or the basic coextensive receptive field structure, suggesting that the LM-OFF field is not generated by an inner retinal inhibitory pathway. We conclude that the opponent S-ON and LM-OFF responses originate from the excitatory receptive field centers of S-ON and LM-OFF cone bipolar cells, and that the LM-OFFand ON-surrounds of these parallel bipolar inputs largely cancel, explaining the small, spatially coextensive but spectrally antagonistic receptive field structure of the blue-ON ganglion cell.

In the primate visual system approximately 20 morphologically distinct pathways originate from retinal ganglion cells and project in parallel to the lateral geniculate nucleus (LGN) and/or the superior colliculus. Understanding of the properties of these pathways and the significance of such extreme early pathway diversity for later visual processing is limited. In a companion study we found that the magnocellular LGN-projecting parasol ganglion cells also projected to the superior colliculus and showed Y-cell receptive field structure supporting the hypothesis that the parasol cells are analogous to the well studied alpha-Y cell of the cat's retina. We here identify a novel ganglion cell class, the smooth monostratified cells, that share many properties with the parasol cells. Smooth cells were retrogradely stained from tracer injections made into either the LGN or superior colliculus and formed inner-ON and outer-OFF populations with narrowly monostratified dendritic trees that surprisingly appeared to perfectly costratify with the dendrites of parasol cells. Also like parasol cells, smooth cells summed input from L-and M-cones, lacked measurable S-cone input, showed high spike discharge rates, high contrast and temporal sensitivity, and a Y-cell type nonlinear spatial summation. Smooth cells were distinguished from parasol cells however by smaller cell body and axon diameters but ϳ2 times larger dendritic tree and receptive field diameters that formed a regular but lower density mosaic organization. We suggest that the smooth and parasol populations may sample a common presynaptic circuitry but give rise to distinct, parallel achromatic spatial channels in the primate retinogeniculate pathway.

Purpose:To measure the apparent diffusion coefficient (ADC) of hyperpolarized (HP) 3 He gas using diffusion weighted MRI in healthy volunteers and patients with emphysema and examine the reproducibility and volume dependency. Materials and Methods:A total of eight healthy volunteers and 16 patients with emphysema were examined after inhalation of HP 3 He gas mixed with nitrogen (N 2 ) during breathhold starting from functional residual capacity (FRC) in supine position. Coronal diffusion-sensitized MR images were acquired. Each subject was imaged on three separate days over a seven-day period and received two different volumes (6% and 15% of total lung capacity [TLC]) of HP 3 He each day. ADC maps and histograms were calculated. The mean and standard deviation (SD) of the ADC at different days and volumes were compared. Results:The reproducibility of the mean ADC and SD over several days was good in both healthy volunteers and patients (SD range of 0.003-0.013 cm 2 /second and 0.001-0.009 cm 2 /second at 6% and 15% of TLC for healthy volunteers, and a SD range of 0.001-0.041 cm 2 /second and 0.001-0.011 cm 2 /second, respectively, for patients). A minor but significant increase in mean ADC with increased inhaled gas volume was observed in both groups. Conclusion:Mean ADC and SD of HP 3 He MRI is reproducible and discriminates well between healthy controls and patients with emphysema at the higher gas volume. This method is robust and may be useful to gain new insights into the pathophysiology and course of emphysema. THE HABIT OF SMOKING is increasing worldwide and so is one of its direct consequences, i.e., the chronic obstructive pulmonary disease (COPD). By the year 2020, COPD is expected to rank third as a cause of mortality and fifth of morbidity (1). A validated imaging technique that is sensitive to very early structural changes in the lungs could be helpful in the design of therapy and management of emphysema.MRI using hyperpolarized (HP) gases as helium ( 3 He) have emerged as a promising technique for studies of the structure and function of the lungs. Inhalation of HP 3 He can be used not only to derive information related to regional ventilation but also to the size of the alveoli. This is accomplished by measurement of the apparent diffusion coefficient (ADC) of inhaled HP 3 He. When HP 3 He is inhaled, diffusion of the gas is restricted by the boundaries of the alveoli and if restricted diffusion measurement conditions are met, the measured ADC will reflect the size of the peripheral airway spaces (2-4). It could thereby allow quantification of the structural changes (of the lungs) in emphysema. The ADC has been shown to increase in animals with elastase-induced emphysema (5). Studies have also been performed in small numbers of healthy adult subjects and subjects with lung disease (6 -12). In these studies, the ADC values in emphysematous lungs were increased relative to ADC values obtained in subjects with healthy lungs.