Florey Department of Neuroscience and Mental Health - Research Publications
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ItemBottom-of-sulcus dysplasia: the role of 18F-FDG PET in identifying a focal surgically remedial epileptic lesion(SPRINGERNATURE, 2020-12-15)PURPOSE: Bottom-of-sulcus dysplasia (BOSD) is a type of focal cortical dysplasia and an important cause of intractable epilepsy. While the MRI features of BOSD have been well documented, the contribution of PET to the identification of these small lesions has not been widely explored. The aim of this study was to investigate the role of F-18 fluorodeoxyglucose (18F-FDG) PET in the identification of BOSD. METHODS: Twenty patients with BOSD underwent both 18F-FDG PET and structural MRI scans as part of preoperative planning for surgery. Visual PET analysis was performed, and patients were classified as positive if they exhibited a focal or regional hypometabolic abnormality, or negative in the absence of a hypometabolic abnormality. MRI data were reviewed to determine if any structural abnormality characteristic of BOSD were observed before and after co-registration with PET findings. RESULTS: PET detected hypometabolic abnormalities consistent with the seizure focus location in 95% (19/20) of cases. Focal abnormalities were detected on 18F-FDG PET in 12/20 (60%) patients, while regional hypometabolism was evident in 7/20 (35%). BOSD lesions were missed in 20% (4/20) of cases upon initial review of MRI scans. Co-registration of 18F-FDG PET with MRI enabled detection of the BOSD in all four cases where the lesion was initially missed. CONCLUSION: Our findings show that 18F-FDG PET provides additional clinical value in the localisation and detection of BOSD lesions, when used in conjunction with MRI.
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ItemEarly detection of amyloid load using 18F-florbetaben PET(BMC, 2021-03-27)BACKGROUND: A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. METHODS: The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology. RESULTS: SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. CONCLUSIONS: This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. TRIAL REGISTRATION: Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
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ItemNo Preview AvailableDescending forebrain projections targeting respiratory control areas in the midbrain and brainstem of rats(WILEY, 2020-04)Breathing can be voluntarily modulated via descending inputs from the forebrain to evoke respiratory‐related behaviours, such as vocalization, sniffing, swallowing or breath‐holding. Such behaviors require controlled laryngeal adduction and thus, are conducted during the post‐inspiratory phase of respiratory cycle. However, descending pathways that connect forebrain regions with primary post‐inspiratory control areas such as the pontine Kölliker‐Fuse nucleus (KF) and the medullary Bötzinger complex (BötC) remain to be identified. Here, we investigated the topography of forebrain descending projection neurons to a variety of bulbar respiratory nuclei. We locally microinjected the conventional retrograde tracer cholera toxin subunit B (CT‐B, 100–150nL) into the BötC, KF, the pre‐Bötzinger complex (pre‐BötC), the midline raphé nuclei and the midbrain periaqueductal gray (PAG). Twelve days after unilateral CT‐B injections, brains were sectioned (40μm) and immunohistochemically stained with an anti‐CT‐B antibody. The strength of descending projections was qualitatively assessed: as strong (+++), moderate (++) or weak (+) numbers of CT‐B labeled cell bodies. Retrogradely labelled neurons after unilateral injections into the lateral PAG confirmed the predominantly ipsilateral location of strong and moderate descending projection neurons in the cingulate (+++), pre‐limbic (+++), ectorhinal (++), motor (+++) and insular (++) cortices, the lateral septum (++), amygdala (+++) and hypothalamus (+++). In comparison, retrogradely labeled neurons after unilateral KF injection were also found ipsilaterally in the motor (++), prelimbic (++) and insular cortices (+++), the amygdala (++) and hypothalamus (+++). However, amongst all analysed descending target areas, only the KF receives substantial inputs from the ectorhinal (+++) and endopiriform (++) cortices. In addition, the medullary BötC receives weaker inputs from prelimbic (+) and insular (+) cortices and receives moderate inputs from the amygdala and hypothalamus. Descending projection neurons to the pre‐BötC were in accordance with the literature: motor (+) and insular (+) cortices, amygdala (+++) and hypothalamus (++). Finally, descending inputs to the medullary raphé obscurus and raphé magnus nuclei also arose from motor, prelimbic and insular cortices, amygdala and hypothalamus. However, these projections were significantly weaker compared to KF or PAG. The results suggest that descending forebrain projections into respiratory control areas are organized in general pathways that originate from motor, prelimbic and insular cortices as well as the amygdala and hypothalamus. However, only the KF, a key area for the gating of post‐inspiratory activity and respiratory plasticity, receives projections arising from the endopiriform and ectorhinal cortex. The functional implications of these descending control pathways need to be explored in future studies. Support or Funding Information Melbourne Research Scholarship (University of Melbourne) [181858] to PT‐B.
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ItemNo Preview AvailableRelaxin-3 receptor (RXFP3) mediated modulation of central respiratory activity(WILEY, 2020-04)The neuropeptide, relaxin‐3, is expressed by pontine nucleus incertus (NI) neurons. Relaxin‐3 and synthetic agonist peptides modulate arousal and cognitive processes via activation of the rela xin‐ family peptide 3 receptor (RXFP3). We recently demonstrated that a double‐chain RXFP3 peptidomimetic (RXFP3‐A2) in the nucleus of the solitary tract (NTS) triggered a mild stimulation of respiration and augmented the chemoreceptor reflex in an in situ perfused brainstem preparation ( Furuya et al., 2020). In the present study, we assessed the central respiratory effects of systemic application and local microinjection into the NTS, Kölliker‐Fuse nucleus (KF) or NI of a single chain RXFP3 peptidomimetic (B18) in the perfused brainstem preparation. Systemic application of B18 (2 μM) triggered a dose‐dependent increase in respiratory rate by 22 ± 8%. At this concentration of B18, the NaCN‐evoked (0.1% w/v, 100 μl, bolus injection) tachycardia of the arterial chemoreceptor reflex was augmented by 95 ± 14% compared to control (p<0.001, n=4). Local microinjections into the NTS also increased respiratory frequency (28 ± 5%, p<0.05, n=6) and enhanced the NaCN‐evoked tachycardia by 59%. Microinjections into the KF only triggered a mild increase in respiratory frequency (18 ± 7%, p<0.05, n=6) but had no effect on the NaCN‐evoked chemoreceptor reflex. Finally, microinjections into the NI (n=6) had no effect on either stationary breathing activity, or on the chemoreceptor reflex. We conclude that relaxin‐3 neurons target RXFP3 in respiratory control areas and acts as a general respiratory stimulant, causing mild increases in respiratory frequency. Importantly, RXFP3 stimulation significantly enhanced the respiratory response of arterial chemoreceptor reflex, implicating a major neuromodulatory role in this specific reflex pathway.
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ItemNo Preview AvailableSpinal Oxygen Sensors (SOS): A Novel Oxygen Sensing Mechanism Involved in Cardiovascular Responses to Hypoxia(WILEY, 2020-04)BACKGROUND In healthy individuals, when blood oxygenation decreases, cardiorespiratory reflexes are triggered in an attempt to restore oxygen supply to vital organs. The carotid bodies are the primary respiratory oxygen chemoreceptors but cardiovascular responses to hypoxia such as increase in heart rate and blood pressure persist in their absence, suggesting an additional high‐fidelity oxygen sensor. Previously we discovered that spinal sympathetic preganglionic neurons (SPN), are exquisitely sensitive to oxygen; here we investigate the oxygen sensing mechanisms and test the role of these spinal oxygen sensors (SOS) in cardiorespiratory responses to asphyxia‐like stimuli. OBJECTIVE To study the cellular oxygen sensing mechanism and contribution of the SOS in responses to cardiorespiratory crisis. METHODS We investigated the cellular mechanism of oxygen sensing in artificially‐perfused (in situ) and slice (in vitro) thoracic spinal cord preparations, recording sympathetic nerve root and single cell responses to hypoxia during pharmacological interrogation. To determine if the SOS are involved in cardiorespiratory responses to asphyxia, we also used an in situ rat spinal cord – carotid body ‐ brainstem preparation in which each oxygen sensitive compartment is separately perfused while recording phrenic (respiratory) and splanchnic (sympathetic) nerve activity. RESULTS Our data suggest the SOS use a novel oxygen sensing mechanism. This mechanism involves two interacting NADPH and oxygen‐dependent enzymes: Neuronal Nitric Oxide Synthase (NOS1) and NADPH oxidase (NOX2). NOS1 is expressed in surprising abundance in the SOS and is oxygen sensitive across the entire physiological range. Hence, in the presence of oxygen, NOS1 is likely to utilize most of the available NADPH in the cell. When oxygenation falls during hypoxia, NOS1 activity is reduced, increasing NADPH availability for NOX2. NOX2 produces Reactive Oxygen Species (ROS) which in turn, activate ROS‐dependent internal Ca2+ stores and/or Ca2+ channels leading to increased intracellular Ca2+, neuronal firing and, consequently, SOS responses to hypoxia. Functionally, during hypoxia, the SOS enhance sympathetic and breathing activity, while shortening apnea and gasping towards recovery, and are capable of triggering brief periods of sympathetic and respiratory‐like activity in the brainstem’s absence. CONCLUSIONS The results provide critical new knowledge required to unlock the cellular mechanisms involved in how the body mounts emergency responses to conditions that involve chronic and acute hypoxia. Support or Funding Information University of Calgary Eyes High; Hotchkiss Brain Institute; Alberta Children’s Hospital Research Institute; Alberta Innovates Health Solutions; MITACS Globalink; Canadian Institutes of Health Research.
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ItemNo Preview AvailableVolumetric mapping of the functional neuroanatomy of the brainstem respiratory network in the perfused brainstem preparation of rats(WILEY, 2020-04)One of the major goals of modern neuroscience is to understand the relationship between the functional neuroanatomy/connectivity of neural circuits and the behavior of an animal. The key challenge to addressing this goal with respect to control of breathing is the distributed nature of the respiratory network. While in cortical networks, short‐range connections (10–100 μm) out‐number long‐range connections (1+ mm), the opposite may be true of brainstem circuits. Specifically, anatomical tracing studies have identified many long‐range projections between brainstem respiratory nuclei that led to the concept that the brainstem respiratory network is compartmentally organized. Thus, measuring the functional neuroanatomy of the respiratory network—a task required to phenotype the functional role of neuronal populations identified in molecular mapping studies—requires monitoring the activity of respiratory neurons which may be spread over many millimeters. We hypothesized that the spatio‐temporal structure of the brainstem respiratory network is sufficient to generate macroscopic local field potentials (LFPs), and if so, respiratory (r) LFPs could be used to map the functional neuroanatomy of the respiratory network in single preparations. To address our hypothesis, we developed an approach using silicon multi‐electrode arrays to record spontaneous LFPs from hundreds of electrode sites across the ponto‐medullary volume of the respiratory network while monitoring the respiratory motor pattern on phrenic and vagal nerves. Our results revealed the expression of rLFPs across the brainstem respiratory network. rLFPs were expressed selectively at the three transitions between respiratory phases: (1) from late‐expiration (E2) to inspiration (I), (2) from I to post‐inspiration (PI), and (3) from PI to E2. Thus, respiratory network activity was maximal at respiratory phase transitions, rather than being equally distributed across the respiratory cycle. Spatially, the E2‐I (inspiratory on‐switch), and PI‐E2 transitions were localized to the ventral and dorsal respiratory groups, respectively, whereas the I‐PI (inspiratory off‐switch) transition was distributed across the ventral, dorsal and pontine respiratory groups. An independent component analysis (ICA) confirmed this spatio‐temporal organisation of rLFPs and identified a traveling wave of rLFPs that occurred at the I‐PI transition. Finally, a group‐wise ICA demonstrated that all preparations exhibited rLFPs with a similar temporal structure. Overall, under intact network conditions, our results confirm that inspiration is initiated by the pre‐Bötzinger complex, whereas post‐inspiration and late‐expiration depend on activity throughout the brainstem respiratory network. In conclusion, we have developed a general approach to volumetrically map spontaneous‐ or evoked‐respiratory network activity at the brainstem‐wide scale in single preparations to inform our understanding of the network mechanisms underlying the neural control of breathing. Support or Funding Information This work was supported by grants from the Australian Research Council (to MD), National Institutes of Health (to TED) and the Hartwell Foundation (to RFG).