Sex differences in vocal learning ability in songbirds are linked with differences in flexible rhythm pattern perception.

Humans readily recognize familiar rhythmic patterns, such as isochrony (equal timing between events) across a wide range of rates. This reflects a facility with perceiving the relative timing of events, not just absolute interval durations. Several lines of evidence suggest this ability is supported by precise temporal predictions arising from forebrain auditory-motor interactions. We have shown previously that male zebra finches, Taeniopygia guttata, which possess specialized auditory-motor networks and communicate with rhythmically patterned sequences, share our ability to flexibly recognize isochrony across rates. To test the hypothesis that flexible rhythm pattern perception is linked to vocal learning, we ask whether female zebra finches, which do not learn to sing, can also recognize global temporal patterns. We find that females can flexibly recognize isochrony across a wide range of rates but perform slightly worse than males on average. These findings are consistent with recent work showing that while females have reduced forebrain song regions, the overall network connectivity of vocal premotor regions is similar to males and may support predictions of upcoming events. Comparative studies of male and female songbirds thus offer an opportunity to study how individual differences in auditory-motor connectivity influence perception of relative timing, a hallmark of human music perception.

Rhythmic abilities in humans and non-human animals: a review and recommendations from a methodological perspective.

Rhythmic behaviour is ubiquitous in both human and non-human animals, but it is unclear whether the cognitive mechanisms underlying the specific rhythmic behaviours observed in different species are related. Laboratory experiments combined with highly controlled stimuli and tasks can be very effective in probing the cognitive architecture underlying rhythmic abilities. Rhythmic abilities have been examined in the laboratory with explicit and implicit perception tasks, and with production tasks, such as sensorimotor synchronization, with stimuli ranging from isochronous sequences of artificial sounds to human music. Here, we provide an overview of experimental findings on rhythmic abilities in human and non-human animals, while critically considering the wide variety of paradigms used. We identify several gaps in what is known about rhythmic abilities. Many bird species have been tested on rhythm perception, but research on rhythm production abilities in the same birds is lacking. By contrast, research in mammals has primarily focused on rhythm production rather than perception. Many experiments also do not differentiate between possible components of rhythmic abilities, such as processing of single temporal intervals, rhythmic patterns, a regular beat or hierarchical metrical structures. For future research, we suggest a careful choice of paradigm to aid cross-species comparisons, and a critical consideration of the multifaceted abilities that underlie rhythmic behaviour. This article is part of the theme issue 'Synchrony and rhythm interaction: from the brain to behavioural ecology'.

An ecological approach to measuring synchronization abilities across the animal kingdom.

In this perspective paper, we focus on the study of synchronization abilities across the animal kingdom. We propose an ecological approach to studying nonhuman animal synchronization that begins from observations about when, how and why an animal might synchronize spontaneously with natural environmental rhythms. We discuss what we consider to be the most important, but thus far largely understudied, temporal, physical, perceptual and motivational constraints that must be taken into account when designing experiments to test synchronization in nonhuman animals. First and foremost, different species are likely to be sensitive to and therefore capable of synchronizing at different timescales. We also argue that it is fruitful to consider the latent flexibility of animal synchronization. Finally, we discuss the importance of an animal's motivational state for showcasing synchronization abilities. We demonstrate that the likelihood that an animal can successfully synchronize with an environmental rhythm is context-dependent and suggest that the list of species capable of synchronization is likely to grow when tested with ecologically honest, species-tuned experiments. This article is part of the theme issue 'Synchrony and rhythm interaction: from the brain to behavioural ecology'.

Vocal learning and flexible rhythm pattern perception are linked: Evidence from songbirds.

Rhythm perception is fundamental to speech and music. Humans readily recognize a rhythmic pattern, such as that of a familiar song, independently of the tempo at which it occurs. This shows that our perception of auditory rhythms is flexible, relying on global relational patterns more than on the absolute durations of specific time intervals. Given that auditory rhythm perception in humans engages a complex auditory-motor cortical network even in the absence of movement and that the evolution of vocal learning is accompanied by strengthening of forebrain auditory-motor pathways, we hypothesize that vocal learning species share our perceptual facility for relational rhythm processing. We test this by asking whether the best-studied animal model for vocal learning, the zebra finch, can recognize a fundamental rhythmic pattern-equal timing between event onsets (isochrony)-based on temporal relations between intervals rather than on absolute durations. Prior work suggests that vocal nonlearners (pigeons and rats) are quite limited in this regard and are biased to attend to absolute durations when listening to rhythmic sequences. In contrast, using naturalistic sounds at multiple stimulus rates, we show that male zebra finches robustly recognize isochrony independent of absolute time intervals, even at rates distant from those used in training. Our findings highlight the importance of comparative studies of rhythmic processing and suggest that vocal learning species are promising animal models for key aspects of human rhythm perception. Such models are needed to understand the neural mechanisms behind the positive effect of rhythm on certain speech and movement disorders.

Using FDA-approved drugs as off-label fluorescent dyes for optical biopsies: from in silico design toex vivoproof-of-concept.

Optical biopsies bring the microscope to the patient rather than the tissue to the microscope, and may complement or replace the tissue-harvesting component of the traditional biopsy process with its associated risks. In general, optical biopsies are limited by the lack of endogenous tissue contrast and the small number of clinically approvedin vivodyes. This study tests multiple FDA-approved drugs that have structural similarity to research dyes as off-labelin situfluorescent alternatives to standardex vivohematoxylin & eosin tissue stain. Numerous drug-dye combinations shown here may facilitate relatively safe and fastin situor possiblyin vivostaining of tissue, enabling real-time optical biopsies and other advanced microscopy technologies, which have implications for the speed and performance of tissue- and cellular-level diagnostics.

Investigation of confocal microscopy for differentiation of renal cell carcinoma versus benign tissue. Can an optical biopsy be performed?

OBJECTIVE: Novel optical imaging modalities are under development with the goal of obtaining an "optical biopsy" to efficiently provide pathologic details. One such modality is confocal microscopy which allows in situ visualization of cells within a layer of tissue and imaging of cellular-level structures. The goal of this study is to validate the ability of confocal microscopy to quickly and accurately differentiate between normal renal tissue and cancer. METHODS: Specimens were obtained from patients who underwent robotic partial nephrectomy for renal mass. Samples of suspected normal and tumor tissue were extracted from the excised portion of the kidney and stained with acridine orange. The stained samples were imaged on a Nikon E600 C1 Confocal Microscope. The samples were then submitted for hematoxylin and eosin processing and read by an expert pathologist to provide a gold-standard diagnosis that can later be compared to the confocal images. RESULTS: This study included 11 patients, 17 tissue samples, and 118 confocal images. Of the 17 tissue samples, 10 had a gold-standard diagnosis of cancer and seven were benign. Of 118 confocal images, 66 had a gold-standard diagnosis of cancer and 52 were benign. Six confocal images were used as a training set to train eight observers. The observers were asked to rate the test images on a six point scale and the results were analyzed using a web based receiver operating characteristic curve calculator. The average accuracy, sensitivity, specificity, and area under the empirical receiver operating characteristic curve for this study were 91%, 98%, 81%, and 0.94 respectively. CONCLUSION: This preliminary study suggest that confocal microscopy can be used to distinguish cancer from normal tissue with high sensitivity and specificity. The observers in this study were trained quickly and on only six images. We expect even higher performance as observers become more familiar with the confocal images.

Improvement in optical fiber bundle-based imaging using synchronized fiber motion.

Image quality in fiber bundle-based imaging systems is inherently limited by the size and spacing of the individual fiber cores. The fiber bundle limits the achievable spatial resolution and superimposes a fixed pattern of signal variability across the image. To overcome these limitations, piezoelectric tubes were used to synchronously dither the fiber bundle on both ends. Experimental results using the dithering approach with a commercial fiber bundle showed a substantial decrease in fixed pattern noise and an increase in spatial resolution.

Seasonal trends in underwater ambient noise near St. Lawrence Island and the Bering Strait.

We measured spatial and temporal patterns of ambient noise in dynamic, relatively pristine Arctic marine habitats and evaluate the contributions of environmental and human noise sources. Long-term acoustic recorders were deployed around St. Lawrence Island and the Bering Strait region within key feeding and migratory corridors for protected species that are inherently important to Native Alaskan cultures. Over 3000 h of data from 14 recorders at nine sites were obtained from October 2014 to June 2017. Spatial and temporal ambient noise patterns were quantified with percentile statistics in 1/3rd-octave bands (0.02-8 kHz). Ice presence strongly influenced ambient noise by influencing the physical environment and presence of marine mammals. High variability in noise was observed within and between sites, largely as a function of ice presence and associated factors. Acute contributions of biological and anthropogenic sources to local ambient noise are compared to monthly averages, demonstrating how they influence Arctic soundscapes.

Low-frequency temporary threshold shift not observed in spotted or ringed seals exposed to single air gun impulses.

Underwater hearing thresholds were measured at 100 Hz in trained spotted (Phoca largha) and ringed seals (Pusa hispida) before and immediately following voluntary exposure to impulsive noise from a seismic air gun. Auditory responses were determined from psychoacoustic data and behavioral responses were scored from video recordings. Four successive exposure conditions of increasing level were tested, with received unweighted sound exposure levels from 165 to 181 dB re 1 µPa2 s and peak-to-peak sound pressures from 190 to 207 dB re 1 µPa. There was no evidence that these single seismic exposures altered hearing-including in the highest exposure condition, which matched previous predictions of temporary threshold shift (TTS) onset. Following training at low exposure levels, relatively mild behavioral responses were observed for higher exposure levels. This demonstrates that individuals can learn to tolerate loud, impulsive sounds, but does not necessarily imply that similar sounds would not elicit stronger behavioral responses in wild seals. The absence of observed TTS confirms that regulatory guidelines (based on M-weighting) for single impulse noise exposures are conservative for seals. However, additional studies using multiple impulses and/or higher exposure levels are needed to quantify exposure conditions that do produce measurable changes in hearing sensitivity.

Characterization of TCP-1 probes for molecular imaging of colon cancer.

Molecular probes capable of detecting colorectal cancer (CRC) are needed for early CRC diagnosis. The objective of this study was to characterize c[CTPSPFSHC]OH (TCP-1), a small peptide derived from phage display selection, for targeting human CRC xenografts using technetium-99m ((99m)Tc)-labeled TCP-1 and fluorescent cyanine-7 (Cy7)-labeled form of the peptide (Cy7-TCP-1). (99m)Tc-TCP-1 was generated by modifying TCP-1 with succinimidyl-6-hydrazino-nicotinamide (S-HYNIC) followed by radiolabeling. In vitro saturation binding experiments were performed for (99m)Tc-TCP-1 in human HCT116 colon cancer cells. SCID mice with human HCT116 cancer xenografts were imaged with (99m)Tc-TCP-1 or control peptide using a small-animal SPECT imager: Group I (n=5) received no blockade; Group II (n=5) received a blocking dose of non-radiolabeled TCP-1. Group III (n=5) were imaged with (99m)Tc-labeled control peptide (inactive peptide). SCID mice with human PC3 prostate cancer xenografts (Group IV, n=5) were also imaged with (99m)Tc-TCP-1. Eight additional SCID mice bearing HCT116 xenografts in dorsal skinfold window chambers (DSWC) were imaged by direct positron imaging of (18)F-fluorodeoxyglucose ((18)F-FDG) and fluorescence microscopy of Cy7-TCP-1. In vitro(99m)Tc-HYNIC-TCP-1 binding assays on HCT 116 cells indicated a mean Kd of 3.04±0.52nM. In cancer xenografts, (99m)Tc-TCP-1 radioactivity (%ID/g) was 1.01±0.15 in the absence of blockade and was reduced to 0.26±0.04 (P<0.01) with blockade. No radioactive uptake was observed in the PC3 tumors with (99m)Tc-TCP-1 or HCT116 tumors with inactive peptide. Cy7-TCP-1 activity localized not only in metabolically active tumors, as defined by (18)F-FDG imaging, but also in peritumoral microvasculature. In conclusion, TCP-1 probes may have a distinct targeting mechanism with high selectivity for CRC and tumor-associated vasculature. Molecular imaging with TCP-1 probes appears promising to detect malignant colorectal lesions.

Natural exposure to domoic acid causes behavioral perseveration in Wild Sea lions: Neural underpinnings and diagnostic application.

Domoic acid is a naturally occurring algal toxin that causes neurological symptoms and mortality in exposed marine life. California sea lions (Zalophus californianus) are the most visible victims, and suffer epilepsy and progressive hippocampal atrophy. Despite its reliable neurological effects, little is known about how exposure to domoic acid alters behavior, which is critical for understanding the impact of toxic exposure on long-term survival in sea lions and other exposed animals, including humans. Better understanding of the behavioral effects may also inform veterinary diagnosis and treatment. Anecdotally, exposed sea lions have been reported to show enhanced perseverative behavior. To assess the neurobehavioral effects of domoic acid, we compared veterinary diagnoses, measures of hippocampal volume from in vivo MRI, and behavioral measures of habituation and dishabituation in 27 wild sea lions undergoing rehabilitation. The sample was divided post-hoc between subjects with clear veterinary diagnoses of chronic domoic acid toxicosis and those with no evidence of the disease. In the behavioral task, subjects were exposed repeatedly to sounds from two source locations, and, following a short delay, exposed again. Veterinary diagnosis of domoic acid toxicosis was associated with extent of hippocampal damage, predicted delayed habituation in phase 1, and enhanced dishabituation in phase 2. Receiver operating characteristic analysis indicated that delayed habituation in phase 1 was diagnostically predictive. Enhanced dishabituation in phase 2 was correlated with reduced right ventral hippocampal volume. Together, delayed habituation and enhanced dishabituation following domoic acid exposure indicate a clinically relevant and potentially maladaptive behavioral pattern of perseveration.

Beat Keeping in a Sea Lion As Coupled Oscillation: Implications for Comparative Understanding of Human Rhythm.

Human capacity for entraining movement to external rhythms-i.e., beat keeping-is ubiquitous, but its evolutionary history and neural underpinnings remain a mystery. Recent findings of entrainment to simple and complex rhythms in non-human animals pave the way for a novel comparative approach to assess the origins and mechanisms of rhythmic behavior. The most reliable non-human beat keeper to date is a California sea lion, Ronan, who was trained to match head movements to isochronous repeating stimuli and showed spontaneous generalization of this ability to novel tempos and to the complex rhythms of music. Does Ronan's performance rely on the same neural mechanisms as human rhythmic behavior? In the current study, we presented Ronan with simple rhythmic stimuli at novel tempos. On some trials, we introduced "perturbations," altering either tempo or phase in the middle of a presentation. Ronan quickly adjusted her behavior following all perturbations, recovering her consistent phase and tempo relationships to the stimulus within a few beats. Ronan's performance was consistent with predictions of mathematical models describing coupled oscillation: a model relying solely on phase coupling strongly matched her behavior, and the model was further improved with the addition of period coupling. These findings are the clearest evidence yet for parity in human and non-human beat keeping and support the view that the human ability to perceive and move in time to rhythm may be rooted in broadly conserved neural mechanisms.

Pilot Clinical Evaluation of a Confocal Microlaparoscope for Ovarian Cancer Detection.

OBJECTIVE: The aim of this study is to evaluate the performance of a confocal fluorescence microlaparoscope for in vivo detection of ovarian cancer. METHODS/MATERIALS: Seventy-one patients scheduled for open or laparoscopic oophorectomy were consented for the imaging study. High-resolution confocal microlaparoscopic images of the epithelial surface of the ovary were acquired in vivo or ex vivo after tissue staining using acridine orange. Standard histologic evaluation of extracted tissue samples was performed and used as the gold standard of disease diagnosis. Trained human observers from different specialties viewed the microlaparoscopic images, rating each image on a 6-point scale ranging from "definitely not cancer" to "definitely cancer." Receiver operating characteristic curves were generated using these scores and the gold standard histopathologic diagnosis. Area under the receiver operating characteristic curve (AUC) was calculated as a performance metric. RESULTS: Forty-five of the consented patients were used in the final evaluation study. From these 45 patients, 63 tissue locations or samples were identified and imaged with the confocal microlaparoscope. Twenty of the samples were high-grade cancers, and the remaining 43 samples were normal or noncancerous. Twenty-three of the samples were imaged in vivo, and the remaining 40 samples were imaged ex vivo. The average AUC score and standard error (SE) for detection of cancer in all images were 0.88 and 0.02, respectively. An independent-samples t test was conducted to compare AUC scores for in vivo and ex vivo conditions. No statistically significant difference in the AUC score for in vivo (AUC, 0.850; SE, 0.049) and ex vivo (AUC, 0.888; SE, 0.027) conditions was observed, t(6) = 1.318, P = 0.2355. CONCLUSIONS: Area under the receiver operating characteristic curve scores indicate that high-resolution in vivo images obtained by the confocal laparoscope can distinguish between normal and malignant ovarian surface epithelium. In addition, in vivo performance is similar to that which can be obtained from ex vivo tissue.

Algal toxin impairs sea lion memory and hippocampal connectivity, with implications for strandings.

Domoic acid (DA) is a naturally occurring neurotoxin known to harm marine animals. DA-producing algal blooms are increasing in size and frequency. Although chronic exposure is known to produce brain lesions, the influence of DA toxicosis on behavior in wild animals is unknown. We showed, in a large sample of wild sea lions, that spatial memory deficits are predicted by the extent of right dorsal hippocampal lesions related to natural exposure to DA and that exposure also disrupts hippocampal-thalamic brain networks. Because sea lions are dynamic foragers that rely on flexible navigation, impaired spatial memory may affect survival in the wild.

Analysis of multimode fiber bundles for endoscopic spectral-domain optical coherence tomography.

A theoretical analysis of the use of a fiber bundle in spectral-domain optical coherence tomography (OCT) systems is presented. The fiber bundle enables a flexible endoscopic design and provides fast, parallelized acquisition of the OCT data. However, the multimode characteristic of the fibers in the fiber bundle affects the depth sensitivity of the imaging system. A description of light interference in a multimode fiber is presented along with numerical simulations and experimental studies to illustrate the theoretical analysis.

Confocal microlaparoscope for imaging the fallopian tube.

Recent evidence suggests that ovarian cancer can originate in the fallopian tube. Unlike many other cancers, poor access to the ovary and fallopian tubes has limited the ability to study the progression of this deadly disease and to diagnosis it during the early stage when it is most amenable to therapy. A rigid confocal microlaparoscope system designed to image the epithelial surface of the ovary in vivo was previously reported. A new confocal microlaparoscope with an articulating distal tip has been developed to enable in vivo access to human fallopian tubes. The new microlaparoscope is compatible with 5-mm trocars and includes a 2.2-mm-diameter articulating distal tip consisting of a bare fiber bundle and an automated dye delivery system for fluorescence confocal imaging. This small articulating device should enable the confocal microlaparoscope to image early stage ovarian cancer arising inside the fallopian tube. Ex vivo images of animal tissue and human fallopian tube using the new articulating device are presented along with in vivo imaging results using the rigid confocal microlaparoscope system.

Increasing the QOF upper payment threshold in general practices in England: impact of implementing government proposals.

BACKGROUND: General practices in the UK receive incentive payments for managing patients with selected chronic conditions under the Quality and Outcomes Framework (QOF) scheme. Payments are made when a negotiated threshold percentage of patients receive the appropriate intervention. AIM: From 2013-2014 in England the Department of Health has proposed that this negotiated threshold is replaced with a value equal to the 75th percentile of national performance to attract maximum payments. This is an investigation of the potential impact of this change on practice income and workload. DESIGN AND SETTING: Analysis of 2011-2012 QOF dataset (the latest available) which covers 8123 GP practices and 55.5 million patients in England. METHOD: The 75th percentile of performance was calculated for 52 clinical indicators and applied to 2011-2012 performance. Estimations were made of financial and workload impacts on practices, and whether practices with different characteristics would be disproportionately affected. RESULTS: The proposed changes will result in an increase in the upper payment threshold of each clinical indicator by a mean of 7.47% (range 2.16-38.87%). If performance remains static practices would lose a mean of 47.68 (0-108.33) QOF points, equivalent to a mean financial change of -£279.60 (-£35 352.50 to +£19 957.78) per practice for these 52 indicators. CONCLUSION: Increasing the QOF upper payment threshold to the 75th percentile of national performance will, if clinical performance remains static, substantially reduce the mean number of QOF points achieved per practice. However, this translates into only a small mean loss of income per practice.

Design and Performance of a Multi-Point Scan Confocal Microendoscope.

Confocal fluorescence microendoscopy provides high-resolution cellular-level imaging via a minimally invasive procedure, but requires fast scanning to achieve real-time imaging in vivo. Ideal confocal imaging performance is obtained with a point scanning system, but the scan rates required for in vivo biomedical imaging can be difficult to achieve. By scanning a line of illumination in one direction in conjunction with a stationary confocal slit aperture, very high image acquisition speeds can be achieved, but at the cost of a reduction in image quality. Here, the design, implementation, and experimental verification of a custom multi-point aperture modification to a line-scanning multi-spectral confocal microendoscope is presented. This new design improves the axial resolution of a line-scan system while maintaining high imaging rates. In addition, compared to the line-scanning configuration, previously reported simulations predicted that the multi-point aperture geometry greatly reduces the effects of tissue scatter on image quality. Experimental results confirming this prediction are presented.

A California sea lion (Zalophus californianus) can keep the beat: motor entrainment to rhythmic auditory stimuli in a non vocal mimic.

Is the ability to entrain motor activity to a rhythmic auditory stimulus, that is "keep a beat," dependent on neural adaptations supporting vocal mimicry? That is the premise of the vocal learning and synchronization hypothesis, recently advanced to explain the basis of this behavior (A. Patel, 2006, Musical Rhythm, Linguistic Rhythm, and Human Evolution, Music Perception, 24, 99-104). Prior to the current study, only vocal mimics, including humans, cockatoos, and budgerigars, have been shown to be capable of motoric entrainment. Here we demonstrate that a less vocally flexible animal, a California sea lion (Zalophus californianus), can learn to entrain head bobbing to an auditory rhythm meeting three criteria: a behavioral response that does not reproduce the stimulus; performance transfer to a range of novel tempos; and entrainment to complex, musical stimuli. These findings show that the capacity for entrainment of movement to rhythmic sounds does not depend on a capacity for vocal mimicry, and may be more widespread in the animal kingdom than previously hypothesized.

Ultrathin single-channel fiberscopes for biomedical imaging.

Ultrathin flexible fiberscopes typically have separate illumination and imaging channels and are available in diameters ranging from 0.5 to 2.5 mm. Diameters can potentially be reduced by combining the illumination and imaging paths into a single fiberoptic channel. Single-channel fiberscopes must incorporate a system to minimize Fresnel reflections from air-glass interfaces within the common illumination and detection path. The Fresnel reflection at the proximal surface of the fiber bundle is particularly problematic. This paper describes and compares methods to reduce the background signal from the proximal surface of the fiber bundle. Three techniques are evaluated: (1) antireflective (AR)-coating the proximal face of the fiber, (2) incorporating crossed polarizers into the light path, and (3) a novel technique called numerical aperture sharing, whereby a portion of the image numerical aperture is devoted to illumination and a portion to detection.