Is silence golden? Effects of auditory stimuli and their absence on adult hippocampal neurogenesis

Imke Kirste
• Zeina
Nicola • Golo Kronenberg
Tara L Walker
Robert C Liu
Gerd Kempermann
Is silence golden? Effects of auditory stimuli and their absence on adult hippocampal neurogenesis
10.1007/s00429-013-0679-3Received: 9 July 2013 / Accepted: 16 November 2013 / Published online: 1 December 2013SHORT COMMUNICATIONPlasticityStem cellsHippocampusMouseLearning
We have previously hypothesized that the reason why physical activity increases precursor cell proliferation in adult neurogenesis is that movement serves as non-specific signal to evoke the alertness required to meet cognitive demands. Thereby a pool of immature neurons is generated that are potentially recruitable by subsequent cognitive stimuli. Along these lines, we here tested whether auditory stimuli might exert a similar non-specific effect on adult neurogenesis in mice. We used the standard noise level in the animal facility as baseline and compared this condition to white noise, pup calls, and silence. In addition, as patterned auditory stimulus without ethological relevance to mice we used piano music by Mozart (KV 448). All stimuli were transposed to the frequency range of C57BL/6 and hearing was objectified with acoustic evoked potentials. We found that except for white noise all stimuli, including silence, increased precursor cell proliferation (assessed 24 h after labeling with bromodeoxyuridine, BrdU). This could be explained by significant increases in BrdU-labeled Sox2-positive cells (type-1/2a). But after 7 days, only silence remained associated with increased numbers of BrdU-labeled cells. Compared to controls at this stage, exposure to silence had generated significantly increased numbers of BrdU/NeuN-labeled neurons. Our results indicate that the unnatural absence of auditory input as well as spectrotemporally rich albeit ethological irrelevant stimuli activate precursor cells-in the case of silence also leading to greater numbers of newborn immature neurons-whereas ambient and unstructured background auditory stimuli do not.

Introduction

Adult neurogenesis adds plasticity to the dentate gyrus of the hippocampus and is involved in key functions such as pattern separation (Aimone et al. 2010;Clelland et al. 2009) and avoidance of catastrophic interference (Appleby and Wiskott 2009;Wiskott et al. 2006) by adding flexibility to the network in situations where novel information has to be integrated into established representations (Garthe et al. 2009;Dupret et al. 2008). Adult neurogenesis is regulated by behavioral activity. Both physical activity and exposure to a challenging environment increase adult neurogenesis but do so by different means . Non-specific stimuli like physical activity enhance the proliferation of precursor cells and lead to an increased potential in form of a larger pool of ''neuroblasts'' and immature neurons that can be recruited in case of a cognitive challenge. In contrast, exposure to an enriched environment promotes the survival of newborn neurons. Accordingly, the two interventions turned out to be additive in their effect (Fabel et al. 2009).

The new immature neurons own particular functionality in that they are more likely to generate action potentials in response to incoming stimuli due to their particular balance between excitatory and inhibitory input (Marin-Burgin et al. 2012). The threshold for LTP induction is reduced in these neurons (Schmidt-Hieber et al. 2004;Snyder et al. 2001). In fact, the LTP that is measurable in the dentate gyrus under physiological conditions is contributed by the newborn neurons during this critical period of their development (Garthe et al. 2009;Saxe et al. 2006). Thus, the immature new neurons are assumed to be more easily excitable than older cells, biasing the input towards the more plastic subpopulation of cells (Marin-Burgin et al. 2012). The hypothesis is that this mechanism allows flexible adaptation and learning of new information in previously established contexts. Non-specific stimuli would increase precursor cell proliferation to increase a pool of cells that can be recruited if cognitive demand arises (for detailed discussion see: Fabel et al. 2009).

The finding that exercise would have this effect on proliferation raised the question, whether other non-specific stimuli would also lead to an increased availability of potentially recruitable cells. Presumably, the intrinsic stimulus during physical activity essentially consists of proprioception and vision. Likewise, there are numerous reports on links between the vestibular system and hippocampal function [(Brandt et al. 2005); see Ref. Smith et al. (2010) for review] even though effects on adult neurogenesis have not yet been specifically addressed. In order to identify relevant sensory stimuli independent of locomotion, we here focused on auditory input as a potential signal to affect adult hippocampal neurogenesis.

Noise trauma with inner ear hair cell loss has led to a reduction of precursor cell proliferation in the hippocampus of rats (Kraus et al. 2010). A potential positive regulatory effect of sound on the early steps of adult hippocampal neurogenesis, however, has not yet been explored. We asked how different types of auditory stimuli would affect the baseline regulation of adult hippocampal neurogenesis (Fig. 1a).

We used ambient noise in the animal facility (animal house noise) as baseline and exposed our mice to four different conditions: (1) white noise as unstructured auditory stimulus; (2) mouse pup calls as structured stimulus that is for mice common and relevant; (3) Mozart piano music as a structured stimulus, unknown and presumably irrelevant to mice; and (4) silence.

Materials and methods

Animals

All experiments were performed according to national and institutional guidelines and were approved by the Institutional Animal Care and Use Committee (IACUC) of Emory University.

Forty female C57BL/6J mice were obtained from The Jackson Laboratory (Bar Harbor, Maine, USA) and were 6 to 8 weeks old at the beginning of the experiments. For all experiments, mice were held under standard laboratory housing conditions with a 12-h light/dark cycle and ad libitum access to food and water. Delivered mice were given a minimum of 5 days for habituation after arrival and housed in groups of five animals per cage (N = 10 per group).

In comparison to other mouse strains, C57BL/6 animals have certain advantages in adult neurogenesis research because they typically show high neurogenic activity within the dentate gyrus, which responds readily to extrinsic stimuli . We thus decided to use C57BL/6 despite the age-related presbyacusis that is typical for that strain (Hunter and Willott 1987).

Auditory brainstem response

To control for potential hearing loss, 10 additional animals were used for measurement of the auditory brainstem response (ABR) in order to determine the average hearing ability of this strain at the given age of 8 weeks. This information was used to define the exposure parameters for the animals in the experiment.

Before testing, mice were anesthetized with 100 mg/kg body weight Ketamine and 0.3 mg/kg Medetomidine by intraperitoneal injection. During recording of the ABR, the eyes were covered with eye ointment to prevent dryness.

Once no more motor reflexes could be induced from the animal, silver wires were placed subdermally posterior to the stimulated ear, at the skull midline (ground) and at the contralateral bulla.

The recordings were done with a calibrated sound delivery system (Tucker-Davis Technologies, Gainesville, FL, USA) and BioSig program. Click trains and tones at 7, 32 or 65 kHz were presented to the anesthetized females at a sampling rate of 223,214.06 per second. All tones were presented with 3 ms duration, intensity in the range of 0 dB SPL to 75 dB SPL, and an onset/offset ramp of 1.5 ms. Auditory evoked activity was recorded, amplified (910,000), and filtered (10 Hz-3 kHz). The hearing threshold was defined as the lowest intensity at which reliable responses were recorded.

At the end of the recordings, animals were injected subcutaneously with 0.05 ml lactated Ringer solution to prevent dehydration. The mice were monitored until they awoke and normal grooming and drinking behavior was observed.

Exposure to sound stimuli Ten animals of each group were placed into an anechoic sound isolation box (Acoustic Systems, Austin, TX, USA) for 2 h/day at the beginning of the dark phase of the light-  dark cycle. Dependent on the experimental group, they were either exposed to standard animal house noise (group designated as ''Ambient''), isolation from all sounds (''Silence''), white noise (''White noise'', with a bandwidth of 4-80 kHz), previously recorded pup calls (''Pup calls'') or Mozart's Sonata for two pianos in D major, KV 448 (''Mozart''). The music was presented with a sample rate of 97,656.25 per second. The other sounds were presented at a sampling rate of 223,214.06 per second. The Mozart piece was transposed into the hearing range of C57BL/6J mice. First, a low pass filter was set to 1,236 Hz and applied ten times to the music. The wav file was then transposed by five octaves. Afterwards a high-pass filter was set to 5,953 Hz and applied two times. Spectral analysis showed a peak at 10 kHz. More than 90 % of the power lay between 5 and 20 kHz. Spectral analysis of the pup calls showed an average frequency of 65 kHz; the pup calls had been collected and modified as described elsewhere (Liu et al. 2003). The white noise was applied at an intensity of 70 dB SPL. All other stimuli varied in intensity (70 ± 10 dB SPL).

Effects on differentiation

Immunohistochemistry

To assess effects of auditory stimuli on precursor cell proliferation, the animals were exposed to the stimulus 2 h/ day for 3 consecutive days, followed by an intraperitoneal injection of 50 mg/kg bodyweight Bromodeoxyuridine (BrdU, Sigma) 24 h after the last exposure (Fig. 1a). Again 24 h later, mice were killed and the brain was removed.

To address net neurogenesis (survival and differentiation), animals were injected with BrdU (50 mg/kg) and exposed to auditory stimulus for seven consecutive days. Perfusion was performed 24 h after the last exposure. In this particular paradigm BrdU counts reflect early survival rates of newly generated cells.

For the collection of the brains, all animals were deeply anesthetized with a mixture of 10 % Ketamine (0.3 ml/ 20 g body weight) and 2 % Xylaxin (0.1 ml/20 g bodyweight) and perfused transcardially with 0.9 % NaCl followed by 4 % paraformaldehyde (PFA) in 0.1 M KPBS buffer, pH 7.4. Brains were dissected from the skull, postfixed in 4 % PFA at 4°C for 24 h and then transferred into 30 % sucrose in 0.1 M phosphate buffer, pH 7.4, for dehydration until they had sunk. Brains were then cut on a dry ice-cooled copper block with a table top sliding microtome (Leica, Bensheim) into 40-lm-thick coronal sections. Slides were stored at 4°C in cryoprotectant solution containing 25 % ethylene glycol, 25 % glycerol, 25 % glycerin and 0.05 M phosphate buffer.

All sections were stained free floating with all antibodies diluted in Tris-buffered saline (TBS), pH 7.4, containing 3 % donkey serum and 0.1 %Triton X-100. For BrdU-immunohistochemistry, one-in-six sections from each brain were transferred into TBS and washed briefly. Sections were pretreated with 0.6 % H 2 O 2 to block endogenous tissue peroxidase. After rinsing in TBS, the DNA was denatured in 2 N HCl for 30 min at 37°C. Afterwards the sections were rinsed in 0.1 M borate buffer, pH 8.5, and thoroughly washed in TBS. Brain slices were incubated with the primary antibody overnight at 4°C. Primary and secondary antibodies were diluted in TBS supplemented with 0.1 % Triton X-100 and 3 % donkey serum (TBS-plus). As primary antibody we used rat anti-BrdU in a concentration of 1:500 (Harlan Seralab, Loughborough, UK). On the next day, the sections were rinsed in TBS and TBS-plus and incubated with the secondary antibody for 2 h at room temperature. As secondary antibody we used donkey anti-rat-biotin-SP (Dianova, Hamburg, Germany) at a concentration of 1:250. ABC reagent (Vectastain Elite, Vector Laboratories, Burlingame, CA, USA) was applied for 1 h at a concentration of 9 ll/ml. Diaminobenzidine (DAB) (Sigma, Munich, Germany) was used as a chromogen at a concentration of 0.25 mg/ml in TBS with 0.01 % H 2 O 2 and 0.04 % nickel chloride. The stained sections were thoroughly washed, incubated in Neoclear for 10 min and mounted with Neomount.

Immunofluorescence

For immunofluorescence, 1-in-12 series of each brain were triple-labeled. The sections were transferred into TBS and washed briefly. The DNA was denatured in 2 N HCl for 30 min at 37°C. Sections were then rinsed in 0.1 M borate buffer, pH 8.5, and thoroughly washed in TBS and TBSplus. The brain sections were incubated with the primary antibodies overnight at 4°C. Primary and secondary antibodies were diluted in TBS supplemented with 0.1 % Triton X-100 and 3 % donkey serum (TBS-plus). The next day, sections were rinsed in TBS and TBS-plus and incubated with secondary antibodies for 4 h at room temperature in the dark. Sections were then washed with TBS and coversliped in polyvinyl alcohol with diazabicyclooctane (DABCO) as anti-fading agent.

Quantification and imaging

Quantification of cells labeled with DAB were determined using light microscopy on sections 240 lm apart for BrdU covering the entire hippocampus in its rostrocaudal extension as described previously . Briefly, cells located in the granule cell layer and adjacent subgranular zone, defined as a two-cell bodies-wide zone of the hilus along the base of the granule cell layer were counted. Cells in the uppermost focal plane were excluded to avoid oversampling. For light microscopical analyses, a Leica CTR 6000 Microscope was used.

Phenotypic analyses of BrdU-positive cells in the stated differentiation stages were performed using multiplestained series on sections 480 lm apart, also covering the entire hippocampus, using a spectral confocal microscope (TCS SP2 and TCS SP5; Leica, Nussloch, Germany). Appropriate gain and black level settings were determined on control slices stained with secondary antibodies alone. All images were taken in sequential scanning mode and further processed in Adobe Photoshop 7.0 and CS3. Only general contrast adaptations were made and images were not otherwise manipulated.

Statistical analysis

Statistical analysis was performed either with Origin8 for Windows. Factorial analysis of variance (ANOVA) was performed for all comparisons of morphological data. Twoway ANOVA was followed by Fisher's post hoc test, where appropriate. Differences were considered statistically significant at p \ 0.05. All graphs are displayed as mean ± standard error of the mean (SEM).

Results

With increasing age C57BL/6 mice undergo severe progressive sensorineural hearing loss (presbyacusis) starting around 4-5 months of age (Hunter and Willott 1987). To ensure the audibility of the auditory stimuli to our 2-monthold mice, we measured the auditory brainstem response (acoustic evoked potentials) to click sounds in C57BL/6 mice (Fig. 1b). This verified that the auditory stimuli that we intended to use in exposure would be above threshold for C57BL/6 at this age. Clicks equivalent to all of our stimuli are able to drive neural responses at the distinct frequency with the applied 70 dB SPL. Ambient baseline noise in the animal facility (Ambient) served as physiological baseline for our study. Animals were exposed to the specific stimuli for 2 h per day for 3 days (Fig. 1a, c) in an anechoic chamber. One day after labeling cells with BrdU, White noise did not result in changing numbers of BrdU-positive cells, but all other stimuli increased proliferation (ANOVA: F (4.39) = 12.17, p = 1.62 9 10 -6 , Fig. 1d, e). The greatest numbers of labeled cells were seen for Silence and Mozart. When we broke down these numbers according to the expression of Sox2 as marker for early progenitor cell stages (type-1/ 2a, Fig. 1f), we saw that this increase was largely explained at this developmental stage (Fig. 1g). The stimuli indeed increased precursor cell proliferation.

At 7 days after division, the subset of cells that are destined for neuronal differentiation have exited from the cell cycle and only the minor fraction of label-retaining precursor cells remained proliferative (Encinas et al. 2011;Kempermann et al. 2003). The following period coincides with the electrophysiologically critical time window. We found that at this stage only the Silence group showed increased numbers of BrdU-positive cells, whereas all other groups were indistinguishable from the Ambient controls (ANOVA: F (4.42) = 10.73, p = 1.41251 9 10 -6 Fig. 1h, i). The Silence and Ambient groups were further analyzed for the phenotype of the newborn cells. As known from other experiments, approximately two-thirds of these cells were neurons (based on NeuN expression) and around 15 % were S100b-positive astrocytes. The proportion of neurons was increased to 62 % in the silence condition from 57 % in the Ambient noise group and the difference barely missed conventional statistical significance (p = 0.056). In absolute terms, Silence resulted in statistically increased levels of neurogenesis (BrdU/NeuN-double-positive cells) at this stage (p = 0.008, Fig. 1k).

Discussion

The present study shows that auditory stimuli can induce a response at the level of adult neurogenesis compared to normal baseline ambient noise or unstructured white noise. More interestingly, however, we found that silence and ethologically irrelevant sounds (Mozart) showed a stronger on proliferation effect than presumably natural and relevant sounds like pup calls. Both Mozart and Silence also represent highly novel stimuli, in line with the idea that adult hippocampal neurogenesis plays a role in the integration of novel information into pre-existing contexts.

To our initial surprise, silence, i.e., the complete absence of auditory input, was the only stimulus that elicited a strong response at the level of immature (7 day old) new neurons. But of the tested paradigms, silence might be the most arousing, because it is highly atypical under wild conditions and must thus be perceived as alerting. Functional imaging studies indicate that trying to hear in silence activates the auditory cortex, putting ''the sound of silence'', the absence of expected sound, at the same level with actual sounds (Kraemer et al. 2005;Voisin et al. 2006). The alert elicited by such unnatural silence might stimulate neurogenesis as preparation for future cognitive challenges.

As in our previous set of experiments, one could now call for a combination of the non-specific and the specific stimulus in order to see whether a learning stimulus can recruit new neurons from the pool of new neurons generated in response to exposure to silence, as was the case for physical activity (Fabel et al. 2009). Given the small effect size here and challenges to the experimental design because of the different temporal properties of the two stimuli, this experiment is not trivial and, if done, should possibly be included into larger-scale studies on the general mechanisms underlying such two-step regulation. Based on the available data, we would predict that silence-activated progenitor cells should be usable for the response to cognitive challenges, because these new neurons have survived the initial wave of cell death after cell birth in the adult hippocampus  and are in a time window or critical period, during which the survival-promoting forces are effective (Tashiro et al. 2007;Kee et al. 2007;Gould et al. 1999).

Loud white noise can be a strong stressor (Lai 1987;Cheng et al. 2011). In our study, we purposefully used white noise that did not reach this damaging level. Our data did not reveal any substantial difference between ambient animal house noise and white noise. The white noise condition thus also serves as control for the anechoic chamber in which the animals were exposed to the sounds.

In any case, the role of stress in the regulation of adult hippocampal neurogenesis is complex. While strong acute social stress downregulates adult neurogenesis, the picture is less clear in other situations (Lucassen et al. 2010). The experience of sudden silence will represent a stressor, but so does the exposure to a running wheel (Van Praag et al. 1999). So the presence of stress per se is not incompatible with an increase in adult neurogenesis and the activation that is required for the neurogenic response might even be considered as ''good stress'' or eustress.

While few humans will agree that Mozart is ''ethologically irrelevant noise,'' for mice it should be. We have chosen Mozart's Sonata for two pianos (KV 448) somewhat tongue-in-cheek, because it has received a notorious reputation in the context of the so-called ''Mozart effect'', the controversial claim that listening to this sonata was sufficient to elicit improved learning in humans (Fudin and Lembessis 2004;Jenkins 2001). One study claimed that the effect on humans could be replicated in rats (Rauscher et al. 1998) and one report showed improved T-maze learning in mice after exposure to Mozart but not Beethoven (Aoun et al. 2005). The ''Mozart effect'' is largely discredited, also due to a rather unprecedented financial exploitation, even though there are actually interesting observations related to this paradigm, including reproducible studies on reduced epileptiform changes in the EEG (Lin et al. 2011) or on energy expenditure in preterm infants (Lubetzky et al. 2010). Such results are usually explained through an arousal elicited by the music (Lubetzky et al. 2010;Steele 2000). In this view, the Mozart piece KV 448 (first movement) would be nothing more but a particularly effective way to elicit a quite generic response. What is characteristic about the particular piece, however, is that it is highly patterned and has a rather fast beat. It represents an auditory stimulus that is not natural to mice and does not convey ethologically relevant information about the world. Nevertheless, its patterned nature might still resonate with sensory and cognitive mechanisms available to the mouse (compare, for example: (Schneider et al. 2010)). It would represent a stimulus of novelty and might thus also affect neurogenesis. We found that exposure to Mozart indeed induced an arousal-like effect at the precursor cell level. Unlike the complete absence of auditory signals, however, this increase in proliferating Sox2positive cells was not followed by an increased availability of immature neurons. Why that might be, we can only speculate, but the important conclusion here is that regulation of neurogenesis obviously responds differentially to different auditory stimuli.

Adult neurogenesis has been hypothesized as crucial for flexible adaptations to environmental changes and thus displays an evolutionary advantage (Kempermann 2012). Modulation of the dentate gyrus cytoarchitecture caused by auditory stimuli is a particular case of experiencing the outside world, to which the animal has to respond. Our findings of different neurogenic responses to sounds be they structured or unstructured, relevant or irrelevant, and even present or absent, might reflect the preparation for novel information and behavioral contingencies, and thus increase the ability to adapt to environmental changes. Indeed, as acoustic stimuli (or possibly their absence) gain meaning to an animal through experience, auditory cortical plasticity occurs that may functionally improve the processing of those sounds, as has been demonstrated for pup calls (Liu and Schreiner 2007;Galindo-Leon et al. 2009).

Studies on auditory-dependent learning have also revealed changes in hippocampal activation (McIntosh and Gonzalez-Lima 1998;Grasby et al. 1993), and the conscious perception of sounds appears to activate the hippocampus (Laureys et al. 2000). These therefore support the idea that the hippocampus is also a site of higher order integration of sensory inputs (Braak et al. 1996;Jones and Powell 1970). this project IK was a fellow of Max Planck International Research School LIFE, Berlin. We are grateful to Dr. Anje Sporbert at Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch to support this project by providing technical assistance and access to the Confocal Microscope, and Dr. Annette Hammes for access to the Leica CTR 6000.

Conflict of interest

The authors declare no competing financial interests.

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Pup calls vs. White noise Mozart vs. Pub calls for hearing abilities during the experiments and to adjust the dB levels (b). While white noise did not show any effect on the number of proliferating cells in the adult dentate gyrus, all other stimuli significantly increased the size of the population of BrdU? cells (d, e, a). In case of exposure to silence as well as Mozart's piano music (KV 448), we found particular increase in the population of BrdU-marked Sox2-positive precursor cells (f, g). The side length of the box in the large panel of (f) equals 150 lm. Differentiation, in contrast, was only significantly affected by silence (h, k) with a slight increase in the number of BrdU/NeuN double-positive new Neurons (i)Ambient vs. White noise

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Fig. 1 Regulation of adult hippocampal neurogenesis in dependency
of auditory stimuli. a We used two different approaches to address
both proliferation and survival/differentiation by injection of BrdU
either 24 h before daily sounds exposure or after daily sound exposure
(see ''Materials and methods'' for details). During the auditory
stimulation for 2 h each day, animals were kept in anechoic sound
isolation box to prevent outside interference (c). Auditory brain stem
responses were measured in mice at the experimental age of 8 weeks
to control
Acknowledgements This study was financed from basic institutional funds, with support from NIH DC008343. During her work on
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Change in practice: a qualitative exploration of midwives' and doctors' views about the introduction of STan monitoring in an Australian hospital

M E Mayes
C Wilkinson
S Kuah
G Matthews
D Turnbull
Change in practice: a qualitative exploration of midwives' and doctors' views about the introduction of STan monitoring in an Australian hospital
10.1186/s12913-018-2920-5R E S E A R C H A R T I C L E Open Access
Background: The present study examines the introduction of an innovation in intrapartum foetal monitoring practice in Australia. ST-Analysis (STan) is a technology that adds information to conventional fetal monitoring (cardiotocography) during labour, with the aim of reducing unnecessary obstetric intervention. Adoption of this technology has been controversial amongst obstetricians and midwives, particularly as its use necessitates a more invasive means of monitoring (a scalp clip), compared to external monitoring from cardiotocography alone. If adoption of this technology is going to be successful, then understanding staff opinions about the implementation of STan in an Australian setting is an important issue for maternity care providers and policy makers. Methods: Using a maximum variation purposive sampling method, 18 interviews were conducted with 10 midwives and 8 doctors from the Women's and Children's Hospital, South Australia to explore views about the introduction of the new technology. The data were analysed using Framework Analysis. Results: Midwives and doctors indicated four important areas of consideration when introducing STan: 1) philosophy of care; 2) the implementation process including training and education; 3) the existence of research evidence; and 4) attitudes towards the new technology. Views were expressed about the management of change process, the fit of the new technology within the current models of care, the need for ongoing training and the importance of having local evidence.Conclusions: These findings, coupled with the general literature about introducing innovation and change, can be used by other centres looking to introduce STan technology.

Background

The Australian healthcare sector is currently undergoing change, facing ongoing demands from drives for reform [1]. Additionally, it faces significant challenges in coping with constantly changing technology [2]. From an international perspective, the recent amount of innovation and the commensurate impact on health care has been unprecedented in history, both clinically and economically [3]. Although medical teams are continuously being confronted with ongoing changes to the way they practice, it is important to acknowledge that implementing new technology into routine care can be a slow and unpredictable process [4].

Successful implementation of technology has been defined as the incorporation or routine use of such technology within an organisation [5,6]. Failure to adopt new technologies is common, even when there is evidence of potential benefits to patients and to the overall health care system [7,8]. Failure to adopt can come as a result of aspects of the physical environment such as the usability of the technology, or individual factors such as staff and patient opinions and attitudes. Understanding the views of staff can be particularly important when introducing new technology, as front-line users are critical for the success of the implementation [9]. Some of the key person-orientated factors identified as contributing to the uptake of technological innovations are: authority structures/senior management support [6]; attitudes and perceptions of key staff members [7]; consistencies of values in reference to clinical practice [10]; and knowledge transfer and training [11,12].

Research shows that the failure to assess the human aspect of the implementation of technology can result in misuse, which has implications for patient safety [13]. Organisational issues such as miscommunication between staff and decreased ability to deviate from routine are two key issues. This may be due to the fact that implementation of new technology often requires experimentation, using trial and error to find solutions that work [14] and helpseeking [15]. Failed investments in technology can be costly and cause dissatisfaction among employees [16]. Therefore, staff views and opinions must be sought to understand the technology implementation process from an organisational perspective.

A recent innovation in the foetal monitoring industry is ST-analysis (STan) (introduced in Sweden in 2000 by Neoventa Medical), which is a method and devices that monitor the foetus during labour and as a concept has a strong focus on education and training. The existing standard of care in Australian hospitals includes the use of cardiotocography (CTG) monitoring of the foetus. CTG exclusively monitors the heart rate of the foetus and is most often monitored externally via telemetry [17]. CTG has a high false positive rate of over 50%, and if used alone can increase the chance of interventions, such as emergency caesarean sections and operative vaginal births, without any significant benefit to the perinatal outcome [17]. STan is recommended for use in high-risk pregnancies and aims to overcome the shortcomings of CTG by assessing the foetal heartbeat, in conjunction with the foetal response to reduced availability of oxygen (hypoxia) [17]. This is made possible by an internal monitoring instrument, a foetal scalp electrode ("scalp clip"). The scalp clip then assists in differentiating between a foetus exposed to hypoxia that is compensating well and a foetus that is unable to compensate according to the analysis of the ST interval in the ECG [17]. STan technology has been trialled and introduced into hospitals throughout Europe, the United Kingdom and the USA and has had inconsistent clinical results [18]. However, the caesarean section rates vary widely in these settings ranging from 16% in Norway through to 22% in the United Kingdom compared with 30% in Australia [19]. A research investigation into barriers to uptake of STan in Swedish, Norwegian and hospitals in the UK was conducted 13 years after the commencement of the randomised controlled trials. The study found the main barriers to uptake included low commitment in the implementation process and absence of opinion leaders. [20]. At the broader international level however, there been a failure to investigate organisational issues associated with the implementation of STan.

This aim of the current study is to explore the attitudes and concerns of midwives and doctors about the introduction of STan in an Australian context. The setting for the current study is the first hospital to introduce STan in Australia as a part of a trial 1 [21]. It is hoped that this study will assist in developing an understanding of the contributing factors to the uptake of STan in Australia. It is anticipated that by gaining a more thorough understanding of care provider views, Australian hospitals that introduce this new technology in the future may be better able to manage the associated organisational change.

Method

Context

The study was conducted at the Women's and Children's Hospital in Adelaide, South Australia, a high risk specialist facility with approximately 5000 deliveries per annum. In this setting high risk pregnancies are predominantly monitored using CTG and foetal scalp samples. The study was undertaken in the context of a pilot randomised control trial [21]. The premise for the trial was that the existing mixed findings about STan were not necessarily generalisable to Australia due to variations in clinical practice. Prior to the commencement of the trial an independent international expert in CTG and STan conducted staff training. All midwives and doctors working in the labour ward were also required to undertake a minimum of 2 h of training by "super-users", of which there were 3 doctors and 12 midwives, followed by compulsory assessment. As preparation for introduction of STan monitoring in 2015, all 138 clinicians (100%) were trained and certified (40 medical, 98 midwives).

Participants and recruitment

A maximum variation purposive sampling method was used to produce a sample broadly representative of the population of interest [22][23][24]. We aimed to interview staff with a range of clinical experiences based on years of service at the hospital and roles in various clinical areas. Participants ranged in age between 24 and 58 and included eight doctors and ten midwives.

Data collection

Data were collected via audiotaped semi-structured oneto-one interviews at the hospital between June 2015 and August 2015. This corresponded to the time that the pilot trial was commencing although STan had already been introduced into the hospital 7 months prior to this period. The interview approach is appropriate for this qualitative study as it provides flexibility and depth in acquired information and allows the participants to fully explain their views and experiences [25]. The first author who was not associated with the hospital and who had no vested interests conducted all interviews. Thus the participants were able to establish rapport and trust in the researcher by understanding that their honest opinions would be kept anonymous and independent of hospital administration.

The interview schedule consisted of ten questions that first asked about the participants' opinions of the use of STan, followed by more general questions concerning health care innovation and the organisational change process (Additional file 1). In order to ensure consistency across interviews, the interviewer followed the question guide closely with the intention of not influencing participant responses [26].

The average duration of the interviews was 13 min. The nature of a busy working hospital resulted in some interviews being restricted in terms of duration. Some midwives and doctors had little time while they were on shift to discuss their answers in depth with the interviewer, however a number of initial interviews were lengthy. These interviews provided in-depth information, which was often repeated in later interviews in less depth by subsequent participants. After 12 interviews, the data were initially analysed by the researcher and respondent validation was sought [27] via a meeting that included some staff who were participants in the study. Feedback indicated a high level of face validity in the findings. Interviews continued until data saturation was achieved at around participant 15; however, continuation of data collection occurred until participant 18, to ensure that all clinical roles were appropriately represented [27]. The final findings of the study were presented to staff again to re-check for face validity.

Data analysis

The initial three interviews were transcribed verbatim by the first author to gain familiarity with the data [28] and the subsequent 15 audio files were sent to a professional transcription service where they were also transcribed verbatim. A coding list was developed guided by the objectives of the study and the themes developed as a consequence of the face validity testing process for the initial data. To ensure interpretive rigour [29], two additional researchers reviewed the themes and codes and adjustments were made. In addition, an audit trail was kept through the process of data collection to ensure transparency and to assist with later analysis [30].

Framework analysis

Data were analysed via Framework Analysis, a form of thematic analysis, widely used in applied health research, which produces highly structured output data that allows for comprehensive and systematic data analysis [31]. The following 7-step process was used: 1. Transcription. 2. Familiarisation with the transcript. 3. Coding. 4. Developing an analytical framework. 5. Applying the analytical framework to the raw data. 6. Charting data into the framework matrix. 7. Interpreting the data [32].

Results

The final data consisted of 18 interviews with 8 doctors and 10 midwives (Table 1).

Four major themes that describe the opinions and perceptions of staff were identified:

Philosophy of care; Implementation process including education and training; Research evidence; Attitudes toward the STan technology

In the presentation of results, the interviewees are referred to with their interview number and professional group membership.

Philosophy of care

A number of factors in relation to staff values and philosophies of care for labouring women were expressed as reasons for reservation about Stan. Participants, most notably the midwives, reported that the introduction of STan monitoring would lead to changes in the current model of care, with it becoming more interventional. There was also the perception that STan would create "abnormal" care for laboring women, quite different to a "normal" birthing experience where there is minimal intervention.

…"cause you'd need an epidural and there... to be able to cope with labour… you know the technology is good, but you'd have to have an epidural, then you just... I don't know it's very 'medicalised'". (Interview 5: MW)

In addition to this perceived change in the model of care, many participants made reference to the lack of telemetry with STan (the model bought by the organisation), which allows women to be mobile during labour. It was expressed that this would lead to women being "tied to the bed" (interview 5, MW), resulting in a more lengthy and uncomfortable labour, as well as not being able to get in the bath.

…it will stop her from being able to be mobile, and therefore affect the progress of her labour. So in other words, it's counter-productive. (Interview 7: MW)

Participants also emphasised the importance of taking the preferences of laboring women into account, coupled with a general concern about the extent of intervention for the women and their babies.

And then patient preference as well, so we've got to talk to them about what they want, whether they want to be mobile…I think one of the reservations I have is having to put a scalp electrode on every baby. And I know that this feedback we're getting from some of the women and couples in labour are that they don't really like that. (Interview 2: DOC)

Implementation process, including education and training

Common comments about the implementation of STan were to do with the way in which it was introduced into practice, including issues such as the education and training of staff, timing and approach of the introduction, and the influence of individuals within the organisation.

Interviews revealed diversity in experiences with the education and training program. Some reported it to be a "very rushed session…" (Interview 5 MW); in contrast others commented: "we've all been offered plenty of opportunity for training, we've been offered lots of support…" (Interview 1: MW). Some participants indicated feeling "overwhelmed, as there was not adequate time to prepare for both the information overload and the exam following." (Interview 17: MW)

…there was enormous unnecessary pressure, um at that time when the initial information was handed out, with a test involved that we were told we must pass… at the initial start I think that created a lot of tension and a lot of um a bit of a barrier for some people to think that this is a good thing… (Interview 17: MW)

Overall, the comments about training indicated that there was need for ongoing support and practical training on the ward.

…education is going to be a big part of it, making sure we all understand how to use it, how it works, what the limitations are, the benefits are, before we actually have to use it in our day-to-day practice. (Interview 2: DOC, (Doctor)) Participants also reported receiving conflicting information by their national professional body at the time STan was introduced, which resulted in staff finding it "really confusing" (Interview 10, DOC).

It was rolled out at the same time that we did the FSCP [Foetal Scalp Clip Protocol], which was from the RANZCOG guidelines for foetal monitoring and they're slightly different. So that added to some of the confusion. So I think it was a bit of a timing issue.(Interview 5: MW) In addition, participants described a delay between education and training about STan to it being introduced onto the ward. There was widespread belief that this created a lack of confidence in staff using the technology and resulted in some anxiety and frustration when it came to using it on the ward.

…the actual sort of teaching and learning, theoretical learnings were a fair long way away from the actual physical introduction of the technology. So I think you do find that you've forgotten pretty much most of it by the time. (Interview 4: MW)

There were also reservations about the way STan was introduced by the organisation, with one participant describing it feeling very "sudden" (Interview 14: MW). Participants expressed the need for a more collaborative approach in the early stages to increase awareness and a sense of ownership in practice over the change.

…in general when there's change introduced, whether it's technology or not, one of the most important things is talking to the people it's going to affect before it's introduced. (Interview 2: DOC) "Internal influencers" were observed as being a key barrier to the uptake of STan. This was described as the lack of endorsement by key staff members, together with the hierarchical nature of the hospital environment.

…people had a lot of different feelings about it. Like some people thought it wasn't really useful, other people were really, really for STan, and then the whole bunch of other people kind of like in the middle… STan doesn't really get mentioned unless certain people are around. (Interview 3: MW)

As a result of difficulties with training and the limited opportunities to use the technology, participants expressed the desire to see more results from using STan. One participant commented: "I've just got to actually see the technology being used more to work out what I think about it" (Interview 15: DOC).

I've had pretty minimal experience… we're still not using it very often I've got to say… (Interview 2: DOC)

Research evidence

The interviews revealed a range of sometimes conflicting views about the research evidence. Perceptions about lack of clinical evidence about the benefits of STan, was a prominent barrier to uptake for many participants, in particular doctors.

I think if there's substantial evidence behind the change in practice people are more likely to support it. (Interview 15: DOC).

At the same time, participants expressed the belief that existing international evidence on the effectiveness of STan would not be relevant for the Australian population.

…because it [STan] hasn't been used in our patient population, which is pretty different to the patient populations it's been used on in Europe. We don't have any local data at all. And the way we manage our women and how high risk some of our women are is different to the patient populations that they've studied as well… (Interview 2: DOC)

Many participants also agreed that conducting the trial at the hospital was a good thing because the data would be relevant to their patient population.

I think it's good that we're doing a study, certainly a trial here…rather than basing our data on things that are done in other countries, or other states. (Interview

13: DOC)

Other concerns were about the concurrent routine implementation of the technology and the research trial. Participants expressed feelings of discomfort and emphasised the need for the trial to be completed first. Participants expressed anxiety about the reliance on the technology to produce an electronic alarm prior to decisions to go to operative delivery. Some believed this to be difficult for those who have to make the final decision in instances that the output of the monitor was at odds with prior clinical experience of monitoring with CTG alone.

I think it's more concerning for people who've been working in obstetrics for longer, and seeing CTGs they would have normally taken to section, and not being able to do that now. Or sitting on them for longer is... makes them a little bit nervous. (Interview 15: DOC)

Alternatively, some participants reported that they believed STan actually creates a sense of ease, as the decision to go to operative birth is assisted by the technology and that removing the opinions of individuals can be a positive thing.

Attitudes towards the STan technology

The final theme that emerged was concerned with the added benefits of STan, feelings of distrust toward the technology and operational issues with respect to the machine itself. One participant suggested that "it helps us to interpret CTGs where they're not clear cut" (Interview 2: DOC). This would suggest that there are levels of trust in the technology, with it being able to provide further information that is needed to assist the decision making process. In contrast, some participants felt that the move away from clinical judgement and the reliance on the machine was concerning, reporting that there was a need for appropriate and correct interpretation.

I think it also needs to be used appropriately, but also interpreted appropriately too, because we're going to be watching this screen a lot more, and looking at this trace... (Interview 1 MW) Some participants suggested that they understood the technology would alarm when necessary, but that high quality education about interpreting the alarm signals was needed in order for clinicians to be confident about decisions to proceed or not, to caesarean section. Others commented on the need to "all believe in the same technology" (Interview 8: MW) and that this would help team cohesion and acceptance of STan throughout the ward.

"I don't want to be making big decisions at this stage without consulting someone who's more used to using the technology. So, yeah, so that doesn't... that's not always available. So I think that's one of the barriers to picking it up, if there's no-one who's more experienced or more confident whether around, then perhaps they don't want to start it in the first place" (Interview 12: DOC).

'Operational factors' , associated with the technology, was one of the most widely reported barriers to using STan. One participant commented on STan as being "sort of a bit sub-standard" (Interview 5: MW), while others reported only using the machines as CTG monitors, which is in line with their current practice.

But we haven't actually switched them over to be STan enabled. We've just used them purely as a foetal monitor like we would use a (brand name) one that we've got. (Interview 1: MW) The requirement to apply the scalp clip at the outset irrespective of the clinical situation was also a barrier for some.

I guess it's the fact that you have to actually put in the scalp clip on to like any woman that you're considering, and you have to do it before you know anything's happened for it to be effective. (Interview 3: MW)

Discussion

The current study investigated midwives' and doctors' views about the introduction of STan foetal monitoring and is the first study of its kind in an Australian setting. STan monitoring is not used in any other centre in Australia and is yet to be recommended by the professional bodies because of a lack of evidence that it is beneficial in an Australian setting. At the time of the trial and current study the existing evidence base was not necessarily generalizable to Australia, as the Australian emergency caesarean section rate is significantly higher than other settings for STan trials [18,19,33,34],. 2 Should STan technology prove clinically efficacious in an Australian setting, this research will facilitate its successful its introduction, including the implementation of training and education. STan generally represents a change in practice from the method of using CTG for feotal monitoring, which has been clinical practice for over 40 years [17]. The discussion of the findings will be presented from the perspective of introducing organisational change.

The findings of this study suggest that some resistance to STan currently exists at the study hospital. It reveals a number of cognitive and interpersonal barriers to uptake. Cognitive factors consider the way participants think about technology, including operational factors and their attitudes towards innovations in general [35]. Interpersonal factors, such as the impact of key individuals on the change management were also found [35]. Additionally, education and training was noted to be a significant factor related to the implementation of STan.

The current study offers important insight into how healthcare professionals respond to the introduction and implementation of new technology. Research has found a number of barriers to the uptake of STan in Swedish hospitals [19]. The current study found a number of similar barriers exist for doctors and midwives in an Australian setting, including those related to philosophy of care; training and education and attitudes toward the technology. The present research reveals two other important aspects, namely the implementation process and perceptions about the research evidence and its fit with clinical knowledge.

STan foetal monitoring was perceived to be incongruent with the current philosophy of care. The findings suggest participants believed that the introduction of STan would increase interventions and result in a more "medicalised" process of labour, which many midwives and some doctors believe to be an undesirable outcome. This view is consistent with previous findings in the organisational culture and change literature, which indicates that resistance is significantly influenced by the values of the people within an organisation and specifically a failure to align the change with these values [11]. This may have been more pronounced in the current study as a majority of the midwives had been a part of the organisation for on average 17 years and therefore will strongly align with the culture and values present [11].. This lack of alignment with the values of the individuals and teams involved with the move to use STan technology was broadly associated with participants' attitudes toward the technology. Participants' discussions about the use of STan were framed by perceptions of difficulty in the interpretation of the STan traces as well as the need for more experienced users. This aligns with the literature about technological innovation, which indicates that the perceived ease of use of technology has significant positive influence on actual usage and uptake of innovation [36].

Further, Attewell [12] emphasises the role of organisational learning, skill development, and a reduced knowledge base as potential barriers to adoption of innovation, and found that as knowledge barriers are lowered, the spread of innovation gains momentum [12]. According to Edmondson, Bohmer and Pisano [35], successful implementation includes a four-stage process including: individual enrolment to motivate the team, preparatory practice sessions and early trials within the organization, and promoted process improvement through reflective practices [35].

As health care organisations often rely on hierarchical structures, individual influencers have the ability to affect the implementation process [37]. This is demonstrated in the current study and is present in the literature of learning behaviour in the workplace, where "psychological safety" [8] is a concern for employees. Psychological safety impacts on an individual's ability to feel comfortable openly making and learning from mistakes [8]. Participants discussed the anxiety observed in colleagues who had to make key decisions about acting on STan traces, which may also be impacted on by the organisational culture of the hospital. Authority structures can promote or inhibit collective learning in a number of ways. Individuals in positions of authority, such as project and team leaders, may influence the technology learning process by coordinating the activities in an implementation project. Furthermore, people are highly aware of the behaviour of those in positions of authority [38] and dependent on them for recognition and preferred assignments [39,40].

The results also reveal that the lack of professional body endorsement of STan was associated with discomfort in the routine use of the technology. The status of the research evidence was an important issue within the participant population, and this can relate to psychological safety [8] in the profession. This was further complicated by the presence of contrasting expert knowledge regarding foetal monitoring as well as varying comfort levels of experienced practitioners with different monitoring methods [41].

The study must be considered within its limitations. It was conducted as a "snapshot" in time, representing only initial responses to the implementation of STan. In addition, the interviews took place at one Australian site, which may not be translatable to other hospitals around Australia. However, the sample represented a number of areas and roles across the maternity ward and a wide range of views about STan were obtained. Findings from the current study may be relevant to other Australian hospitals preparing for the implementation of STan monitoring. Moreover, the general literature about barriers to the implementation of new technology may assist in planning for and education about STan monitoring.

Conclusion

This study explored the views of healthcare professionals in relation to the introduction of STan for feotal monitoring during labour. We found that the views were influenced by four main factors: alignment with the hospital's philosophy of care, training and the process of the introduction to STan, the impact of current available research evidence, and the general attitudes to the new technology. Participants made suggestions for increased and ongoing education and the need for a collaborative implementation process, to improve the understanding and uptake of STan within the organisation. It is the suggestion of the authors that this study be repeated after the results from the randomised control trial are released.

Endnotes 1 At the time of the study, STan was not supported in Australian guidelines. 2 After the current study was completed an RCT was published regarding the US population who have a similarly high caesarean section rate of 30% [19,33]. However, the two settings are not directly comparable as the model of care differs with the US having minimal Midwife driven care [34].The STan method was found to produce insignificant differences in caesarean section outcomes compared with standard CTG [34].

I
feel a little bit uncomfortable about it. I would like the trial done before we used it routinely. (Interview 15: DOC) Many participants reported reservations about using the technology in the absence of endorsement by professional bodies. I guess I would be a bit wary about the fact that our College doesn't support STan at this stage…and the RANZCOG foetal monitoring guidelines are different to I guess what we've been using. (Interview 13: DOC)

Table 1
1Participant characteristics One participant did not report their years of service I can also see it maybe being a bit more interventional, 'cause women have to have their membranes ruptured, and have to have the scalp clip on the baby's head, so just those simple things can be interventional. (Interview 1: MW, [Midwife])Profession
Mean Age
(range)

Gender
Team areas represented
Mean years
of service

10 Midwives
53 (45-58)
10 females
Midwifery Group Practice; Pregnancy Induction Assessment Suite; Delivery Suite
17

8 Doctors
33 (24-44)
2 males
6 females

Obstetrics and Gynaecology; Women's and Baby's division.
3 a

a

Definitely examples that I've seen anecdotally on the labour ward where people [women in labour] have not been taken to section 'cause people [clinicians] are more comfortable to sit on traces we would have normally sectioned. (Interview 15: DOC)
AcknowledgementsCate Fanning assisted in data collection. We thank the participating doctors and midwives from the Women's and Children's Hospital.Availability of data and materialsThe datasets generated during the current study are not publically available as consent was not obtained for this during the recruitment process, but may be made available from the corresponding author on reasonable request.Authors' contributionsAll authors conceptualised the study. MM, DT and CW designed the methodology. MM developed the data collection methods and carried out the data collection under the supervision of CW. She performed the analysis and drafted the manuscript under the supervision of DT. SK and GM assisted with supervision at the Women's and Children's Hospital. All authors commented on drafts and approved the final version.Ethics approval and consent to participate Ethical approval was gained May 2015 by the Women's and Children's Health Network Human Research Ethics Committee of the Women's and Children's Hospital (reference number: SSA/15/WCHN/65). At the beginning of an interview, each participant had the opportunity to read an information sheet and was also informed verbally about the research purpose. In addition, participants were assured of the confidentiality of their data and were informed that they could stop the interview at any point. Participants expressed their informed consented and signed a consent from. All recruited participants went through with the complete interview. Finally, all identifiable information was removed from interview transcripts.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Submit your next manuscript to BioMed Central and we will help you at every step:
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