Focused ultrasound-mediated delivery of viral neuronal tracers in marmosets.

In this issue of Cell Reports Methods, Parks et al. present an approach to non-invasively deliver adeno-associated viruses in a marmoset model using focused ultrasound (FUS) for neuronal tracing. The optimization of this technique in this non-human primate model is highly valuable for future FUS-mediated drug delivery studies.

Characterization of central manifestations in patients with Niemann-Pick disease type C.

PURPOSE: Niemann-Pick disease type C (NPC) is a rare lysosomal storage disease characterized by progressive neurodegeneration and neuropsychiatric symptoms. This study investigated pathophysiological mechanisms underlying motor deficits, particularly speech production, and cognitive impairment. METHODS: We prospectively phenotyped 8 adults with NPC and age-sex-matched healthy controls using a comprehensive assessment battery, encompassing clinical presentation, plasma biomarkers, hand-motor skills, speech production, cognitive tasks, and (micro-)structural and functional central nervous system properties through magnetic resonance imaging. RESULTS: Patients with NPC demonstrated deficits in fine-motor skills, speech production timing and coordination, and cognitive performance. Magnetic resonance imaging revealed reduced cortical thickness and volume in cerebellar subdivisions (lobule VI and crus I), cortical (frontal, temporal, and cingulate gyri) and subcortical (thalamus and basal ganglia) regions, and increased choroid plexus volumes in NPC. White matter fractional anisotropy was reduced in specific pathways (intracerebellar input and Purkinje tracts), whereas diffusion tensor imaging graph theory analysis identified altered structural connectivity. Patients with NPC exhibited altered activity in sensorimotor and cognitive processing hubs during resting-state and speech production. Canonical component analysis highlighted the role of cerebellar-cerebral circuitry in NPC and its integration with behavioral performance and disease severity. CONCLUSION: This deep phenotyping approach offers a comprehensive systems neuroscience understanding of NPC motor and cognitive impairments, identifying potential central nervous system biomarkers.

Targeted manipulation of pain neural networks: The potential of focused ultrasound for treatment of chronic pain.

Focused ultrasound (FUS) is a promising technology for facilitating treatment of brain diseases including chronic pain. Focused ultrasound is a unique modality for delivering therapeutic levels of energy into the body, including the central nervous system (CNS). It is non-invasive and can target spatially localized effects through the intact skull to cortical or subcortical regions of the brain. FUS can achieve three different mechanisms of action in the brain that are relevant for chronic pain treatment: (1) localized thermal ablation of neural tissue; (2) localized and transient disruption of the blood-brain barrier for targeted drug delivery to CNS structures; and (3) inhibition or stimulation of neuronal activity in targeted regions. This review provides an in-depth look at the technology of FUS with emphasis placed on applications to CNS-based treatments of chronic pain. While still in the early stages of clinical translation and with some technical challenges remaining, we suggest that FUS has great potential as a novel approach for manipulating CNS networks involved in pain treatment.

Secondary effects on brain physiology caused by focused ultrasound-mediated disruption of the blood-brain barrier.

Focused ultrasound (FUS) combined with microbubbles is a non-invasive method for targeted, reversible disruption of the blood-brain barrier (FUS-BBB opening). This approach holds great promise for improving delivery of therapeutics to the brain. In order to achieve this clinically important goal, the approach necessarily breaks a protective barrier, temporarily, which plays a fundamental role in maintaining a homeostatic environment in the brain. Preclinical and clinical research has identified a set of treatment parameters under which this can be performed safely, whereby the BBB is disrupted to the point of being permeable to normally non-penetrant agents without causing significant acute damage to endothelial or neuronal cells. Much of the early work in this field focused on engineering questions around how to achieve optimal delivery of therapeutics via BBB disruption. However, there is increasing interest in addressing biological questions related to whether and how various aspects of neurophysiology might be affected when this fundamental protective barrier is compromised by the specific mechanisms of FUS-BBB opening. Improving our understanding of these secondary effects is becoming vital now that FUS-BBB opening treatments have entered clinical trials. Such information would help to safely expand FUS-BBB opening protocols into a wider range of drug delivery applications and may even lead to new types of treatments. In this paper, we will critically review our current knowledge of the secondary effects caused by FUS-BBB opening on brain physiology, identify areas that remain understudied, and discuss how a better understanding of these processes can be used to safely advance FUS-BBB opening into a wider range of clinical applications.

The cost of consent: why healthcare providers must be compliant with the Montgomery principles.

The cost of clinical negligence in the UK has continued to rise despite no increase in claims numbers from 2016 to 2019. In the US, medical malpractice claim rates have fallen each year since 2001 and the payout rate has stabilized. In Germany, malpractice claim rates for spinal surgery fell yearly from 2012 to 2017, despite the number of spinal operations increasing. In Australia, public healthcare claim rates were largely static from 2008 to 2013, but private claims rose marginally. The cost of claims rose during the period. UK and Australian trends are therefore out of alignment with other international comparisons. Many of the claims in orthopaedics occur as a result of "failure to warn", i.e. lack of adequately documented and appropriate consent. The UK and USA have similar rates (26% and 24% respectively), but in Germany the rate is 14% and in Australia only 2%. This paper considers the drivers for the increased cost of clinical negligence claims in the UK compared to the USA, Germany and Australia, from a spinal and orthopaedic point of view, with a focus on "failure to warn" and lack of compliance with the principles established in February 2015 in the Supreme Court in the case of Montgomery v Lanarkshire Health Board. The article provides a description of the prevailing medicolegal situation in the UK and also calculates, from publicly available data, the cost to the public purse of the failure to comply with the principles established. It shows that compliance with the Montgomery principles would have an immediate and lasting positive impact on the sums paid by NHS Resolution to settle negligence cases in a way that has already been established in the USA. Cite this article: Bone Joint J 2020;102-B(5):550-555.

The neurovascular response is attenuated by focused ultrasound-mediated disruption of the blood-brain barrier.

Focused ultrasound (FUS)-induced disruption of the blood-brain barrier (BBB) is a non-invasive method to target drug delivery to specific brain areas that is now entering into the clinic. Recent studies have shown that the method has several secondary effects on local physiology and brain function beyond making the vasculature permeable to normally non-BBB penetrant molecules. This study uses functional MRI methods to investigate how FUS BBB opening alters the neurovascular response in the rat brain. Nine rats underwent actual and sham FUS induced BBB opening targeted to the right somatosensory cortex (SI) followed by four runs of bilateral electrical hind paw stimulus-evoked fMRI. The neurovascular response was quantified using measurements of the blood oxygen level dependent (BOLD) signal and cerebral blood flow (CBF). An additional three rats underwent the same FUS-BBB opening followed by stimulus-evoked fMRI with high resolution BOLD imaging and BOLD imaging of a carbogen-breathing gas challenge. BOLD and CBF measurements at two different stimulus durations demonstrate that the neurovascular response to the stimulus is attenuated in both amplitude and duration in the region targeted for FUS-BBB opening. The carbogen results show that the attenuation in response amplitude, but not duration, is still present when the signaling mechanism originates from changes in blood oxygenation instead of stimulus-induced neuronal activity. There is some evidence of non-local effects, including a possible global decrease in baseline CBF. All effects are resolved by 24 h after FUS-BBB opening. Taken together, these results suggest that FUS-BBB opening alters that state of local brain neurovascular physiology in such a way that hinders its ability to respond to demands for increased blood flow to the region. The mechanisms for this effect need to be elucidated.

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

Accurate modeling of temporal correlations in rapidly sampled fMRI time series.

Rapid imaging techniques are increasingly used in functional MRI studies because they allow a greater number of samples to be acquired per unit time, thereby increasing statistical power. However, temporal correlations limit the increase in functional sensitivity and must be accurately accounted for to control the false-positive rate. A common approach to accounting for temporal correlations is to whiten the data prior to estimating fMRI model parameters. Models of white noise plus a first-order autoregressive process have proven sufficient for conventional imaging studies, but more elaborate models are required for rapidly sampled data. Here we show that when the "FAST" model implemented in SPM is used with a well-controlled number of parameters, it can successfully prewhiten 80% of grey matter voxels even with volume repetition times as short as 0.35 s. We further show that the temporal signal-to-noise ratio (tSNR), which has conventionally been used to assess the relative functional sensitivity of competing imaging approaches, can be augmented to account for the temporal correlations in the time series. This amounts to computing the t-score testing for the mean signal. We show in a visual perception task that unlike the tSNR weighted by the number of samples, the t-score measure is directly related to the t-score testing for activation when the temporal correlations are correctly modeled. This score affords a more accurate means of evaluating the functional sensitivity of different data acquisition options.

Focused ultrasound induced opening of the blood-brain barrier disrupts inter-hemispheric resting state functional connectivity in the rat brain.

Focused ultrasound (FUS) is a technology capable of delivering therapeutic levels of energy through the intact skull to a tightly localized brain region. Combining the FUS pressure wave with intravenously injected microbubbles creates forces on blood vessel walls that open the blood-brain barrier (BBB). This noninvasive and localized opening of the BBB allows for targeted delivery of pharmacological agents into the brain for use in therapeutic development. It is possible to use FUS power levels such that the BBB is opened without damaging local tissues. However, open questions remain related to the effects that FUS-induced BBB opening has on brain function including local physiology and vascular hemodynamics. We evaluated the effects that FUS-induced BBB opening has on resting state functional magnetic resonance imaging (rs-fMRI) metrics. Data from rs-fMRI was acquired in rats that underwent sham FUS BBB vs. FUS BBB opening targeted to the right primary somatosensory cortex hindlimb region (S1HL). FUS BBB opening reduced the functional connectivity between the right S1HL and other sensorimotor regions, including statistically significant reduction of connectivity to the homologous region in the left hemisphere (left S1HL). The effect was observed in all three metrics analyzed: functional connectivity between anatomically defined regions, whole brain voxel-wise correlation maps based on anatomical seeds, and spatial patterns from independent component analysis. Connectivity metrics for other regions where the BBB was not perturbed were not affected. While it is not clear whether the effect is vascular or neuronal in origin, these results suggest that even safe levels of FUS BBB opening have an effect on the physiological processes that drive the signals measured by BOLD fMRI. As such these effects must be accounted for when carrying out studies using fMRI to evaluate the effects of pharmacological agents delivered via FUS-induced BBB opening.

Optimizing Data for Modeling Neuronal Responses.

In this technical note, we address an unresolved challenge in neuroimaging statistics: how to determine which of several datasets is the best for inferring neuronal responses. Comparisons of this kind are important for experimenters when choosing an imaging protocol-and for developers of new acquisition methods. However, the hypothesis that one dataset is better than another cannot be tested using conventional statistics (based on likelihood ratios), as these require the data to be the same under each hypothesis. Here we present Bayesian data comparison (BDC), a principled framework for evaluating the quality of functional imaging data, in terms of the precision with which neuronal connectivity parameters can be estimated and competing models can be disambiguated. For each of several candidate datasets, neuronal responses are modeled using Bayesian (probabilistic) forward models, such as General Linear Models (GLMs) or Dynamic Casual Models (DCMs). Next, the parameters from subject-specific models are summarized at the group level using a Bayesian GLM. A series of measures, which we introduce here, are then used to evaluate each dataset in terms of the precision of (group-level) parameter estimates and the ability of the data to distinguish similar models. To exemplify the approach, we compared four datasets that were acquired in a study evaluating multiband fMRI acquisition schemes, and we used simulations to establish the face validity of the comparison measures. To enable people to reproduce these analyses using their own data and experimental paradigms, we provide general-purpose Matlab code via the SPM software.

Functional Sensitivity of 2D Simultaneous Multi-Slice Echo-Planar Imaging: Effects of Acceleration on g-factor and Physiological Noise.

Accelerated data acquisition with simultaneous multi-slice (SMS) imaging for functional MRI studies leads to interacting and opposing effects that influence the sensitivity to blood oxygen level-dependent (BOLD) signal changes. Image signal to noise ratio (SNR) is decreased with higher SMS acceleration factors and shorter repetition times (TR) due to g-factor noise penalties and saturation of longitudinal magnetization. However, the lower image SNR is counteracted by greater statistical power from more samples per unit time and a higher temporal Nyquist frequency that allows for better removal of spurious non-BOLD high frequency signal content. This study investigated the dependence of the BOLD sensitivity on these main driving factors and their interaction, and provides a framework for evaluating optimal acceleration of SMS-EPI sequences. functional magnetic resonance imaging (fMRI) data from a scenes/objects visualization task was acquired in 10 healthy volunteers at a standard neuroscience resolution of 3 mm on a 3T MRI scanner. SMS factors 1, 2, 4, and 8 were used, spanning TRs of 2800 ms to 350 ms. Two data processing methods were used to equalize the number of samples over the SMS factors. BOLD sensitivity was assessed using g-factors maps, temporal SNR (tSNR), and t-score metrics. tSNR results show a dependence on SMS factor that is highly non-uniform over the brain, with outcomes driven by g-factor noise amplification and the presence of high frequency noise. The t-score metrics also show a high degree of spatial dependence: the lower g-factor noise area of V1 shows significant improvements at higher SMS factors; the moderate-level g-factor noise area of the parahippocampal place area shows only a trend of improvement; and the high g-factor noise area of the ventral-medial pre-frontal cortex shows a trend of declining t-scores at higher SMS factors. This spatial variability suggests that the optimal SMS factor for fMRI studies is region dependent. For task fMRI studies done with similar parameters as were used here (3T scanner, 32-channel RF head coil, whole brain coverage at 3 mm isotropic resolution), we recommend SMS accelerations of 4x (conservative) to 8x (aggressive) for most studies and a more conservative acceleration of 2x for studies interested in anterior midline regions.

Preclinical evaluation of a low-frequency transcranial MRI-guided focused ultrasound system in a primate model.

This study investigated thermal ablation and skull-induced heating with a 230 kHz transcranial MRI-guided focused ultrasound (TcMRgFUS) system in nonhuman primates. We evaluated real-time acoustic feedback and aimed to understand whether cavitation contributed to the heating and the lesion formation. In four macaques, we sonicated thalamic targets at acoustic powers of 34-560 W (896-7590 J). Tissue effects evaluated with MRI and histology were compared to MRI-based temperature and thermal dose measurements, acoustic emissions recorded during the experiments, and acoustic and thermal simulations. Peak temperatures ranged from 46 to 57 °C, and lesions were produced in 5/8 sonicated targets. A linear relationship was observed between the applied acoustic energy and both the focal and brain surface heating. Thermal dose thresholds were 15-50 cumulative equivalent minutes at 43 °C, similar to prior studies at higher frequencies. Histology was also consistent with earlier studies of thermal effects in the brain. The system successfully controlled the power level and maintained a low level of cavitation activity. Increased acoustic emissions observed in 3/4 animals occurred when the focal temperature rise exceeded approximately 16 °C. Thresholds for thermally-significant subharmonic and wideband emissions were 129 and 140 W, respectively, corresponding to estimated pressure amplitudes of 2.1 and 2.2 MPa. Simulated focal heating was consistent with the measurements for sonications without thermally-significant acoustic emissions; otherwise it was consistently lower than the measurements. Overall, these results suggest that the lesions were produced by thermal mechanisms. The detected acoustic emissions, however, and their association with heating suggest that cavitation might have contributed to the focal heating. Compared to earlier work with a 670 kHz TcMRgFUS system, the brain surface heating was substantially reduced and the focal heating was higher with this 230 kHz system, suggesting that a reduced frequency can increase the treatment envelope for TcMRgFUS and potentially reduce the risk of skull heating.

Model predictive filtering MR thermometry: Effects of model inaccuracies, k-space reduction factor, and temperature increase rate.

PURPOSE: Evaluate effects of model parameter inaccuracies (thermal conductivity, k, and ultrasound power deposition density, Q), k-space reduction factor (R), and rate of temperature increase ( T˙) in a thermal model-based reconstruction for MR-thermometry during focused-ultrasound heating. METHODS: Simulations and ex vivo experiments were performed to investigate the accuracy of the thermal model and the model predictive filtering (MPF) algorithm for varying R and T˙, and their sensitivity to errors in k and Q. Ex vivo data was acquired with a segmented EPI pulse sequence to achieve large field-of-view (192 × 162 × 96 mm) four-dimensional temperature maps with high spatiotemporal resolution (1.5 × 1.5 × 2.0 mm, 1.7 s). RESULTS: In the simulations, 50% errors in k and Q resulted in maximum temperature root mean square errors (RMSE) of 6 °C for model only and 3 °C for MPF. Using recently developed methods, estimates of k and Q were accurate to within 3%. The RMSE between MPF and true temperature increased with R and T˙. In the ex vivo study the RMSE remained below 0.7 °C for R ranging from 4 to 12 and T˙ of 0.28-0.75 °C/s. CONCLUSION: Errors in MPF temperatures occur due to errors in k and Q. These MPF temperature errors increase with increase in R and T˙, but are smaller than those obtained using the thermal model alone.

Evaluation of 2D multiband EPI imaging for high-resolution, whole-brain, task-based fMRI studies at 3T: Sensitivity and slice leakage artifacts.

Functional magnetic resonance imaging (fMRI) studies that require high-resolution whole-brain coverage have long scan times that are primarily driven by the large number of thin slices acquired. Two-dimensional multiband echo-planar imaging (EPI) sequences accelerate the data acquisition along the slice direction and therefore represent an attractive approach to such studies by improving the temporal resolution without sacrificing spatial resolution. In this work, a 2D multiband EPI sequence was optimized for 1.5mm isotropic whole-brain acquisitions at 3T with 10 healthy volunteers imaged while performing simultaneous visual and motor tasks. The performance of the sequence was evaluated in terms of BOLD sensitivity and false-positive activation at multiband (MB) factors of 1, 2, 4, and 6, combined with in-plane GRAPPA acceleration of 2× (GRAPPA 2), and the two reconstruction approaches of Slice-GRAPPA and Split Slice-GRAPPA. Sensitivity results demonstrate significant gains in temporal signal-to-noise ratio (tSNR) and t-score statistics for MB 2, 4, and 6 compared to MB 1. The MB factor for optimal sensitivity varied depending on anatomical location and reconstruction method. When using Slice-GRAPPA reconstruction, evidence of false-positive activation due to signal leakage between simultaneously excited slices was seen in one instance, 35 instances, and 70 instances over the ten volunteers for the respective accelerations of MB 2×GRAPPA 2, MB 4×GRAPPA 2, and MB 6×GRAPPA 2. The use of Split Slice-GRAPPA reconstruction suppressed the prevalence of false positives significantly, to 1 instance, 5 instances, and 5 instances for the same respective acceleration factors. Imaging protocols using an acceleration factor of MB 2×GRAPPA 2 can be confidently used for high-resolution whole-brain imaging to improve BOLD sensitivity with very low probability for false-positive activation due to slice leakage. Imaging protocols using higher acceleration factors (MB 3 or MB 4×GRAPPA 2) can likely provide even greater gains in sensitivity but should be carefully optimized to minimize the possibility of false activations.

Evaluation of a three-dimensional MR acoustic radiation force imaging pulse sequence using a novel unbalanced bipolar motion encoding gradient.

PURPOSE: MR guided focused ultrasound procedures require accurate focal spot localization in three dimensions. This study presents a three-dimensional (3D) pulse sequence for acoustic radiation force imaging (ARFI) that efficiently localizes the focal spot by means of ultrasound induced tissue displacement over a large field-of-view. METHODS: A novel unbalanced bipolar motion encoding gradient was implemented to maximize time available for motion encoding, reduce echo times, and allow for longer echo train lengths. Two advanced features, kz reduction factor (KZRF) and kz -level interleaving, were implemented to reduce tissue heating. Studies in gelatin phantoms compared the location of peak displacement and temperature measured by 3D MR thermometry. MR-ARFI induced tissue heating was evaluated through a parametric study of sequence parameters and MR thermometry measurements during repeated application of ARFI sonication patterns. Sequence performance was characterized in the presence of respiration and tissue inhomogeneity. RESULTS: The location of peak displacement and temperature rise agreed within 0.2 ± 0.1 mm and 0.5 ± 0.3 mm in the transverse and longitudinal direction, respectively. The 3D displacement maps were acquired safely, and the KZRF and kz -level interleaving features reduced tissue heating by 51%. High quality displacement maps were obtained despite respiration and tissue inhomogeneities. CONCLUSION: This sequence provides a safe, accurate, and simple approach to localizing the focal spot in three dimensions with a single scan. Magn Reson Med 76:803-813, 2016. © 2015 Wiley Periodicals, Inc.

Prior image based temporally constrained reconstruction algorithm for magnetic resonance guided high intensity focused ultrasound.

PURPOSE: A prior image based temporally constrained reconstruction (PITCR) algorithm was developed for obtaining accurate temperature maps having better volume coverage, and spatial, and temporal resolution than other algorithms for highly undersampled data in magnetic resonance (MR) thermometry. METHODS: The proposed PITCR approach is an algorithm that gives weight to the prior image and performs accurate reconstruction in a dynamic imaging environment. The PITCR method is compared with the temporally constrained reconstruction (TCR) algorithm using pork muscle data. RESULTS: The PITCR method provides superior performance compared to the TCR approach with highly undersampled data. The proposed approach is computationally expensive compared to the TCR approach, but this could be overcome by the advantage of reconstructing with fewer measurements. In the case of reconstruction of temperature maps from 16% of fully sampled data, the PITCR approach was 1.57× slower compared to the TCR approach, while the root mean square error using PITCR is 0.784 compared to 2.815 with the TCR scheme. CONCLUSIONS: The PITCR approach is able to perform more accurate reconstructions of temperature maps compared to the TCR approach with highly undersampled data in MR guided high intensity focused ultrasound.

An evaluation of prospective motion correction (PMC) for high resolution quantitative MRI.

Quantitative imaging aims to provide in vivo neuroimaging biomarkers with high research and diagnostic value that are sensitive to underlying tissue microstructure. In order to use these data to examine intra-cortical differences or to define boundaries between different myelo-architectural areas, high resolution data are required. The quality of such measurements is degraded in the presence of motion hindering insight into brain microstructure. Correction schemes are therefore vital for high resolution, whole brain coverage approaches that have long acquisition times and greater sensitivity to motion. Here we evaluate the use of prospective motion correction (PMC) via an optical tracking system to counter intra-scan motion in a high resolution (800 µm isotropic) multi-parameter mapping (MPM) protocol. Data were acquired on six volunteers using a 2 × 2 factorial design permuting the following conditions: PMC on/off and motion/no motion. In the presence of head motion, PMC-based motion correction considerably improved the quality of the maps as reflected by fewer visible artifacts and improved consistency. The precision of the maps, parameterized through the coefficient of variation in cortical sub-regions, showed improvements of 11-25% in the presence of deliberate head motion. Importantly, in the absence of motion the PMC system did not introduce extraneous artifacts into the quantitative maps. The PMC system based on optical tracking offers a robust approach to minimizing motion artifacts in quantitative anatomical imaging without extending scan times. Such a robust motion correction scheme is crucial in order to achieve the ultra-high resolution required of quantitative imaging for cutting edge in vivo histology applications.

Prospective motion correction of 3D echo-planar imaging data for functional MRI using optical tracking.

We evaluated the performance of an optical camera based prospective motion correction (PMC) system in improving the quality of 3D echo-planar imaging functional MRI data. An optical camera and external marker were used to dynamically track the head movement of subjects during fMRI scanning. PMC was performed by using the motion information to dynamically update the sequence's RF excitation and gradient waveforms such that the field-of-view was realigned to match the subject's head movement. Task-free fMRI experiments on five healthy volunteers followed a 2 × 2 × 3 factorial design with the following factors: PMC on or off; 3.0mm or 1.5mm isotropic resolution; and no, slow, or fast head movements. Visual and motor fMRI experiments were additionally performed on one of the volunteers at 1.5mm resolution comparing PMC on vs PMC off for no and slow head movements. Metrics were developed to quantify the amount of motion as it occurred relative to k-space data acquisition. The motion quantification metric collapsed the very rich camera tracking data into one scalar value for each image volume that was strongly predictive of motion-induced artifacts. The PMC system did not introduce extraneous artifacts for the no motion conditions and improved the time series temporal signal-to-noise by 30% to 40% for all combinations of low/high resolution and slow/fast head movement relative to the standard acquisition with no prospective correction. The numbers of activated voxels (p<0.001, uncorrected) in both task-based experiments were comparable for the no motion cases and increased by 78% and 330%, respectively, for PMC on versus PMC off in the slow motion cases. The PMC system is a robust solution to decrease the motion sensitivity of multi-shot 3D EPI sequences and thereby overcome one of the main roadblocks to their widespread use in fMRI studies.