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Objective: Holographic methods can be used with phased array transducers to shape an ultrasound field. We tested a simple method to create holograms with a hemispherical 1024-element phased array transducer and explored how it could benefit ultrasound-mediated blood-brain barrier (BBB) disruption. Methods: With this method, individual acoustic simulations for each element of the transducer were simultaneously loaded into computer memory. Each element's phase was systematically modulated until the combined field matched a desired pattern. The method was evaluated with a 220 kHz transducer being tested clinically to enhance drug delivery via BBB disruption. The holograms were evaluated in a tissue-mimicking phantom and in vivo in experiments disrupting the BBB in rats and in a macaque. We also explored whether this approach could mitigate secondary reflections from the skull using simulations of transcranial focusing in clinical treatments of transcranial sonication for BBB disruption. Results: This approach can enlarge the focal volume in a patient-specific manner and could reduce the number of sonication targets needed to disrupt large volumes, improve the homogeneity of the disruption, and improve our ability to detect microbubble activity in tissues with low vascular density. Simulations suggest that the method could also mitigate secondary reflections during transcranial sonication.

In natural vision, primates actively move their eyes several times per second via saccades. It remains unclear whether, during this active looking, visual neurons exhibit classical retinotopic properties, anticipate gaze shifts or mirror the stable quality of perception, especially in complex natural scenes. Here, we let 13 monkeys freely view thousands of natural images across 4.6 million fixations, recorded 883 h of neuronal responses in six areas spanning primary visual to anterior inferior temporal cortex and analyzed spatial, temporal and featural selectivity in these responses. Face neurons tracked their receptive field contents, indicated by category-selective responses. Self-consistency analysis showed that general feature-selective responses also followed eye movements and remained gaze-dependent over seconds of viewing the same image. Computational models of feature-selective responses located retinotopic receptive fields during free viewing. We found limited evidence for feature-selective predictive remapping and no viewing-history integration. Thus, ventral visual neurons represent the world in a predominantly eye-centered reference frame during natural vision.

An interconnected group of cortical regions distributed across the primate inferotemporal cortex forms a network critical for face perception. Understanding the microarchitecture of this face network can refine mechanistic accounts of how individual areas function and interact to support visual perception. To address this, we acquire a unique dataset in macaque monkeys combining fMRI to localize face patches in vivoand then ex vivohistology to resolve their histo-architecture across cortical depths in the same individuals. Our findings reveal that face patches differ based on cytochrome oxidase (CO) and, to a lesser extent, myelin staining, with the middle lateral (ML) face patch exhibiting pronounced CO staining. Histo-architectonic differences are less pronounced when using probabilistic definitions of face patches, underscoring the importance of precision mapping integrating in vivoand ex vivomeasurements in the same individuals. This study indicates that the macaque face patch network is composed of architectonically distinct components.

How does the brain encode information about the environment? Decades of research have led to the pervasive notion that the object-processing pathway in primate cortex consists of multiple areas that are each specialized to process different object categories (such as faces, bodies, hands, non-face objects and scenes). The anatomical consistency and modularity of these regions have been interpreted as evidence that these regions are innately specialized. Here, we propose that ventral-stream modules do not represent clusters of circuits that each evolved to process some specific object category particularly important for survival, but instead reflect the effects of experience on a domain-general architecture that evolved to be able to adapt, within a lifetime, to its particular environment. Furthermore, we propose that the mechanisms underlying the development of domains are both evolutionarily old and universal across cortex. Topographic maps are fundamental, governing the development of specializations across systems, providing a framework for brain organization.

Our assignment was to review the development of the face-processing network, an assignment that carries the presupposition that a face-specific developmental program exists. We hope to cast some doubt on this assumption and instead argue that the development of face processing is guided by the same ubiquitous rules that guide the development of cortex in general.

Here we report that monkeys raised without exposure to faces did not develop face domains, but did develop domains for other categories and did show normal retinotopic organization, indicating that early face deprivation leads to a highly selective cortical processing deficit. Therefore, experience must be necessary for the formation (or maintenance) of face domains. Gaze tracking revealed that control monkeys looked preferentially at faces, even at ages prior to the emergence of face domains, but face-deprived monkeys did not, indicating that face looking is not innate. A retinotopic organization is present throughout the visual system at birth, so selective early viewing behavior could bias category-specific visual responses toward particular retinotopic representations, thereby leading to domain formation in stereotyped locations in inferotemporal cortex, without requiring category-specific templates or biases. Thus, we propose that environmental importance influences viewing behavior, viewing behavior drives neuronal activity, and neuronal activity sculpts domain formation.

Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.

We report a large spin-up glitch in PSR J1846-0258 which coincided with the onset of magnetar-like behavior on 2006 May 31. We show that the pulsar experienced an unusually large glitch recovery, with a recovery fraction of Q = 8.7 +- 2.5, resulting in a net decrease of the pulse frequency. Such a glitch recovery has never before been observed in a rotation-powered pulsar (RPP); however, similar but smaller glitch over-recovery has been recently reported in the magnetar AXP 4U 0142+61 and may have occurred in SGR 1900+14. We also report a large increase in the timing noise of the source. We discuss the implications of the unusual timing behavior in PSR J1846-0258 on its status as the first identified magnetically active RPP.

We present timing data spanning 6.4 yr for the young and energetic PSR J0205+6449, in the supernova remnant 3C 58. Data were obtained with the Rossi X-ray Timing Explorer, the Jodrell Bank Observatory, and the Robert C. Byrd Green Bank Telescope. We present phase-coherent timing analyses showing timing noise and two spin-up glitches with fractional frequency increases of [?]3.4 x 10-7 near MJD 52555 and [?]3.8 x 10-6 between MJDs 52777 and 53062. These glitches are unusually large if the pulsar was created in the historical supernova in 1181, as has been suggested. For the X-ray timing, we developed a new unbinned maximum likelihood method for determining pulse arrival times, which performs significantly better than the traditional binned techniques. In addition, we present an X-ray pulse profile analysis of four years of RXTE data showing that the pulsar is detected up to [?]40 keV. We also present the first measurement of the phase offset between the radio and X-ray pulse for this source, showing that the radio pulse leads the X-ray pulse by ph = 0.10 +- 0.01 in phase. We compile all known measurements of the phase offsets between radio and X-ray and radio and g-ray pulses for X-ray and g-ray pulsars. We show that there is no relationship between pulse period and phase offset, supported by our measurement of the phase offset for PSR J0205+6449.

The rotation-powered pulsar PSR J1846-0258 in the supernova remnant Kes 75 was recently shown to have exhibited magnetar-like X-ray bursts in mid-2006. Radio emission has not yet been observed from this source, but other magnetar-like sources have exhibited transient radio emission following X-ray bursts. We report on a deep 1.9 GHz radio observation of PSR J1846-0258 with the 100 m Green Bank Telescope in late 2007, designed to search for radio pulsations or bursts from this target. We have also analyzed three shorter serendipitous 1.4 GHz radio observations of the source taken with the 64 m Parkes telescope during the 2006 bursting period. We detected no radio emission from PSR J1846-0258 in either the Green Bank or Parkes data sets. We place an upper limit of 4.9 mJy on coherent pulsed emission from PSR J1846-0258 based on the 2007 November 2 observation, and an upper limit of 27 mJy around the time of the X-ray bursts. Serendipitously, we observed radio pulses from the nearby RRAT J1846-02, and place a 3 s confidence level upper limit on its period derivative of 1.7 x 10[?]13, implying its surface dipole magnetic field is less than 2.6 x 1013 G.

We have conducted a radio pulsar survey of 56 unidentified g-ray sources from the third EGRET catalog that are at intermediate Galactic latitudes (5deg < |b| < 73deg). For each source, four interleaved 35 minute pointings were made with the 13 beam, 1400 MHz multibeam receiver on the Parkes 64 m radio telescope. This covered the 95% error box of each source at a limiting sensitivity of ~0.2 mJy to pulsed radio emission for periods P [?] 10 ms and dispersion measures [?]50 pc cm-3. Roughly half of the unidentified g-ray sources at |b| > 5deg with no proposed active galactic nucleus counterpart were covered in this survey. We detected nine isolated pulsars and four recycled binary pulsars, with three from each class being new discoveries. Timing observations suggest that only one of the pulsars has a spin-down luminosity that is even marginally consistent with the inferred luminosity of its coincident EGRET source. Our results suggest that population models, which include the Gould Belt as a component, overestimate the number of isolated pulsars among the midlatitude Galactic g-ray sources, and that it is unlikely that Gould Belt pulsars make up the majority of these sources. However, the possibility of steep pulsar radio spectra and the confusion of terrestrial radio interference with long-period pulsars (P [?] 200 ms) having very low dispersion measures ([?]10 pc cm-3, expected for sources at a distance of less than about 1 kpc) prevent us from strongly ruling out this hypothesis. Our results also do not support the hypothesis that millisecond pulsars make up the majority of these sources. Nonpulsar source classes should therefore be further investigated as possible counterparts to the unidentified EGRET sources at intermediate Galactic latitudes.

The article presents information related to stereopsis or binocular depth perception. Stereopsis is the ability to see three-dimensionally. In two-dimensional works of art, stereopsis and relative motion only reveals the flatness of the canvas. Stereoblindness may prove an asset to an artist, as a person lacking stereopsis might become more sensitive to other monocular depth cues, such as shading, perspective, and occlusion. The best way to evaluate stereoacuity is to test it directly.

We present the first phase-coherent measurement of a braking index for the young, energetic rotation-powered pulsar PSR J1846-0258. This 324 ms pulsar is located at the center of the supernova remnant Kesteven 75 and has a characteristic age of tc = 723 yr, a spin-down energy of E = 8.3 x 1036 ergs s-1, and an inferred magnetic field of 4.9 x 1013 G. Two independent phase-coherent timing solutions are derived, which together span 5.5 yr of data obtained with the Rossi X-Ray Timing Explorer. In addition, a partially phase-coherent timing analysis confirms the fully phase-coherent result. The measured value of the braking index, n = 2.65 +- 0.01, is significantly less than 3, the value expected from magnetic dipole radiation, implying another physical process must contribute to the pulsar's rotational evolution. Assuming the braking index has been constant since birth, we place an upper limit on the spin-down age of PSR J1846-0258 of 884 yr, the smallest age estimate of any rotation-powered pulsar.

We present a new phase-coherent timing analysis for the young, energetic pulsar PSR B0540-69 using 7.6 yr of data from the Rossi X-Ray Timing Explorer. We measure the braking index, n = 2.140 +- 0.009, and discuss our measurement in the context of other discordant values reported in the literature. We present an improved source position from the phase-coherent timing of the pulsar, to our knowledge, the first of its kind from X-ray pulsar timing. In addition, we detect evidence for a glitch that had been previously reported but later disputed. The glitch occurred at MJD 51,335 +- 12 with Dn/n = (1.4 +- 0.2) x 10-9 and Dimg1.gif/img1.gif = (1.33 +- 0.02) x 10-4. We calculate that the glitch activity parameter for PSR B0540-69 is 2 orders of magnitude smaller than that of the Crab pulsar, which otherwise has very similar properties. This suggests that neutron stars of similar apparent ages, rotation properties, and inferred dipolar B fields can have significantly different internal properties.

We present an updated timing solution for the young, energetic pulsar PSR B1509-58 based on 21.3 yr of radio timing data and 7.6 yr of X-ray timing data. No glitches have occurred in this time span, in contrast to other well-studied young pulsars, which show frequent glitches. We report a measurement of the third frequency derivative of img1.gif = (-1.28 +- 0.21) x 10-31 s-4. This value is 1.65 s from (i.e., consistent with) that predicted by the simple constant magnetic dipole model of pulsar spin-down. We measured the braking index to be n = 2.839 +- 0.003 and show that it varies by 1.5% over 21.3 yr owing to contamination from timing noise. Results of a low-resolution power spectral analysis of the significant noise apparent in the data yield a spectral index of a = -4.6 +- 1.0 for the red-noise component.

Gastric bypass surgery leads to significant and sustained weight loss and a reduction in associated health risks in individuals with severe obesity. While reduced energy intake (EI) is the primary driver of weight loss following surgery, the underlying mechanisms accounting for this energy deficit are not well understood. The evidence base has been constrained by a lack of fit-for-purpose methodology in assessing food intake coupled with follow-up studies that are relatively short-term. This paper describes the underlying rationale and protocol for an observational, fully residential study using covert, objective methodology to evaluate changes in 24-hr food intake in patients (n = 31) at 1-month pre-surgery and 3-, 12- and 24-months post-surgery, compared to weight-stable controls (n = 32). The main study endpoints included change in EI, macronutrient intake, food preferences, and eating behaviours (speed, frequency, and duration of eating). Other physiological changes that may influence EI and weight regulation including changes in body composition, circulating appetite hormones, resting metabolic rate, total energy expenditure and gastrointestinal symptoms were also evaluated. Understanding which mechanisms contribute to a reduction in EI and weight loss post-surgery could potentially help to identify those individuals who are most likely to benefit from gastric bypass surgery as well as those that may need more targeted intervention to optimise their weight loss post-surgery. Furthermore, clarification of these mechanisms may also inform targeted approaches for non-surgical treatments of obesity.

Single units in the cat lateral geniculate nucleus and primary visual cortex show changes in both spontaneous and visually evoked firing as a function of the state of wakefulness. On arousal spontaneous firing is smoother and often reduced, whereas evoked responses are usually enhanced; the result is an increase in the signal-to-noise ratio. Single- and double-label 2-deoxyglucose autoradiographs show further that slow-wave sleep differentially depresses visually evoked activity in the deeper layers of the visual cortex.

The squirrel monkey lacks anatomically demonstrable ocular dominance columns, and physiologically it has an ocular dominance distribution in V1 that is very different from that of macaques, with far fewer cells that strongly favor one eye over the other.We tested an alert squirrel monkey for physiological responses to stereoscopic stimuli by measuring evoked potentials in response to cytclopean patterns generated in dynamic random-dot stereograms. The monkey showed evoked responses both to changes in disparity and to shifts between correlation and uncorrelation between the two eyes. This result strongly suggests that the squirrel monkey can detect stereoscopic depth, which in turn casts some doubt on the assumption that ocular dominance columns bear an important relation to stereopsis.

The biogenic monoamine neurotransmitters octopamine, dopamine and serotonin have been detected in nervous tissue from many insects1. We report here that intact Drosophila melanogaster brains, when incubated with the radioactive amino acids tyrosine and tryptophan, synthesized and accumulated labelled monoamines. In two mutant strains monoamine synthesis was abnormal. The peromutation abolishes the normal circadian rhythm2–4. Brains from peroflies, when incubated in tritiated tyrosine, accumulated one-third as much labelled octopamine as did brains from wild-type flies, but had normal dopamine and serotonin synthesis. In contrast, dopa decarboxylase (Ddc) mutations5,6decreased dopamine and serotonin synthesis but did not affect octopamine synthesis. These results suggest that there are two different aromatic amino acid decarboxylases in Drosophila brains, one that decarboxylates L-dopa and 5-hydroxytryptophan and another that decarboxylates tyrosine. Direct measurement of L-dopa, 5-hydroxytryptophan and tyrosine decarboxylase activities in the different strains confirmed this suggestion.

In normal human subjects, evoked potentials in response to depth reversing two-color dynamic random-dot stereograms disappeared or were greatly reduced at equiluminance, whereas responses to shifts between patterns that were correlated and anticorrelated (for the two eyes) were, for most subjects, actually larger at equiluminance than at non-equiluminance. Responses were only slightly diminished at equiluminance to similar texture-shifting patterns that were identical to the two eyes. These results suggest that a significant fraction of cells with input from both eyes can respond to correlation/anticorrelation shifts, yet are not involved in stereopsis. Also, binocular rivalry may gate the responses of these binocular-nonstereoscopic units.

In this communication we report that four substances, thought to function as neurohormones in Crustacea, all produce long-term changes in the physiological properties of lobster opener muscle preparations. The substances are the amines, octopamine, serotonin and dopamine, and the peptide, proctolin. The actions of these substances are superimposed on the normal synaptic apparatus that utilizes the amino acids GABA and glutamate (probably) as the inhibitory and excitatory neurotransmitter compounds. Serotonin acts on excitatory and inhibitory nerve endings to facilitate transmitter release and directly on muscle fibres to produce a contracture and to induce the appearance of Ca2+ action potentials. The latter two actions of serotonin are shared by proctolin and octopamine as well. Dopamine, on the other hand, relaxes muscle baseline tension. The mechanism of action of these substances at their target site (or sites) has been explored with electrophysiological and biochemical techniques and the results will be presented. In addition preliminary behavioural experiments have been carried out with serotonin and octopamine. These substances produce opposite postures when injected into lobsters. The amines act on central ganglia to produce these effects where they cause a programmed readout of firing of neurones that will produce either a flexed posture (serotonin) or an extended posture (octopamine).

When the primate primary visual cortex, area 17, is stained for the mitochondrial enzyme cytochrome oxidase1, it shows a striking polka-dot pattern (cytochrome oxidase blobs). Area 18, the second visual area, shows a cytochrome-oxidase pattern of coarse alternating thick and thin stripes running perpendicular to the 17–18 border and separated by lighter (inter-stripe) regions. Here we show that the thin cytochrome oxidase stripes, and possibly also the thick stripes, in area 18 receive projections specifically from the blobs in area 17, and that the interstripe regions of 18 receive projections from the interblob matrix of area 17. This indicates a specificity of cortico-cortical connections far exceeding the demands of topographical mapping. Together with our physiological results, it suggests that within the pathway from area 17 to area 18 different kinds of information may be handled separately and in parallel.

Human vision has the remarkable property that, over a wide range, changes in the wavelength composition of the source light illuminating a scene result in very little change in the colour of any of the objects1. This colour constancy can be explained by the retinex theory, which predicts the colour of a point on any object from a computed relationship between the radiation from that point and the radiation from all the other points in the field of view (Fig. 1). Thus the computations for colour perception occur across large distances in the visual field. It has not been clear, however, whether these long-range interactions take place in the retina or the cortex. Reports that long-range colour interactions can be reproduced binocularly when one band of wavelengths enters one eye and a different band enters the other2might seem to establish the cortex as the site of the computation. Many observers, however, see very unsatisfactory colour or no colour at all in this binocular situation, suggesting that the cortex may not be the only site at which the computation is carried out, or even the most important site. We have now tested the role of the cortex in a human subject in whom the nerve fibres connecting cortical areas subserving two separate parts of the visual field had been severed, and find that the cortex is necessary for long-range colour computations.

In primates, both the primary and secondary visual cortical areas can be subdivided histologically by staining for the mitochondrial enzyme cytochrome oxidase1–3. In the primary visual cortex (area 17, the first cortical receiving area for visual information) these histological differences correspond to functional subdivisions1–6, cytochrome-dark regions being concerned with information about colour and cytochrome-light regions concerned with form. Here we report that the second visual area, area 18, which receives its main cortical input from area 17 (refs 7,8), similarly has functional subdivisions that correspond to the cytochrome oxidase staining pattern. In area 18 the segregation between form and colour is maintained, reinforcing our notion that form and colour information follow parallel pathways. The specific differences between cells in areas 17 and 18 suggest that a possible step in hierarchical information processing is spatial generalization, analogous to the difference between simple and complex cells.

One of the problems of working with a number of retarded children is that they are slow to learn to stand and walk, although there may be no apparent physical reason for their delay. Recent research (Bensburg 1965; Zimmer-Hart. Bettison, Copeland. Masters, Zoppa and Mitchell, 1977) suggest that the operant conditioning methods may be effective in overcoming the presumed motivational deficit behind the delay. The research described here, is an attempt to replicate that finding with a support apparatus which is readily available.

The [?]800 year old pulsar J1846-0258 is a unique transition object between rotation-powered pulsars and magnetars: though behaving like a rotation-powered pulsar most of the time, in 2006 it exhibited a distinctly magnetar-like outburst accompanied by a large glitch. Here, we present X-ray timing observations taken with the Rossi X-ray Timing Explorer over a 2.2 year period after the X-ray outburst and glitch had recovered. We observe that the braking index of the pulsar, previously measured to be n = 2.65 +- 0.01, is now n = 2.16 +- 0.13, a decrease of 18% +- 5%. We also note a persistent increase in the timing noise relative to the pre-outburst level. Despite the timing changes, a 2009 Chandra X-ray Observatory observation shows that the X-ray flux and spectrum of the pulsar and its wind nebula are consistent with the quiescent levels observed in 2000.