Development of neonatal-specific sequences for portable ultralow field magnetic resonance brain imaging: a prospective, single-centre, cohort study.

Background: Magnetic Resonance (MR) imaging is key for investigation of suspected newborn brain abnormalities. Access is limited in low-resource settings and challenging in infants needing intensive care. Portable ultralow field (ULF) MRI is showing promise in bedside adult brain imaging. Use in infants and children has been limited as brain-tissue composition differences necessitate sequence modification. The aim of this study was to develop neonatal-specific ULF structural sequences and test these across a range of gestational maturities and pathologies to inform future validation studies. Methods: Prospective cohort study within a UK neonatal specialist referral centre. Infants undergoing 3T MRI were recruited for paired ULF (64mT) portable MRI by convenience sampling from the neonatal unit and post-natal ward. Key inclusion criteria: 1) Infants with risk or suspicion of brain abnormality, or 2) preterm and term infants without suspicion of major genetic, chromosomal or neurological abnormality. Exclusions: presence of contra-indication for MR scanning. ULF sequence parameters were optimised for neonatal brain-tissues by iterative and explorative design. Neuroanatomic and pathologic features were compared by unblinded review, informing optimisation of subsequent sequence generations in a step-wise manner. Main outcome: visual identification of healthy and abnormal brain tissues/structures. ULF MR spectroscopy, diffusion, susceptibility weighted imaging, arteriography, and venography require pre-clinical technical development and have not been tested. Findings: Between September 23, 2021 and October 25, 2022, 102 paired scans were acquired in 87 infants; 1.17 paired scans per infant. Median age 9 days, median postmenstrual age 40+2 weeks (range: 31+3-53+4). Infants had a range of intensive care requirements. No adverse events observed. Optimised ULF sequences can visualise key neuroanatomy and brain abnormalities. In finalised neonatal sequences: T2w imaging distinguished grey and white matter (7/7 infants), ventricles (7/7), pituitary tissue (5/7), corpus callosum (7/7) and optic nerves (7/7). Signal congruence was seen within the posterior limb of the internal capsule in 10/11 infants on finalised T1w scans. In addition, brain abnormalities visualised on ULF optimised sequences have similar MR signal patterns to 3T imaging, including injury secondary to infarction (6/6 infants on T2w scans), hypoxia-ischaemia (abnormal signal in basal ganglia, thalami and white matter 2/2 infants on T2w scans, cortical highlighting 1/1 infant on T1w scan), and congenital malformations: polymicrogyria 3/3, absent corpus callosum 2/2, and vermian hypoplasia 3/3 infants on T2w scans. Sequences are susceptible to motion corruption, noise, and ULF artefact. Non-identified pathologies were small or subtle. Interpretation: On unblinded review, optimised portable MR can provide sufficient contrast, signal, and resolution for neuroanatomical identification and detection of a range of clinically important abnormalities. Blinded validation studies are now warranted. Funding: The Bill and Melinda Gates Foundation, the MRC, the Wellcome/EPSRC Centre for Medical Engineering, the MRC Centre for Neurodevelopmental Disorders, and the National Institute for Health Research (NIHR) Biomedical Research Centres based at Guy's and St Thomas' and South London & Maudsley NHS Foundation Trusts and King's College London.

In vivo T1 mapping of neonatal brain tissue at 64 mT.

PURPOSE: Ultralow-field (ULF) point-of-care MRI systems allow image acquisition without interrupting medical provision, with neonatal clinical care being an important potential application. The ability to measure neonatal brain tissue T1 is a key enabling technology for subsequent structural image contrast optimization, as well as being a potential biomarker for brain development. Here we describe an optimized strategy for neonatal T1 mapping at ULF. METHODS: Examinations were performed on a 64-mT portable MRI system. A phantom validation experiment was performed, and a total of 33 in vivo exams were acquired from 28 neonates with postmenstrual age ranging from 31+4 to 49+0  weeks. Multiple inversion-recovery turbo spin-echo sequences were acquired with differing inversion and repetition times. An analysis pipeline incorporating inter-sequence motion correction generated proton density and T1 maps. Regions of interest were placed in the cerebral deep gray matter, frontal white matter, and cerebellum. Weighted linear regression was used to predict T1 as a function of postmenstrual age. RESULTS: Reduction of T1 with postmenstrual age is observed in all measured brain tissue; the change in T1 per week and 95% confidence intervals is given by dT1  = -21 ms/week [-25, -16] (cerebellum), dT1  = -14 ms/week [-18, -10] (deep gray matter), and dT1  = -35 ms/week [-45, -25] (white matter). CONCLUSION: Neonatal T1 values at ULF are shorter than those previously described at standard clinical field strengths, but longer than those of adults at ULF. T1 reduces with postmenstrual age and is therefore a candidate biomarker for perinatal brain development.

Utility of 7 Tesla MRI for Preoperative Planning of Endoscopic Endonasal Surgery for Pituitary Adenomas.

Objective There is increasing interest in investigating the utility of 7 Tesla (7 T) magnetic resonance imaging (MRI) for imaging of skull base tumors. The present study quantifies visualization of tumor features and adjacent skull base anatomy in a homogenous cohort of pituitary adenoma patients. Methods Eighteen pituitary adenoma patients were scanned at 7 T in this prospective study. All patients had reference standard-of-care clinical imaging at either 3 T (7/18, 39%) or 1.5 T (11/18, 61%). Visualization of tumor features and conspicuity of arteries and cranial nerves (CNs) was rated by an expert neuroradiologist on 7 T and clinical field strength MRI. Overall image quality and severity of image artifacts were also characterized and compared. Results Ability to visualize tumor features did not differ between 7 T and lower field MRI. Cranial nerves III, IV, and VI were better detected at 7 T compared with clinical field strength scans. Cranial nerves III, IV, and VI were also better detected at 7 T compared with only 1.5 T, and CN III was better visualized at 7 T compared with 3 T MRI. The ophthalmic arteries and posterior communicating arteries (PCOM) were better detected at 7 T compared with clinical field strength imaging. The 7 T also provided better visualization of the ophthalmic arteries compared with 1.5 T scans. Conclusion This study demonstrates that 7 T MRI is feasible at the skull base and identifies various CNs and branches of the internal carotid artery that were better visualized at 7 T. The 7 T MRI may offer important preoperative information that can help to guide resection of pituitary adenoma and reduce operative morbidity.

Pituitary adenoma consistency: Direct correlation of ultrahigh field 7T MRI with histopathological analysis.

PURPOSE: Tumor consistency is a critical factor in surgical planning that influences ease of resection and risk of operative morbidity. The ability of MRI to predict tumor consistency tumor consistency has been shown to increase with higher field strength. The present study examined the utility of 7 T (7 T) MRI in predicting the tumor consistency of pituitary adenomas. METHOD: Fifteen patients with pituitary adenomas were preoperatively scanned at 7 T MRI. Regions of interest were drawn around lesions for voxel-based signal intensity (SI) analysis. The percentage of tumor voxels with intensity higher than local gray matter was calculated on T2-weighted imaging. A single neurosurgeon rated tumor firmness for all patients. Histopathological analysis was performed. Radiological tumor features were correlated with intraoperative tumor consistency measurements and histopathology. RESULTS: Tumors rated as 'soft' intraoperatively were hyperintense to local gray matter on T2-weighted imaging. 'Firm' tumors were hypointense to local gray matter. There was no significant difference in SI ratio between soft and firm tumors (p = 0.098). Soft tumors had a significantly higher percentage of tumor voxels greater than local gray matter compared to firm tumors (p = 0.035, Cohen's D-effect size = 1.208). Soft tumors had higher vascularity than firm tumors, p = 0.015. CONCLUSIONS: The signal and contrast advantage conferred by 7 T MRI may provide valuable preoperative information regarding pituitary tumor consistency and physiology. The use of granular, voxel-based analysis maximizes the potential afforded by the high resolution of 7 T imaging, and may be a valuable method of predicting consistency of pituitary adenoma.

Safe guidewire visualization using the modes of a PTx transmit array MR system.

PURPOSE: MRI-guided cardiovascular intervention using standard metal guidewires can produce focal tissue heating caused by induced radiofrequency guidewire currents. It has been shown that safe operation is made possible by using parallel transmit radiofrequency coils driven in the null current mode, which does not induce radiofrequency currents and hence allows safe tissue visualization. We propose that the maximum current modes, usually considered unsafe, be used at very low power levels to visualize conductive wires, and we investigate pulse sequences best suited for this application. METHODS: Spoiled gradient echo, balanced steady-state free precession, and turbo spin echo sequences were evaluated for their ability to visualize a conductive guidewire embedded in a gel phantom when run in maximum current modes at very low power level. Temperature at the guidewire tip was monitored for safety assessment. RESULTS: Excellent guidewire visualization could be achieved using maximum current modes excitation, with the turbo spin echo sequence giving the best image quality. Although turbo spin echo is usually considered to be a high-power sequence, our method reduced all pulses to 1% amplitude (0.01% power), and heating was not detected. In addition, visualization of background tissue can be achieved using null current mode, also with no recorded heating at the guidewire tip even when running at 100% (reported) specific absorption rate. CONCLUSION: Parallel transmit is a promising approach for both guidewire and tissue visualization using maximum and null current modes, respectively, for interventional cardiac MRI. Such systems can switch excitation mode instantaneously, allowing for flexible integration into interactive sequences.

Quantitative assessment of secondary white matter injury in the visual pathway by pituitary adenomas: a multimodal study at 7-Tesla MRI.

OBJECTIVE: The objective of this study was to investigate microstructural damage caused by pituitary macroadenomas by performing probabilistic tractography of the optic tracts and radiations using 7-T diffusion-weighted MRI (DWI). These imaging findings were correlated with neuro-ophthalmological results to assess the utility of ultra-high-field MRI for objective evaluation of damage to the anterior and posterior visual pathways. METHODS: Probabilistic tractography employing 7-T DWI was used to reconstruct the optic tracts and radiations in 18 patients with adenomas and in 16 healthy volunteers. Optic chiasm compression was found in 66.7% of the patients and visual defects in 61.1%. Diffusion indices were calculated along the projections and correlated with tumor volumes and results from neuro-ophthalmological examinations. Primary visual cortical thicknesses were also assessed. RESULTS: Fractional anisotropy was reduced by 21.9% in the optic tracts (p < 0.001) and 17.7% in the optic radiations (p < 0.001) in patients with adenomas. Patients showed an 8.5% increase in mean diffusivity of optic radiations compared with healthy controls (p < 0.001). Primary visual cortical thickness was reduced in adenoma patients. Diffusion indices of the visual pathway showed significant correlations with neuro-ophthalmological examination findings. CONCLUSIONS: Imaging-based quantification of secondary neuronal damage from adenomas strongly correlated with neuro-ophthalmological findings. Diffusion characteristics enabled by ultra-high-field DWI may allow preoperative characterization of visual pathway damage in patients with chiasmatic compression and may inform prognosis for vision recoverability.

An efficient sequence for fetal brain imaging at 3T with enhanced T1 contrast and motion robustness.

PURPOSE: Ultrafast single-shot T2 -weighted images are common practice in fetal MR exams. However, there is limited experience with fetal T1 -weighted acquisitions. This study aims at establishing a robust framework that allows fetal T1 -weighted scans to be routinely acquired in utero at 3T. METHODS: A 2D gradient echo sequence with an adiabatic inversion was optimized to be robust to fetal motion and maternal breathing optimizing grey/white matter contrast at the same time. This was combined with slice to volume registration and super resolution methods to produce volumetric reconstructions. The sequence was tested on 22 fetuses. RESULTS: Optimized grey/white matter contrast and robustness to fetal motion and maternal breathing were achieved. Signal from cerebrospinal fluid (CSF) and amniotic fluid was nulled and 0.75 mm isotropic anatomical reconstructions of the fetal brain were obtained using slice-to-volume registration and super resolution techniques. Total acquisition time for a single stack was 56 s, all acquired during free breathing. Enhanced sensitivity to normal anatomy and pathology with respect to established methods is demonstrated. A direct comparison with a 3D spoiled gradient echo sequence and a controlled motion experiment run on an adult volunteer are also shown. CONCLUSION: This paper describes a robust framework to perform T1 -weighted acquisitions and reconstructions of the fetal brain in utero. Magn Reson Med 80:137-146, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Localization of spontaneous bursting neuronal activity in the preterm human brain with simultaneous EEG-fMRI.

Electroencephalographic recordings from the developing human brain are characterized by spontaneous neuronal bursts, the most common of which is the delta brush. Although similar events in animal models are known to occur in areas of immature cortex and drive their development, their origin in humans has not yet been identified. Here, we use simultaneous EEG-fMRI to localise the source of delta brush events in 10 preterm infants aged 32-36 postmenstrual weeks. The most frequent patterns were left and right posterior-temporal delta brushes which were associated in the left hemisphere with ipsilateral BOLD activation in the insula only; and in the right hemisphere in both the insular and temporal cortices. This direct measure of neural and hemodynamic activity shows that the insula, one of the most densely connected hubs in the developing cortex, is a major source of the transient bursting events that are critical for brain maturation.

First Application of 7-T Magnetic Resonance Imaging in Endoscopic Endonasal Surgery of Skull Base Tumors.

BACKGROUND: Successful endoscopic endonasal surgery for the resection of skull base tumors is reliant on preoperative imaging to delineate pathology from the surrounding anatomy. The increased signal-to-noise ratio afforded by 7-T MRI can be used to increase spatial and contrast resolution, which may lend itself to improved imaging of the skull base. In this study, we apply a 7-T imaging protocol to patients with skull base tumors and compare the images with clinical standard of care. METHODS: Images were acquired at 7 T on 11 patients with skull base lesions. Two neuroradiologists evaluated clinical 1.5-, 3-, and 7-T scans for detection of intracavernous cranial nerves and internal carotid artery (ICA) branches. Detection rates were compared. Images were used for surgical planning and uploaded to a neuronavigation platform and used to guide surgery. RESULTS: Image analysis yielded improved detection rates of cranial nerves and ICA branches at 7 T. The 7-T images were successfully incorporated into preoperative planning and intraoperative neuronavigation. CONCLUSIONS: Our study represents the first application of 7-T MRI to the full neurosurgical workflow for endoscopic endonasal surgery. We detected higher rates of cranial nerves and ICA branches at 7-T MRI compared with 3- and 1.5-T MRI, and found that integration of 7 T into surgical planning and guidance was feasible. These results suggest a potential for 7-T MRI to reduce surgical complications. Future studies comparing standardized 7-, 3-, and 1.5-T MRI protocols in a larger number of patients are warranted to determine the relative benefit of 7-T MRI for endonasal endoscopic surgical efficacy.

Extended RF shimming: Sequence-level parallel transmission optimization applied to steady-state free precession MRI of the heart.

Cardiac magnetic resonance imaging (MRI) at high field presents challenges because of the high specific absorption rate and significant transmit field (B1+ ) inhomogeneities. Parallel transmission MRI offers the ability to correct for both issues at the level of individual radiofrequency (RF) pulses, but must operate within strict hardware and safety constraints. The constraints are themselves affected by sequence parameters, such as the RF pulse duration and TR, meaning that an overall optimal operating point exists for a given sequence. This work seeks to obtain optimal performance by performing a 'sequence-level' optimization in which pulse sequence parameters are included as part of an RF shimming calculation. The method is applied to balanced steady-state free precession cardiac MRI with the objective of minimizing TR, hence reducing the imaging duration. Results are demonstrated using an eight-channel parallel transmit system operating at 3 T, with an in vivo study carried out on seven male subjects of varying body mass index (BMI). Compared with single-channel operation, a mean-squared-error shimming approach leads to reduced imaging durations of 32 ± 3% with simultaneous improvement in flip angle homogeneity of 32 ± 8% within the myocardium.

A dedicated neonatal brain imaging system.

PURPOSE: The goal of the Developing Human Connectome Project is to acquire MRI in 1000 neonates to create a dynamic map of human brain connectivity during early development. High-quality imaging in this cohort without sedation presents a number of technical and practical challenges. METHODS: We designed a neonatal brain imaging system (NBIS) consisting of a dedicated 32-channel receive array coil and a positioning device that allows placement of the infant's head deep into the coil for maximum signal-to-noise ratio (SNR). Disturbance to the infant was minimized by using an MRI-compatible trolley to prepare and transport the infant and by employing a slow ramp-up and continuation of gradient noise during scanning. Scan repeats were minimized by using a restart capability for diffusion MRI and retrospective motion correction. We measured the 1) SNR gain, 2) number of infants with a completed scan protocol, and 3) number of anatomical images with no motion artifact using NBIS compared with using an adult 32-channel head coil. RESULTS: The NBIS has 2.4 times the SNR of the adult coil and 90% protocol completion rate. CONCLUSION: The NBIS allows advanced neonatal brain imaging techniques to be employed in neonatal brain imaging with high protocol completion rates. Magn Reson Med 78:794-804, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

RF system calibration for global Q matrix determination.

The use of multiple transmission channels (known as Parallel Transmission, or PTx) provides increased control of the MRI signal formation process. This extra flexibility comes at a cost of uncertainty of the power deposited in the patient under examination: the electric fields produced by each transmitter can interfere in such a way to lead to excessively high heating. Although it is not possible to determine local heating, the global Q matrix (which allows the whole-body Specific Absorption Rate (SAR) to be known for any PTx pulse) can be measured in-situ by monitoring the power incident upon and reflected by each transmit element during transmission. Recent observations have shown that measured global Q matrices can be corrupted by losses between the coil array and location of power measurement. In this work we demonstrate that these losses can be accounted for, allowing accurate global Q matrix measurement independent of the location of the power measurement devices.

Large dynamic range relative B1+ mapping.

PURPOSE: Parallel transmission (PTx) requires knowledge of the B1+ produced by each element. However, B1+ mapping can be challenging when transmit fields exhibit large dynamic range. This study presents a method to produce high quality relative B1+ maps when this is the case. THEORY AND METHODS: The proposed technique involves the acquisition of spoiled gradient echo (SPGR) images at multiple radiofrequency drive levels for each transmitter. The images are combined using knowledge of the SPGR signal equation using maximum likelihood estimation, yielding an image for each channel whose signal is proportional to the B1+ field strength. Relative B1+ maps are then obtained by taking image ratios. The method was tested using numerical simulations, phantom imaging, and through in vivo experiments. RESULTS: The numerical simulations demonstrated that the proposed method can reconstruct relative transmit sensitivities over a wide range of B1+ amplitudes and at several SNR levels. The method was validated at 3 Tesla (T) by comparing it with an alternative B1+ mapping method, and demonstrated in vivo at 7T. CONCLUSION: Relative B1+ mapping in the presence of large dynamic range has been demonstrated through numerical simulations, phantom imaging at 3T and experimentally at 7T. The method will enable PTx to be applied in challenging imaging scenarios at ultrahigh field. Magn Reson Med 76:490-499, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Parallel transmission for ultrahigh-field imaging.

The development of MRI systems operating at or above 7 T has provided researchers with a new window into the human body, yielding improved imaging speed, resolution and signal-to-noise ratio. In order to fully realise the potential of ultrahigh-field MRI, a range of technical hurdles must be overcome. The non-uniformity of the transmit field is one of such issues, as it leads to non-uniform images with spatially varying contrast. Parallel transmission (i.e. the use of multiple independent transmission channels) provides previously unavailable degrees of freedom that allow full spatial and temporal control of the radiofrequency (RF) fields. This review discusses the many ways in which these degrees of freedom can be used, ranging from making more uniform transmit fields to the design of subject-tailored RF pulses for both uniform excitation and spatial selection, and also the control of the specific absorption rate. © 2015 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

PRIMO: Precise radiofrequency inference from multiple observations.

PURPOSE: This paper presents Precise Radiofrequency Inference from Multiple Observations (PRIMO), a comprehensive reconstruction framework for calibrating MRI systems with parallel transmit and parallel receive radiofrequency capabilities. THEORY AND METHODS: To date, the vast majority of radiofrequency (RF) calibration methods have considered transmit and receive calibration separately, without acknowledging that transmit field calibration sequences measure sufficient data for receive calibration. PRIMO provides a method of extracting both transmit and receive fields from transmit calibration data without presuming knowledge of either. The method is tested for accuracy through simulation, comparison to a gold standard dataset, and is demonstrated on in-vivo data acquired at 3T. RESULTS: PRIMO is shown to produce RF fields faithful to the gold standard with errors of less than 3% in realistic noise conditions. The in-vivo reconstructions demonstrate the method's ability to produce high quality transmit and receive maps, with an 8 transmit/8 receive channel system being fully calibrated in three dimensions in approximately 2 minutes. CONCLUSION: PRIMO provides a unified framework for estimating all transmit and receive fields in a single calibration step. This is becoming increasingly relevant in an era of MRI systems with highly parallel RF architectures.

Direct signal control of the steady-state response of 3D-FSE sequences.

PURPOSE: Parallel transmission (PTx) offers spatial control of radiofrequency (RF) fields that can be used to mitigate nonuniformity effects in high-field MRI. In practice, the ability to achieve uniform RF fields by static shimming is limited by the typically small number of channels. Thus, tailored RF pulses that mix gradient with RF encoding have been proposed. A complementary approach termed "Direct Signal Control" (DSC) is to dynamically update RF shims throughout a sequence, exploiting interactions between each pulse and the spin system to achieve uniform signal properties from potentially nonuniform fields. This work applied DSC to T2-weighted driven-equilibrium three-dimensional fast spin echo (3D-FSE) brain imaging at 3T. THEORY AND METHODS: The DSC concept requires an accurate signal model, provided by extending the spatially resolved extended phase graph framework to include the steady-state response of driven-equilibrium sequences. An 8-channel PTx body coil was used for experiments. RESULTS: Phantom experiments showed the model to be accurate to within 0.3% (root mean square error). In vivo imaging showed over two-fold improvement in signal homogeneity compared with quadrature excitation. Although the nonlinear optimization cannot guarantee a global optimum, significantly improved local solutions were found. CONCLUSION: DSC has been demonstrated for 3D-FSE brain imaging at 3T. The concept is generally applicable to higher field strengths and other anatomies.

Spatially resolved extended phase graphs: modeling and design of multipulse sequences with parallel transmission.

A spatially resolved extended phase graph (SR-EPG) framework is proposed for prediction of echo amplitudes in the presence of spatially variable radio frequency (RF) fields. The method may be used to examine any regularly repeating pulse sequence and provides a design framework for parallel transmission (PTx) systems; in this work signal homogeneity in static pseudo-steady state (SPSS) turbo spin echo (TSE) imaging was investigated. Building on SR-EPG calculations with PTx, a dynamic RF-shimming approach is proposed in which, RF pulse amplitudes and phases are optimized on a per channel and per pulse basis to yield the desired signal response for all echoes. Results show significant improvements over "static" RF shimming (in which the relative amplitude/phase of the PTx channels are fixed for all pulses). SPSS-TSE imaging using dynamic RF shimming resulted in excellent image quality, both in phantoms and in vivo, and confirmed SR-EPG predictions.

Identification and characterisation of midbrain nuclei using optimised functional magnetic resonance imaging.

Localising activity in the human midbrain with conventional functional MRI (fMRI) is challenging because the midbrain nuclei are small and located in an area that is prone to physiological artefacts. Here we present a replicable and automated method to improve the detection and localisation of midbrain fMRI signals. We designed a visual fMRI task that was predicted would activate the superior colliculi (SC) bilaterally. A limited number of coronal slices were scanned, orientated along the long axis of the brainstem, whilst simultaneously recording cardiac and respiratory traces. A novel anatomical registration pathway was used to optimise the localisation of the small midbrain nuclei in stereotactic space. Two additional structural scans were used to improve registration between functional and structural T1-weighted images: an echo-planar image (EPI) that matched the functional data but had whole-brain coverage, and a whole-brain T2-weighted image. This pathway was compared to conventional registration pathways, and was shown to significantly improve midbrain registration. To reduce the physiological artefacts in the functional data, we estimated and removed structured noise using a modified version of a previously described physiological noise model (PNM). Whereas a conventional analysis revealed only unilateral SC activity, the PNM analysis revealed the predicted bilateral activity. We demonstrate that these methods improve the measurement of a biologically plausible fMRI signal. Moreover they could be used to investigate the function of other midbrain nuclei.