Sensory suppression during feeding

Feeding is essential for survival, whereas withdrawal and escape reactions are fundamentally protective. These critical behaviors can compete for an animal's resources when an acutely painful stimulus affects the animal during feeding. One solution to the feeding-withdrawal conflict is to optimize feeding by suppressing pain. We examined whether rats continue to feed when challenged with a painful stimulus. During feeding, motor withdrawal responses to noxious paw heat either did not occur or were greatly delayed. To investigate the neural basis of sensory suppression accompanying feeding, we recorded from brainstem pain-modulatory neurons involved in the descending control of pain transmission. During feeding, pain-facilitatory ON cells were inhibited and pain-inhibitory OFF cells were excited. When a nonpainful somatosensory stimulus preactivated ON cells and preinhibited OFF cells, rats interrupted eating to react to painful stimuli. Inactivation of the brainstem region containing ON and OFF cells also blocked pain suppression during eating, demonstrating that brainstem pain-modulatory neurons suppress motor reactions to external stimulation during homeostatic behaviors.     

Neuronal nonlinearity explains greater visual spatial resolution for darks than lights

Astronomers and physicists noticed centuries ago that visual spatial resolution is higher for dark than light stimuli, but the neuronal mechanisms for this perceptual asymmetry remain unknown. Here we demonstrate that the asymmetry is caused by a neuronal nonlinearity in the early visual pathway. We show that neurons driven by darks (OFF neurons) increase their responses roughly linearly with luminance decrements, independent of the background luminance. However, neurons driven by lights (ON neurons) saturate their responses with small increases in luminance and need bright backgrounds to approach the linearity of OFF neurons. We show that, as a consequence of this difference in linearity, receptive fields are larger in ON than OFF thalamic neurons, and cortical neurons are more strongly driven by darks than lights at low spatial frequencies. This ON/OFF asymmetry in linearity could be demonstrated in the visual cortex of cats, monkeys, and humans and in the cat visual thalamus. Furthermore, in the cat visual thalamus, we show that the neuronal nonlinearity is present at the ON receptive field center of ON-center neurons and ON receptive field surround of OFF-center neurons, suggesting an origin at the level of the photoreceptor. These results demonstrate a fundamental difference in visual processing between ON and OFF channels and reveal a competitive advantage for OFF neurons over ON neurons at low spatial frequencies, which could be important during cortical development when retinal images are blurred by immature optics in infant eyes.Light and dark stimuli are separately processed by ON and OFF channels in the retina and visual thalamus. Surprisingly, although most textbooks assume that ON and OFF visual responses are balanced throughout the visual system, recent studies have identified a pronounced overrepresentation of the OFF visual responses in primary visual cortex (area V1) (1–3). This recent discovery resonates with pioneering studies by Galilei (4) and von Helmholtz (5) who noticed that visual spatial resolution was higher for dark than light stimuli. Galilei (4) related the difference in resolution to the observation that a light patch on a dark background appears larger than the same sized dark patch on a light background, an illusion that von Helmholtz (5) named the “irradiation illusion.” Although this illusion has been studied in the past (6, 7), its underlying neuronal mechanisms remain unknown. It has been suggested that the perceived size differences could be caused by the light scatter in the optics of the eye followed by a neuronal nonlinearity (6, 7), but there are no neuronal measurements of a nonlinearity that fits the explanation. Previous studies revealed differences in response linearity between ON and OFF retinal ganglion cells (8, 9) and horizontal cells (10). However, a main conclusion from these studies was that ON retinal ganglion cells were roughly linear and less rectified than OFF retinal ganglion cells (8, 9), which is exactly the opposite of what would be needed to explain the irradiation illusion. Moreover, it remains unclear if ON/OFF retinal differences in response linearity and response gain propagate from retina to visual cortex. To investigate the neuronal mechanisms of the irradiation illusion, we recorded neuronal activity in the visual thalamus and cortex of anesthetized cats, local field potentials in awake monkeys, and visually evoked potentials in humans. We show that OFF neurons in thalamus and cortex increase their responses roughly linearly with luminance contrast, independently of the background luminance. In contrast, ON neurons saturate their responses with small increases in luminance, and approach the linearity of the OFF neurons only on bright backgrounds that make ON responses weaker. We also show that a simple model that uses an early retinal nonlinearity can explain several seemingly unrelated ON/OFF spatial asymmetries, including the difference in spatial resolution between darks and lights, the spatial frequency dependence of OFF dominance in visual cortex, and the difference in receptive field size between ON and OFF retinal ganglion cells. Moreover, because the asymmetry between ON and OFF neurons is present both at the receptive field center and surround of thalamic neurons, our results strongly suggest that it originates at the level of photoreceptors.     

Prospective randomized study of mode switching in a clinical trial of pacemaker therapy for sinus node dysfunction

INTRODUCTION: Atrial fibrillation (AF) is common in pacemaker patients with sinus node dysfunction (SND) and may result in rapid ventricular pacing (RVP) in the DDDR mode. Mode switching (MS) reduces RVP, but its clinical benefit in patients with SND is unknown. METHODS AND RESULTS: Two hundred two patients in the Mode Selection Trial (MOST; 2,010-patient, 6-year trial of DDDR vs VVIR pacing in SND) randomized to DDDR pacemakers with atrial high-rate episode (AHRE) storage capabilities were subrandomized to MS ON (N = 96) or MS OFF (N = 106). Cardiovascular symptoms, quality of life (QOL), reprogramming due to RVP, death, stroke, and heart failure hospitalization (HFH) were compared between groups. The treatment groups were similar with regard to AF history (59% MS ON vs 57% MS OFF). AHREs occurred in 49% patients during median follow-up of 2.2 years. Median AHRE duration (in min; MS ON 116 vs MS OFF 58, P = 0.29), frequency AHREs/week (MS ON 3.5 vs MS OFF 6.4, P = 0.23), and time spent in AHRE (min/week) (MS ON 450, MS OFF 268) were similar. Reprogramming due to any RVP during AHREs occurred more in MS OFF vs MS ON (13.2% vs 3.1%, P = 0.011) and marginally more for symptomatic RVP (8.5% vs 2.1%, P = 0.062). Cardiovascular symptoms occurred in 93.6% MS ON vs 90.2% MS OFF (P = 0.38). Median number of symptoms reported per visit was similar (MS ON 1.3 vs MS OFF 1.5, P = 0.62). Median symptom frequency/severity, summed and averaged over visits, was similar (MS ON 4.3 vs MS OFF 4.5, P = 0.74). QOL was not different between groups. Death, stroke, and HFH were not different between groups. CONCLUSION: MS reduces pacemaker reprogramming due to RVP during AHREs in a small number of patients but does not improve QOL or cardiovascular symptoms overall among patients with SND.     

TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade

An essential step in intricate visual processing is the segregation of visual signals into ON and OFF pathways by retinal bipolar cells (BCs). Glutamate released from photoreceptors modulates the photoresponse of ON BCs via metabotropic glutamate receptor 6 (mGluR6) and G protein (Go) that regulates a cation channel. However, the cation channel has not yet been unequivocally identified. Here, we report a mouse TRPM1 long form (TRPM1-L) as the cation channel. We found that TRPM1-L localization is developmentally restricted to the dendritic tips of ON BCs in colocalization with mGluR6. TRPM1 null mutant mice completely lose the photoresponse of ON BCs but not that of OFF BCs. In the TRPM1-L-expressing cells, TRPM1-L functions as a constitutively active nonselective cation channel and its activity is negatively regulated by Go in the mGluR6 cascade. These results demonstrate that TRPM1-L is a component of the ON BC transduction channel downstream of mGluR6 in ON BCs.     

Membrane and synaptic properties of developing lateral geniculate nucleus neurons during retinogeniculate axon segregation.

During the first postnatal month in the ferret (Mustela putorius furo), the projections from the retina to the lateral geniculate nucleus (LGN) become segregated into eye-specific layers and ON and OFF sublayers, a process that is thought to depend in part on neuronal activity. Remarkably, virtually nothing is known about the physiological features of LGN neurons during this period. We have recorded intracellularly from 46 A-layer neurons in slices of the ferret LGN between the ages of postnatal days 7 and 33. The passive membrane properties and current-voltage relationships of the developing neurons were similar in many, though not all, respects to those of adult LGN neurons. Action potentials in younger animals were smaller in amplitude and longer in duration than in older animals, but cells at all ages were capable of producing spike trains whose latency and spike number varied with stimulus intensity. In addition, cells at all ages responded with low-threshold potentials upon release from hyperpolarization. Slightly more than half of the LGN neurons responded to optic tract stimulation with excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs), or EPSP-IPSP pairs, beginning with the youngest ages. Thus, as early as the second postnatal week, and much before the onset of pattern vision, LGN neurons have many of the membrane and synaptic properties of adult thalamic neurons. These data are consistent with LGN cells playing a significant role in activity-dependent reshaping of the retinogeniculate pathway.     

Aging of human short-wave cone pathways

The retinal image is sampled concurrently, and largely independently, by three physiologically and anatomically distinct pathways, each with separate ON and OFF subdivisions. The retinal circuitry giving rise to an ON pathway receiving input from the short-wave-sensitive (S) cones is well understood, but the S-cone OFF circuitry is more controversial. Here, we characterize the temporal properties of putative S-cone ON and OFF pathways in younger and older observers by measuring thresholds for stimuli that produce increases or decreases in S-cone stimulation, while the middle- and long-wave-sensitive cones are unmodulated. We characterize the data in terms of an impulse response function, the theoretical response to a flash of infinitely short duration, from which the response to any temporally varying stimulus may be predicted. Results show that the S-cone response to increments is faster than to decrements, but this difference is significantly greater for older individuals. The impulse response function amplitudes for increment and decrement responses are highly correlated across individuals, whereas the timing is not. This strongly suggests that the amplitude is controlled by neural circuitry that is common to S-cone ON and OFF responses (photoreceptors), whereas the timing is controlled by separate postreceptoral pathways. The slower response of the putative OFF pathway is ascribed to different retinal circuitry, possibly attributable to a sign-inverting amacrine cell not present in the ON pathway. It is significant that this pathway is affected selectively in the elderly by becoming slower, whereas the temporal properties of the S-cone ON response are stable across the life span of an individual.     

Does on‐ versus off‐hours presentation impact in‐hospital outcomes of ST‐segment elevation myocardial infarction patients transferred to a tertiary care center?

Objectives : To determine whether in‐hospital outcome differs for transferred patients with ST‐segment elevation myocardial infarction (STEMI) presenting during business (ON) hours vs. after (OFF) hours. Background : Door‐to‐device (DTD) time is a prognostic factor in patients with STEMI and is longer during OFF hours. However, the in‐hospital mortality is controversial. Methods : This registry study included 786 consecutive patients with STEMI referred for primary percutaneous coronary intervention to a tertiary care center with an on‐site cardiac catheterization team 24 hrs a day/7 days (24/7) a week. ON hours were defined as weekdays 8 a.m. to 5 p.m., while OFF hours were defined as all other times, including holidays. The primary outcomes were in‐hospital death, reinfarction, and length of stay (LOS). Results : ON hours (29.5%, n = 232) and OFF hours (70.5%, n = 554) groups had similar demographic and baseline characteristics. A significantly higher proportion of patients presenting ON hours had a DTD time ≤120 min compared to OFF hours patients (32.6% vs. 22.1%, P = 0.007). The rates of in‐hospital death (8.2% vs. 6%), reinfarction (0% vs. 1.1%), and mean LOS (5.7 ± 6 vs. 5.7 ± 5) were not significantly different in the ON vs. OFF hours groups, all P = nonsignificant. Conclusion : In a tertiary care center with an on‐site cardiac catheterization team 24/7, there are no differences in in‐hospital outcomes of transferred patients with STEMI during ON vs. OFF hours. © 2010 Wiley‐Liss, Inc.     

The Impact of Atrial Prevention and Termination Therapies on Atrial Tachyarrhythmia Burden in Patients Receiving a Dual-Chamber Defibrillator for Ventricular Arrhythmias

INTRODUCTION: This prospective, multicenter, randomized trial evaluated the effects of atrial prevention and termination therapies on atrial tachyarrhythmia (ATA) burden in patients with a standard indication for an implantable cardioverter defibrillator (ICD). METHODS: A Jewel AF or GEM III AT ICD was implanted in 451 patients. At 1-month post-implant, patients were randomized to atrial prevention and termination therapies ON ( n = 199) or OFF ( n = 206) and followed for 6 additional months. Automatic atrial shocks were enabled in only 14% of the ON group. The follow-up time after randomization was 6.9 +/- 2.4 months ON versus 6.8 +/- 2.3 months OFF. RESULTS: There were 126/405 (31.1%) patients who had AT/AF episodes during follow-up. Only four patients received a shock to treat ATA's during follow-up. The median ATA burden was 0 hours/month in both the ON and OFF groups ( P = 0.40). The mean ATA burden was 4.3 +/- 20.0 hours/month ON versus 9.0 +/- 50.0 hours/month OFF ( P = 0.11). In a subgroup of 192 patients with a history of ATA's, the median burden was 0 hours/month in the both groups ( P = 0.23). However, the mean burden in this subgroup was 7.6 +/- 27.1 hours/month ON versus 19.2 +/- 73.7 hours/month OFF ( P = 0.056). CONCLUSIONS: In patients receiving an ICD for ventricular arrhythmias, no significant change in ATA burden was observed when atrial prevention and termination therapies were enabled. This may have been due to the low ATA burden in this population. In a subgroup of patients with history of ATA's, there was a trend towards a reduction in mean burden.     

Retina is structured to process an excess of darkness in natural scenes

Retinal ganglion cells that respond selectively to a dark spot on a brighter background (OFF cells) have smaller dendritic fields than their ON counterparts and are more numerous. OFF cells also branch more densely, and thus collect more synapses per visual angle. That the retina devotes more resources to processing dark contrasts predicts that natural images contain more dark information. We confirm this across a range of spatial scales and trace the origin of this phenomenon to the statistical structure of natural scenes. We show that the optimal mosaics for encoding natural images are also asymmetric, with OFF elements smaller and more numerous, matching retinal structure. Finally, the concentration of synapses within a dendritic field matches the information content, suggesting a simple principle to connect a concrete fact of neuroanatomy with the abstract concept of information: equal synapses for equal bits.     

Perioperative Outcomes after On- and Off-Pump Coronary Artery Bypass Grafting

Although numerous reports describe the results of off-pump coronary artery bypass grafting (CABG) at specialized centers and in select patient populations, it remains unclear how off-pump CABG affects real-world patient outcomes. We conducted a large, multicenter observational cohort study of perioperative death and morbidity in on-pump (ON) versus off-pump (OFF) CABG.We reviewed Veterans Affairs Surgical Quality Improvement Program data for all patients (N=65,097) who underwent isolated CABG from October 1997 through April 2011 (intention-to-treat data were available from 2005 onward). The primary outcome was perioperative (30-day or in-hospital) death; the secondary outcomes were perioperative stroke, dialysis dependence, reoperation for bleeding, mechanical circulatory support, myocardial infarction, ventilator support ≥48 hr, and mediastinitis. Propensity scores calculated from age, 17 preoperative risk factors, and year of surgery were used to match 8,911 OFF with 26,733 ON patients.In the complete cohort, compared with the ON patients (n=53,468), the OFF patients (n=11,629) had less perioperative death (2.02% vs 2.53%, P=0.0012) and lower incidences of all morbidities except perioperative myocardial infarction. In the matched cohort, perioperative death did not differ significantly between OFF and ON patients (1.94% vs 2.28%, P=0.06), but the OFF group had lower incidences of all morbidities except for perioperative myocardial infarction and mediastinitis. A subgroup intention-to-treat analysis yielded similar but smaller outcome differences between the ON and OFF groups.Off-pump CABG might be associated with decreased operative morbidity but did not affect operative death, compared with on-pump CABG. Future studies should examine the effect of off-pump CABG on long-term outcomes.     

DL-2-amino-4-phosphonobutyric acid does not eliminate "ON" responses in the visual system of goldfish.

DL-2-Amino-4-phosphonobutyric acid (APB) suppresses activity in retinal ON pathways. It is generally assumed that loss of the ON pathway would result in loss of ON responses in the visual system. We tested this assumption by recording activity from the optic nerves of intact goldfish (Carassius auratus) before and after intraocular injection of APB. Whole-nerve responses to increments and decrements of light were compared to electroretinogram responses and to tectal evoked potentials. APB severely reduced the amplitude of the electroretinogram b-wave but left ON and OFF responses from the optic nerve and tectum intact, although decreased in sensitivity. We conclude that APB does not completely eliminate ON responses in the visual system, at least in goldfish. The selectivity and effectiveness of APB must be evaluated in other species before this agent can be relied upon as a useful tool in understanding the roles of ON and OFF pathways in visual function.     

The effect of atrial pacing therapies on atrial tachyarrhythmia burden and frequency: results of a randomized trial in patients with bradycardia and atrial tachyarrhythmias

OBJECTIVES: The Atrial Therapy Efficacy and Safety Trial (ATTEST) was a prospective, randomized study to evaluate preventive pacing and antitachycardia pacing (ATP) in patients with symptomatic atrial fibrillation (AF) or atrial tachycardia (AT). BACKGROUND: The effect of the combination of atrial prevention and termination algorithms on AT/AF burden and frequency in pacemaker patients is unknown. METHODS: A DDDRP pacemaker (AT500, Medtronic Inc., Minneapolis, Minnesota) with three atrial preventive pacing algorithms and two ATP algorithms was implanted in 368 patients. Patients were randomized one-month post-implant to all prevention and ATP therapies ON or OFF and followed for three months. The OFF group had DDDR pacing at a lower programmed rate of 60 ppm. The AT/AF burden and frequency were determined from daily device counters in 324 patients treated according to protocol. RESULTS: In 17,018 episodes with stored electrograms, appropriate detection was confirmed in 17,004 (99.9%). The median percentage of atrial pacing was 98% in the ON group versus 75% in the OFF group (p < 0.001). Using device-defined criteria for successful termination, ATP terminated 8,590 (54%) of 15,789 treated episodes. The median AT/AF burden during the three-month study period was 4.2 h/month ON versus 1.1 h/month OFF (p = 0.20). The median AT/AF frequency was 1.3 episodes/month ON versus 1.2 episodes/month OFF (p = 0.65). System-related, complication-free survival at four months was 90.2% (Kaplan-Meier estimate). CONCLUSIONS: This DDDRP pacemaker is safe, has accurate AT/AF detection, and provides ATP with 54% efficacy as defined by the device. The atrial prevention and termination therapies combined did not reduce AT/AF burden or frequency in this patient population.     

A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake

CONTEXT: Sunitinib (sunitinib malate; SU11248; Sutent; Pfizer Inc., New York, NY) is a multitarget inhibitor of tyrosine kinases for the treatment of some human cancers. A myxedematous coma in a patient treated with sunitinib for a gastrointestinal stromal tumor was unexpectedly observed. OBJECTIVE: Our objective was to evaluate the effect of sunitinib on thyroid function in 24 patients with gastrointestinal stromal tumors. DESIGN: This was a prospective, observational cohort study. SETTING: The study was performed at two tertiary care hospitals. PATIENTS: A total of 24 patients receiving the following cycles of therapy were included in the study: 4-wk daily treatment at the dose of 50 mg orally (ON) and 2-wk withdrawal (OFF). INTERVENTIONS: Thyroid function tests, ultrasonography, and iodine-123 ((123)I) thyroidal uptake were performed at the end of several ON and OFF periods. RESULTS: After one to six cycles of treatment, 46% of patients developed hypothyroidism. Initially, TSH levels were elevated at the end of ON periods and normalized at the end of OFF periods, but a worsening in following cycles was always observed. Neither echographic alterations nor variations in thyroglobulin and antithyroid autoantibodies were found during the ON and OFF periods. On the contrary, (123)I uptake was significantly reduced at the end of ON periods, with partial or total normalization at the end of OFF periods. CONCLUSIONS: A high prevalence of hypothyroidism, very severe in some cases, was observed during sunitinib. Significant variations in (123)I uptake strongly suggest that the underlying mechanism is an impaired iodine uptake. The absence of thyroid autoimmunity, the lack of a preceding transient hyperthyroidism, and the normal echographic pattern exclude autoimmune and/or destructive mechanisms. Patients on sunitinib should be strictly monitored for the appearance of hypothyroidism and promptly treated.     

Gating currents of the cloned delayed-rectifier K+ channel DRK1.

Gating currents of the cloned delayed-rectifier K+ channel DRK1 expressed in Xenopus oocytes were measured with the open-oocyte Vaseline-gap voltage-clamp technique. DRK1 gating charge had the following salient properties: (i) gating-charge amplitude correlated positively with size of the expressed ionic K+ currents; (ii) the time integral of ON and OFF gating currents was similar, indicating charge conservation and lack of charge immobilization; (iii) the gating-charge activation curve was shallower and had a half-activation potential 15 mV more negative than the activation curve for K+ conductance; (iv) effective valence for the gating current was about two electronic charges per gating subunit; (v) for large depolarizations (to > 0 mV) prominent rising phases were observed during the ON and OFF gating charge, which appeared as shoulders in unsubtracted traces; (vi) for small depolarizing pulses (to < 0 mV) ionic-current activation and deactivation had time constants similar to ON and OFF gating-current decay, respectively; (vii) negative prepulses made more prominent the ON rising phase and delayed ionic and gating currents. The results are consistent with a model for K+ channel activation that has an early slow and/or weakly voltage-dependent transition between early closed states followed by more voltage-dependent transitions between later closed states and a final voltage-independent closed-open transition.     

Effects of intra-aortic balloon pumping on mitral flow dynamics after aortocoronary bypass surgery

Improvement in left ventricular function following intra-aortic balloon pumping (IABP) in 15 patients (aged 51 to 86 years) after coronary artery bypass grafting was evaluated. Using transesophageal atrial echocardiography, the mitral flow velocity integrals in the rapid filling phase (IntR) and in the contraction phase (IntA) were measured from transmitral flow patterns, and the sum of IntR and IntA (IntR + IntA), and the ratios of IntA to IntR (IntA/IntR) were calculated for ON and OFF states of balloon pumping (IABP OFF test). The same parameters were determined during 1:2 assist balloon pumping (IABP 1:2 test); the cardiac cycle with balloon assist was defined as "ON", and that without balloon assist as "OFF". 1. IABP OFF test: IABP increased IntR from 6.4 +/- 1.6 cm to 7.6 +/- 1.9 cm (p less than 0.01), suggesting that a decreased afterload improves left ventricular relaxation. IntA did not change with balloon assist (ON 3.5 +/- 1.2 cm, OFF 3.7 +/- 1.2 cm). IntR + IntA increased from 10.0 +/- 2.0 cm to 11.1 +/- 2.4 cm during IABP (p less than 0.01). IABP reduced the IntA/IntR from 0.62 +/- 0.25 to 0.50 +/- 0.20 (p less than 0.01). The increment in the IntA/IntR without IABP suggests that impaired diastolic filling of the left ventricle due to an increased afterload may be compensated for by enhanced left atrial contraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

A theory of direction selectivity for macaque primary visual cortex

This paper offers a theory for the origin of direction selectivity (DS) in the macaque primary visual cortex, V1. DS is essential for the perception of motion and control of pursuit eye movements. In the macaque visual pathway, neurons with DS first appear in V1, in the Simple cell population of the Magnocellular input layer 4Cα. The lateral geniculate nucleus (LGN) cells that project to these cortical neurons, however, are not direction selective. We hypothesize that DS is initiated in feed-forward LGN input, in the summed responses of LGN cells afferent to a cortical cell, and it is achieved through the interplay of 1) different visual response dynamics of ON and OFF LGN cells and 2) the wiring of ON and OFF LGN neurons to cortex. We identify specific temporal differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated subregions; analysis and simulations confirm the efficacy of the mechanisms proposed. To constrain the theory, we present data on Simple cells in layer 4Cα in response to drifting gratings. About half of the cells were found to have high DS, and the DS was broadband in spatial and temporal frequency (SF and TF). The proposed theory includes a complete analysis of how stimulus features such as SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to determine the preferred direction and magnitude of DS.

This paper proposes a solution to a longstanding question in visual neuroscience, namely, the origin of direction selectivity (DS) in the visual cortex of macaque monkeys. Motion perception is a vital visual capability well developed in primates. As perceiving motion requires perceiving the direction in which a target moves, DS, the ability of visual neurons to sense the direction of movement, is essential for motion perception (1) and for the control of pursuit eye movements (2). For these reasons, understanding DS is an important first step toward understanding how the cortex processes motion signals.DS in cortical neurons was first documented in the cat (3). Since then, it has been found in neurons all along the visual dorsal stream (an area associated with motion processing) in primates like macaque monkeys (4–7), whose vision is like that of humans. Neurons with DS are, in fact, present across species; they are widespread among visual mammals, an experimental fact that testifies to their biological significance.In the visual pathway of macaques, DS appears first in the primary visual cortex (V1), in the Simple cell population of the input layer 4Cα (8). These neurons provide feed-forward direction-selective signals to subsequent cortical layers and brain regions in the dorsal pathway. Thus, to discover the origin of DS, one is led to examining how neurons in layer 4Cα acquire their DS—and that is where it gets interesting: The neurons that provide visual signals to layer 4Cα, the Magnocellular cells in the lateral geniculate nucleus (LGN), are not direction selective (9–12). Yet many of the cells in the input layer of V1 to which they project are direction selective. A fundamental scientific question, therefore, is how 4Cα neurons acquire their DS. That is the question we would like to answer in this paper.Although many papers have been written on DS since its discovery over half a century ago, and there is continued interest in the subject (13–16), no satisfactory mechanistic explanation for the origin of DS in primate cortex has been proposed before now: Early conceptual models of how DS may arise, such as the Reichardt multiplier (17) or the motion energy model (18), were not concerned with biological mechanisms. Later work proposed neural mechanisms for the motion energy model (19), but they are not sufficient for explaining DS in primate cortex. See Discussion for comparisons of different model mechanisms.It is widely accepted that the DS computation requires spatiotemporal inseparability (STI); that is, different subregions of the receptive field have different time courses of response (18, 20, 21). What were lacking were biological mechanisms that could produce STI, and a clear understanding of how DS depends on the interaction between STI and the spatial and temporal character of the visual stimulus. These are the issues we address in this paper.We hypothesize that a plausible biological mechanism is the interplay between 1) the different dynamics of ON and OFF LGN cells and 2) the specific wiring that connects ON and OFF cells to V1. Item 2 refers here to the well-known fact that OFF and ON LGN cells are wired to segregated V1 receptive field subregions (3, 22, 23). Our main contribution is item 1: We identify, in Results, dynamic differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated receptive-field subregions. The mechanisms we propose are biologically grounded, and, as we show, they are sufficient for initiating DS in the feed-forward LGN input to cortical cells.To constrain our theory, we present experimental results on the responses of macaque 4Cα Simple cells to drifting gratings. Most Simple cells we recorded in 4Cα were unambiguously direction selective, preferring, consistently, the same direction over their entire visible ranges of spatial frequency (SF) and temporal frequency (TF); about half of the cells had high DS. Our data reveal also an important characteristic of neurons with DS, namely, the approximate invariance of DS with SF and TF. Explaining the broadband character of DS (in TF and SF) is a challenge for all previous theories. Our theory includes a complete analysis of how stimulus features like SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to explain the broadband character of DS. The theoretical predictions are in good agreement with data.With regard to broader implications, although the theory as described in this paper is specifically about DS, an important message is that, when combining information from multiple channels, slight biases in their temporal filters can greatly enhance the capability of a system. Thus, it may be possible to exploit the temporal axis further in the processing of biological and nonbiological signals, especially in the neural processing of sensory inputs and, possibly, in computer vision.     

Brainstem control of response modes in neurons of the cat''s lateral geniculate nucleus.

The visual pathway from retina through the lateral geniculate nucleus to visual cortex in the cat is comprised of several parallel neuronal streams that independently analyze different aspects of the visual scene. The best known of these are the X and Y pathways that relay through the geniculate A laminae. Recent receptive-field studies of retinal and geniculate neurons suggest that there is a further elaboration of cell types at the level of the lateral geniculate nucleus. That is, two types of geniculate X cells with different temporal patterns of responses to visual stimuli are recognized, one with "nonlagged" features, exhibiting shorter response latencies and another with "lagged" features; all retinal X cells are nonlagged. We asked whether nonlagged and lagged responses represent different cell classes or two response modes of the same cells, perhaps under the control of nonretinal afferents to these relay cells. Accordingly, we studied the effects on appropriate receptive-field properties of electrical activation of the midbrain parabrachial region, which is a major nonretinal input to relay cells. Such parabrachial stimulation made each of the eight lagged X cells much more like nonlagged cells, and this stimulation completely transformed the lagged response profiles of six of the eight cells to nonlagged. We thus conclude that the property of lagged responsiveness, which is an emergent property of the lateral geniculate nucleus, is a different response mode of the same cells that can also display nonlagged responses, rather than representing different cell classes; furthermore, this switching between response modes is, at least partly, under the control of afferents from the parabrachial region.     

Scene statistics and noise determine the relative arrangement of receptive field mosaics

Many sensory systems utilize parallel ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways consist of ensembles or grids of ON and OFF detectors spanning sensory space. Yet, encoding by opponent pathways raises a question: How should grids of ON and OFF detectors be arranged to optimally encode natural stimuli? We investigated this question using a model of the retina guided by efficient coding theory. Specifically, we optimized spatial receptive fields and contrast response functions to encode natural images given noise and constrained firing rates. We find that the optimal arrangement of ON and OFF receptive fields exhibits a transition between aligned and antialigned grids. The preferred phase depends on detector noise and the statistical structure of the natural stimuli. These results reveal that noise and stimulus statistics produce qualitative shifts in neural coding strategies and provide theoretical predictions for the configuration of opponent pathways in the nervous system.

Across many sensory systems, neurons encode information about either increments or decrements of stimuli in the environment, so-called ON and OFF signals. This division between ON and OFF signaling has been observed in visual (1, 2), thermosensory (3), auditory (4), olfactory (5), and electrosensory (6) systems. This organization has the advantage that neurons can be tasked with signaling increments or decrements in steady-state stimulus levels with fewer spikes, thereby resulting in more efficient neural codes (7, 8). Moreover, when the number of potential stimuli is large, neurons often specialize; for example, they only respond to a small region of visual space or a narrow auditory frequency band. The combination of these coding strategies raises two questions. First, how should a particular set of detectors, either the ON or OFF cells, arrange themselves most efficiently to cover stimulus space? Second, what is the optimal relative arrangement of ON and OFF detector grids? For one system, the retina, the answer to the first question is clear from previous work: Detectors of a particular type tile stimulus space and exhibit overlap near the 1-sigma boundary of a Gaussian receptive field (9–13). The answer to the second question, what might be called the “sensor alignment problem,” has received comparatively little attention and is the focus of this study.Conceptually, there are three general possibilities for how the sensor alignment problem could be solved. One possibility is that the grids of sensors are statistically independent, meaning the locations of receptive fields in one grid provide no information about the receptive field locations in the other grid. A second possibility is that the two grids are aligned, meaning the receptive field centers in one grid are closer than expected by chance. The third possibility is that the two grids are antialigned, meaning the receptive field centers in the two grids are further apart than expected by chance. On general information theory grounds, the optimal solution is likely to depend on noise in the encoding process and the statistics of the encoded stimuli (14, 15).While most anatomical studies of retinal mosaics indicate they are statistically independent (16–18, but see ref. 19), we have recently shown that grids of ON and OFF receptive field (henceforth called “mosaics”) formed by retinal ganglion cells (RGCs) are antialigned when those cells encode similar visual features (20). Here, we show how these results can be explained through the lens of efficient coding theory (7). This theory argues that sensory systems should aim to reduce the redundancy present in sensory input while minimizing metabolic costs, thereby reliably encoding natural stimuli with fewer spikes. Efficient coding theory has been successful at explaining many aspects of sensory processing and retinal physiology, including center-surround receptive fields, the formation of mosaics, and a greater proportion of OFF than ON cells (7, 11, 15, 21, 22). Thus, we asked whether efficient coding theory might predict the optimal spatial arrangement of ON and OFF receptive field mosaics within the retina. Our approach to this question involved optimizing a model that approximates the processing performed by many RGCs (21). By maximizing the mutual information between an (input) library of natural images and (output) spike rates, we examined the effects of image statistics and encoding noise on the optimal arrangement of ON and OFF mosaics.In this model, we found that the optimal spatial arrangement was a pair of approximately hexagonal mosaics of ON and OFF receptive fields. However, surprisingly, the relative alignment of these mosaics depended on the input noise, output noise, and the statistics of the natural image set. When output noise was low, the mosaics were aligned, with ON and OFF receptive fields centered at nearby locations more often than expected by chance. When output noise was relatively high, antialignment became the favored arrangement. Surprisingly, the content of the image set also strongly influenced the transition between aligned and antialigned mosaics. In particular, when image sets contained more “outlier” images with particularly large luminance or contrast values, antialignment became the favored state for fixed input and output noise. We demonstrate analytically and confirm computationally that as noise parameters or stimulus statistics vary, mutual information changes smoothly, while the optimal mosaic arrangements undergo a sudden, qualitative shift. Finally, we confirm these predictions by showing that systematic manipulations of the training dataset change the phase boundary in a manner predicted by an analytical model. These findings underscore the crucial role played by both noise and the statistics of natural stimuli for understanding specialization and coordination in sensory processing.     

Breathing pattern in patients with Parkinson's disease

The improvement in motor performance resulting from levodopa administration in patients with Parkinson's disease (PD) provides the opportunity to investigate ventilatory changes brought about by the disease. The aim of this study has been to investigate these changes in order to specify the mechanisms of the impairment in breathing in PD. Breathing patterns at rest were investigated in 11 patients with idiopathic PD both before (OFF) and after (ON) administration of levodopa at a dose improving their motor performance by at least 30%. Airflow (Fleisch head mounted on a mask), rib cage and abdomen movements (inductance plethysmography) were recorded in the OFF condition 1 h after subjects woke up. Subjects then received levodopa and a new set of recordings was obtained 1 h later, in the ON condition. Breath-by-breath processing of recordings was carried out, and tidal volume (VT), inspiratory (TI) and expiratory (TE) durations were measured. The main finding was a lengthening of TI resulting in a decrease in ventilation and in VT/TI, and an increase in TI/TTOT in the ON compared to the OFF condition. In the ON condition abnormal rib cage-abdomen plots patterns were found in four out of six subjects. A hypothesis on the effect of PD on breathing is proposed on grounds of normal diaphragmatic activity but impaired activity of the other respiratory muscles and more specifically the intercostal muscles.