Stimulus Integration and Parsing in the Primate Auditory Midbrain

Integrating information from multiple sources is a crucial function of the brain. Examples of such integration include multiple stimuli of different modalties, such as visual and auditory, multiple stimuli of the same modality, such as auditory and auditory, and integrating stimuli from the sensory organs (i.e. ears) with stimuli delivered from brain-machine interfaces.

The overall aim of this body of work is to empirically examine stimulus integration in these three domains to inform our broader understanding of how and when the brain combines information from multiple sources.

First, I examine visually-guided auditory, a problem with implications for the general problem in learning of how the brain determines what lesson to learn (and what lessons not to learn). For example, sound localization is a behavior that is partially learned with the aid of vision. This process requires correctly matching a visual location to that of a sound. This is an intrinsically circular problem when sound location is itself uncertain and the visual scene is rife with possible visual matches. Here, we develop a simple paradigm using visual guidance of sound localization to gain insight into how the brain confronts this type of circularity. We tested two competing hypotheses. 1: The brain guides sound location learning based on the synchrony or simultaneity of auditory-visual stimuli, potentially involving a Hebbian associative mechanism. 2: The brain uses a ‘guess and check’ heuristic in which visual feedback that is obtained after an eye movement to a sound alters future performance, perhaps by recruiting the brain’s reward-related circuitry. We assessed the effects of exposure to visual stimuli spatially mismatched from sounds on performance of an interleaved auditory-only saccade task. We found that when humans and monkeys were provided the visual stimulus asynchronously with the sound but as feedback to an auditory-guided saccade, they shifted their subsequent auditory-only performance toward the direction of the visual cue by 1.3-1.7 degrees, or 22-28% of the original 6 degree visual-auditory mismatch. In contrast when the visual stimulus was presented synchronously with the sound but extinguished too quickly to provide this feedback, there was little change in subsequent auditory-only performance. Our results suggest that the outcome of our own actions is vital to localizing sounds correctly. Contrary to previous expectations, visual calibration of auditory space does not appear to require visual-auditory associations based on synchrony/simultaneity.

My next line of research examines how electrical stimulation of the inferior colliculus influences perception of sounds in a nonhuman primate. The central nucleus of the inferior colliculus is the major ascending relay of auditory information before it reaches the forebrain, and thus an ideal target for understanding low-level information processing prior to the forebrain, as almost all auditory signals pass through the central nucleus of the inferior colliculus before reaching the forebrain. Thus, the inferior colliculus is the ideal structure to examine to understand the format of the inputs into the forebrain and, by extension, the processing of auditory scenes that occurs in the brainstem. Therefore, the inferior colliculus was an attractive target for understanding stimulus integration in the ascending auditory pathway.

Moreover, understanding the relationship between the auditory selectivity of neurons and their contribution to perception is critical to the design of effective auditory brain prosthetics. These prosthetics seek to mimic natural activity patterns to achieve desired perceptual outcomes. We measured the contribution of inferior colliculus (IC) sites to perception using combined recording and electrical stimulation. Monkeys performed a frequency-based discrimination task, reporting whether a probe sound was higher or lower in frequency than a reference sound. Stimulation pulses were paired with the probe sound on 50% of trials (0.5-80 µA, 100-300 Hz, n=172 IC locations in 3 rhesus monkeys). Electrical stimulation tended to bias the animals’ judgments in a fashion that was coarsely but significantly correlated with the best frequency of the stimulation site in comparison to the reference frequency employed in the task. Although there was considerable variability in the effects of stimulation (including impairments in performance and shifts in performance away from the direction predicted based on the site’s response properties), the results indicate that stimulation of the IC can evoke percepts correlated with the frequency tuning properties of the IC. Consistent with the implications of recent human studies, the main avenue for improvement for the auditory midbrain implant suggested by our findings is to increase the number and spatial extent of electrodes, to increase the size of the region that can be electrically activated and provide a greater range of evoked percepts.

My next line of research employs a frequency-tagging approach to examine the extent to which multiple sound sources are combined (or segregated) in the nonhuman primate inferior colliculus. In the single-sound case, most inferior colliculus neurons respond and entrain to sounds in a very broad region of space, and many are entirely spatially insensitive, so it is unknown how the neurons will respond to a situation with more than one sound. I use multiple AM stimuli of different frequencies, which the inferior colliculus represents using a spike timing code. This allows me to measure spike timing in the inferior colliculus to determine which sound source is responsible for neural activity in an auditory scene containing multiple sounds. Using this approach, I find that the same neurons that are tuned to broad regions of space in the single sound condition become dramatically more selective in the dual sound condition, preferentially entraining spikes to stimuli from a smaller region of space. I will examine the possibility that there may be a conceptual linkage between this finding and the finding of receptive field shifts in the visual system.

In chapter 5, I will comment on these findings more generally, compare them to existing theoretical models, and discuss what these results tell us about processing in the central nervous system in a multi-stimulus situation. My results suggest that the brain is flexible in its processing and can adapt its integration schema to fit the available cues and the demands of the task.

The Barriers to the Integration of the Uterine Balloon Tamponade into South Africa and Ghana's Health Systems for the Management of Postpartum Hemorrhage

Background

Postpartum hemorrhage is the most significant contributor to maternal mortality globally, claiming 140,000 lives annually. Postpartum hemorrhage is a leading cause of maternal death in South Africa, with the literature indicating that 80 percent of the postpartum hemorrhage deaths in South Africa are avoidable. Ghana, as of 2010, witnesses 2700 maternal deaths annually, primarily because of poor quality of care in health facilities and services being difficult to access. As per WHO recommendations, uterotonics are integral to treating postpartum hemorrhage as soon as it is diagnosed. In case of persistent bleeding or limited availability of uterotonics, the uterine balloon tamponade (UBT) can be used as a second line of defense. If both these measures are unable to counter the bleeding, providers must perform surgical interventions. Literature on the UBT, as one tool in the protocol to address postpartum hemorrhage, has shown it to have success rates ranging from 60 to 100 percent. Despite the potential to lower the number of postpartum hemorrhage deaths in South Africa and Ghana, the UBT has not been incorporated widely in South Africa and Ghana. The aim of this study is to describe the barriers involved with integrating the UBT into South Africa and Ghana’s health systems to address postpartum hemorrhage.

Methods

The study took place in multiple sites in South Africa (Cape Town, Johannesburg, Durban and Mpumalanga) and in Accra, Ghana. South Africa and Ghana were selected because postpartum hemorrhage contributes greatly to their maternal mortality numbers and there is potential in both countries to lower those rates through greater use of the UBT. A total of 25 participants were interviewed through purposive sampling, snowball sampling and participant referrals, and included various categories of stakeholders integral to the integration process of a medical device. Individual in-depth interviews were used for data collection, with interview questions being tailored to each stakeholder category. The focus of the interviews was on the protocol used to counter postpartum hemorrhage, the frequency with which the UBT is used as part of the protocol, and the process of integrating it into the South Africa and Ghana’s health systems. The data collected were coded using NVivo and analyzed using content analysis.

Results

The barriers to integration of the uterine balloon tamponade to address postpartum hemorrhage in South Africa and Ghana were evident on the political, economic and health delivery levels. The results indicated that the barriers to integration in South Africa included the low recognition of postpartum hemorrhage as a problem, the lack of clarity surrounding the role of the Medicines Control Council as a regulatory body for medical devices, and low awareness of the UBT as an intervention to control postpartum hemorrhage. The barriers in Ghana were the cash constraints experienced by the Ghana Health Services to fund medical devices, a heavy reliance on donors for funding, and the lack of consistent knowledge on processes involving clinical trials for new medical devices in Ghana.

Conclusion

Existing literature on methods to counter postpartum hemorrhage to reduce maternal mortality has focused on and emphasized the efficacy of the UBT. Despite overwhelming evidence supporting the use of the UBT, many health systems across the world, particularly low-income countries, do not have access to the device owing to numerous barriers in integrating the device into obstetric care. This study illustrates the need to focus on incorporating the UBT into health systems for greater availability to health workers and its use as standard of care. Ultimately, this study can be used as a stepping-stone for more research on this subject, providing evidence to influence policymakers to integrate the UBT into their protocols for postpartum hemorrhage response.