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. 2021 Jun 13;34(6):667–675. doi: 10.1177/19714009211021781

Edge-enhancing gradient echo with multi-image co-registration and averaging (EDGE-MICRA) for targeting thalamic centromedian and parafascicular nuclei

Erik H Middlebrooks 1,2,*,✉, Lela Okromelidze 1,*, Chen Lin 1, Ayushi Jain 1, Erin Westerhold 1, Anthony Ritaccio 3, Alfredo Quiñones-Hinojosa 2, Vivek Gupta 1, Sanjeet S Grewal 2
PMCID: PMC8649196  PMID: 34121497

Abstract

Background and purpose

Deep brain stimulation of the thalamus is an effective treatment for multiple neurological disorders. The centromedian and parafascicular nuclei are recently emerging targets for multiple conditions, such as epilepsy and Tourette syndrome; however, their limited visibility on conventional magnetic resonance imaging sequences has been a major obstacle. The goal of this study was to demonstrate the feasibility of a high-resolution and high-contrast targeting sequence for centromedian-parafascicular deep brain stimulation using a recently described magnetic resonance imaging sequence, three-dimensional edge-enhancing gradient echo.

Methods

The three-dimensional edge-enhancing gradient echo sequence was performed on a normal volunteer for a total of six acquisitions. Multi-image co-registration and averaging was performed by first co-registering each of the six scans and then averaging to produce an edge-enhancing gradient echo-multi-image co-registration and averaging scan. The averaging was also performed for two, three, four and five scans to assess the change in the signal-to-noise ratio and identify the ideal balance of image quality and scan time.

Results

The edge-enhancing gradient echo-multi-image co-registration and averaging scan allowed clear boundary delineation of the centromedian and parafascicular nuclei. The signal-to-noise ratio increased as a function of increasing scan number, but the added gain was small beyond four scans for the imaging parameters used in this study.

Conclusions

The recently described three-dimensional edge-enhancing gradient echo sequence provides an easily implementable approach, using widely available magnetic resonance imaging technology without complex post-processing techniques, to delineate centromedian and parafascicular nuclei for deep brain stimulation targeting.

Keywords: Epilepsy, deep brain stimulation, centromedian nucleus, parafascicular nucleus

Introduction

Over the past several decades, there has been an increasing application of neuromodulation to treat various neurological disorders. Recently, there has been increasing interest in the centromedian and parafascicular nuclei complex of the thalamus in numerous conditions, such as Parkinson disease,1,2 epilepsy,3–8 Tourette syndrome,9–13 pain,14–16 and others.

According to the the International Tourette Deep Brain Stimulation Registry and Database, the centromedian/parafascicular region has been reported to be the most commonly targeted brain area for Tourette syndrome worldwide. 9 Retrospective studies of centromedian/parafascicular deep brain stimulation (DBS) have demonstrated beneficial effects on tic frequency and severity which were confirmed by prospective, double-blind randomised trials.10–13 For epilepsy, DBS of the anterior nucleus of the thalamus (ANT) was recently approved by the US Food and Drug Administration for treating refractory epilepsy.17,18 However, patients with temporal onset have better outcomes17,18 from ANT DBS when compared to those with networks that do not involve the limbic circuit, leading to increased interest in other thalamic targets, such as the centromedian nucleus and parafascicular nucleus.19,20 In particular, the centromedian nucleus has been shown as an efficacious target for extra-limbic epilepsy, specifically generalised and frontal epilepsy syndromes. 3

One major barrier to successful surgical therapy has been the limited visibility of these targets on conventional magnetic resonance imaging (MRI) sequences leading to an overreliance on indirect targeting methods with a general consensus that centromedian/parafascicular nuclei are not able to be visualised on conventional MRI. 21 Unfortunately, variations in normal anatomy and acquired shape changes due to atrophy in the setting of epilepsy produce wide variability in the accuracy of such fixed coordinate-based targets, potentially resulting in off-target implants.22,23 Therefore, direct targeting methods with higher accuracy of delineation of intrathalamic nuclei are necessary. The magnetisation-prepared rapid gradient echo (MPRAGE) imaging that applies two inversion times (MP2RAGE) sequence has been proposed as a potential method for centromedian nucleus visualisation, but complex post-processing and edge enhancement was necessary to improve visualisation of the centromedian nucleus. 24

In this proof of concept study, we explore the utility of a recently described three-dimensional (3D) sequence, edge-enhancing gradient echo (3D-EDGE), as an easily implementable method for reliable visualisation and targeting of the centromedian/parafascicular nuclei. 25 3D-EDGE has unique contrast properties that exploit subtle differences in T1 relaxation of myelinated and non-myelinated tissues, making it a potentially valuable approach for detecting histological differences within the thalamic nuclei that are not well detected by existing imaging methods. 25 Improved delineation of targets within the thalamus serves to provide an accurate, patient-specific direct surgical target and may ultimately lead to improved outcomes after DBS.

Methods

Image acquisition

The study was approved by the Mayo Clinic Institutional Review Board. The 3D-EDGE sequence was performed on a normal volunteer using a 3 Tesla Siemens Prisma (Siemens Healthineers AG, Erlangen, Germany) with a 64-channel phased-array head and neck coil. The 3D-EDGE utilised a MPRAGE sequence acquired in the sagittal plane with a non-selective inversion pulse with inversion times (TIs) of 442 ms, flip angle of 8°, TR of 2 s, TE of 2.66 ms, isotropic resolution of 1 × 1 × 1 mm, receiver bandwidth of 270 Hz/Px, echo spacing of 6.4 ms, turbo factor of 154, acceleration factor of GRAPPA of 2 and slice partial Fourier of 7/8. The resultant acquisition time was 4.32 minutes. The scan was repeated a total of six times. For image normalisation, a standard MPRAGE and fast grey matter acquisition and T1 inversion recovery (FGATIR) were also acquired, as previously described. 26

Image processing

The six 3D-EDGE acquisitions were co-registered using a linear registration algorithm in Statistical Parametric Mapping v. 12 (https://www.fil.ion.ucl.ac.uk/spm/) with a normalised mutual information objective function and fourth degree B-spline interpolation. The co-registered images were then averaged to generate 3D-EDGE multi-image co-registration and averaging (EDGE-MICRA) images. To assess the effect of incremental image acquisitions, the averaging was performed with two, three, four, five and six total scans.

Image quality

SNR of a single acquisition was compared to each EDGE-MICRA average image (average of two to six scans). SNR was calculated as the mean signal intensity of a region of interest encompassing the thalami divided by the standard deviation of the background signal outside of the head. The plot of SNR versus the number of averages was fit to a polynomial curve in Prism v. 8.1.1 (GraphPad Software, San Diego, CA, USA). The theoretical SNR gain with complex averaging in k-space was also plotted as a reference and calculated as the baseline SNR of a single acquisition multiplied by the square root of the number of acquisitions that were averaged.

Atlas registration

The EDGE-MICRA with six total averaged images was linearly co-registered to the MPRAGE using statistical parametric mapping. The MPRAGE was then normalised to the Montreal Neurological Institute (MNI) template space using the SyN registration approach in advanced normalisation tools (http://stnava.github.io/ANTs/), 27 and the resulting transformation was applied to the EDGE-MICRA. The normalised EDGE-MICRA was resampled to 0.5 × 0.5 × 0.5 mm resolution. An overlay of the Schaltenbrand and Wahren atlas was applied, as derived from the Neuroimaging and Surgical Technologies Lab (http://nist.mni.mcgill.ca) multicontrast PD25 atlas.28–30

Results

The EDGE-MICRA contrast allowed clear boundary delineation of several relevant thalamic nuclei, including the centromedian and parafascicular nuclei. Axial and coronal videos are shown in Supplementary videos 1 and 2, respectively. Representative images with Schaltenbrand and Wahren atlas overlay are shown in Figure 1. The centromedian nucleus is identified as an area of higher signal intensity compared to its border with the more hypointense mediodorsal nucleus and lateral ventral thalamic nuclei (Figure 1(a) and (d), Figure 2(a) and (d)). On standard MPRAGE (Figure 1(b) and (e), Figure 2(b) and (e)) and FGATIR (Figure 1(c) and (f), Figure 2(c) and (f)), the centromedian nucleus boundaries are not readily discernable. The parafascicular nucleus is located medial and inferior to the centromedian nucleus – inferior to the mediodorsal nucleus – and can be well visualised as a more hypointense structure compared to the more hyperintense lateral boundary (Figure 3(a) and (d)). The boundaries of the parafascicular nucleus are not well delineated on MPRAGE (Figure 3(b) and (e)) or FGATIR (Figure 3(c) and (f)).

Figure 1.

Figure 1.

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Axial (a) EDGE-MICRA, (b) MPRAGE and (c) FGATIR images at MNI z = 3. Axial (a) EDGE-MICRA image with the centromedian nucleus (CM) outlined from the Schaltenbrand and Wahren atlas. The CM can be visualised as a hyperintense ovoid nucleus lying medial and inferior to the more hypointense mediodorsal nucleus (M), anterior to the more hypointense medial pulvinar (PuM) and medial to the ventral intermediate nucleus (Vim). (e) Axial MPRAGE and (f) FGATIR at the same level shows poor definition of the internal thalamic structure and CM (outline). EDGE-MICRA: three-dimensional edge-enhancing gradient echo multi-image co-registration and averaging; FGATIR: fast grey matter acquisition and T1 inversion recovery; MNI: Montreal Neurological Institute; MPRAGE: magnetisation-prepared rapid gradient echo.

Figure 2.

Figure 2.

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Coronal (a) EDGE-MICRA, (b) MPRAGE and (c) FGATIR images at MNI y = −20. Coronal (a) EDGE-MICRA image with the centromedian nucleus (CM) outlined from the Schaltenbrand and Wahren atlas. The CM can be visualised as a hyperintense ovoid nucleus lying medial and inferior to the more hypointense mediodorsal nucleus (M) and medial to the parafascicular nucleus (Pf). The lamella medialis (LaM) is also well visualised separating the mediodorsal nucleus from the pulvinar oromedialis (Puom). (e) Coronal MPRAGE and (f) FGATIR at the same level shows poor definition of the internal thalamic structure and CM (outline). EDGE-MICRA: three-dimensional edge-enhancing gradient echo multi-image co-registration and averaging; FGATIR: fast grey matter acquisition and T1 inversion recovery; MNI: Montreal Neurological Institute; MPRAGE: magnetisation-prepared rapid gradient echo.

Figure 3.

Figure 3.

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Axial (a) EDGE-MICRA, (b) FGATIR and (c) MPRAGE images at MNI z = 0. (d) Axial EDGE-MICRA illustrating the hypointense parafascicular (Pf) thalamic nucleus (outline from the Schaltenbrand and Wahren atlas). Axial (e) FGATIR and (f) MPRAGE show poor definition of the boundaries of Pf (outline). EDGE-MICRA: three-dimensional edge-enhancing gradient echo multi-image co-registration and averaging; FGATIR: fast grey matter acquisition and T1 inversion recovery; MNI: Montreal Neurological Institute; MPRAGE: magnetisation-prepared rapid gradient echo.

A comparison of differing numbers of averaged images was performed to determine the ideal balance of scan time and satisfactory image quality. As expected, there was an increase in SNR with increasing numbers of acquisitions (SNR(n) = –1.4n2 + 15.7n + 19.9; r2 = 0.998, where n is the number of averages); however, the gain began to plateau after four acquisitions (Figure 4). Most landmarks were apparent at an average of two scans, but with reduced noise and slightly increased visual contrast with higher scan numbers. Visual inspection suggested three averaged acquisitions as an ideal balance between imaging time, SNR and contrast for the utilised scan parameters.

Figure 4.

Figure 4.

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(Top) Relationship of measured signal-to-noise ratio (SNR; r² = 0.998) and theoretical SNR with increasing number of averaged scans from complex averaging in k-space. (Bottom) Representative images for increasing number of scan averages from a single acquisition (n = 1) to six averaged scans (n = 6).

Discussion

In this study, we describe a novel application of a recently proposed MRI sequence, 3D-EDGE, to delineate the centromedian and parafascicular nuclei for purposes of direct surgical targeting. The unique contrast properties of 3D-EDGE provide a new approach for detecting histological differences in some thalamic nuclei. As the sequence can be obtained using routine magnetic field strengths and base pulse sequences, it is a promising new highly practical approach to DBS targeting within the thalamus.

Middlebrooks et al. recently described the 3D-EDGE sequence for the improved detection of focal cortical dysplasia in epilepsy. 25 The unique contrast of this sequence, however, may have additional applications. The concept of 3D-EDGE is based on the normal variation in longitudinal (T1) relaxation of grey matter and white matter. By selecting an inversion time that is optimised to produce a similar signal intensity in grey matter and white matter, but with opposing polarity, voxels having a variable degree of myelinated and non-myelinated tissue will show different degrees of signal cancelation. The result is effectively a ‘myelin-weighted image’, in which voxels containing a relatively similar volume of myelinated and unmyelinated tissue will show greater signal cancellation. These properties can be exploited to detect subtle variations in myelin content of thalamic nuclei.

While 3D-EDGE is a high contrast sequence, it does suffer from inherently lower SNR compared with conventional MPRAGE. To compensate for the decreased SNR, while maintaining high spatial resolution, a long acquisition time with multiple averages is needed. To achieve satisfactory SNR, we took the approach of averaging multiple acquisitions (MICRA) in the imaging space, rather than increasing the acquisition number in k-space.31,32 While averaging in k-space is a valid alternative approach, the SNR gain with MICRA is close to the theoretical SNR gain with complex averaging in k-space, as shown in Figure 5. As such, we preferred the MICRA approach due to several key advantages. First, by acquiring relatively short individual scans at the penalty of reduced SNR, the effect of motion is minimised compared to a single, long acquisition. The scan is not only less susceptible to motion when shorter, but patient motion during a short scan can also be rectified by excluding problematic individual scans or repeating scans. The MICRA approach also gives greater flexibility more easily to achieve the desired SNR across a variety of platforms, such as lower field strength scanners. Likewise, when high acceleration factors are unachievable (e.g. use of single-channel transmit/receive coil), MICRA can allow the achievement of high spatial resolution and satisfactory SNR without excessively long individual scans that are subject to greater patient motion. Finally, MICRA can be applied irrespective of acceleration techniques used, making it universally applicable to changes in imaging technology.

Figure 5.

Figure 5.

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(a) Sagittal EDGE-MICRA images illustrating the hypointense anterior thalamic nucleus (ANT) that lies superior to the termination of the mammillothalamic tract (MMT). (b) Coronal EDGE-MICRA image again showing the ANT as a hypointense structure medial to the more hyperintense internal medullary lamina and MMT. Sagittal (c) and coronal (d) FGATIR images are shown for comparison. EDGE-MICRA: three-dimensional edge-enhancing gradient echo multi-image co-registration and averaging; FGATIR: fast grey matter acquisition and T1 inversion recovery.

DBS of the centromedian and parafascicular nuclei have gained increasing attention in the treatment of many disorders, including Tourette’s syndrome, neuropathic pain and epilepsy, particularly Lennox–Gastaut syndrome. 20 Unfortunately, the results of clinical trials of centromedian/parafascicular DBS have been mixed, which is likely in part due to variation in targeting.3,4,8,33,34 The centromedian nucleus is a spherical structure measuring approximately 1 cm and makes up part of the posterior intralaminar thalamus. The parafascicular nucleus is located medial and inferior to the centromedian nucleus, inferior to the mediodorsal nucleus. 20 To date, few studies have addressed visualisation of the centromedian and parafascicular nuclei. The ability to delineate these structures has largely been elusive with standard structural MRI techniques. Warren et al. recently proposed the use of MPRAGE imaging that applies two inversion times (MP2RAGE) to identify the centromedian and parafascicular complex. 24 Since the contrast of these structures is still minimal on MP2RAGE, additional post-processing was required (application of Sobel edge detection) to achieve adequate boundary visualisation. 24 Li et al. also recently proposed the use of quantitative susceptibility mapping to identify the centromedian nucleus. 35 While promising, the lack of a 3D isotropic acquisition limits the applicability to surgical planning, as well as the requirement of complex post-processing techniques. Due to the lack of the widespread availability of MP2RAGE and quantitative susceptibility mapping, as well as the need for complex post-processing, EDGE-MICRA offers a more easily implementable approach to visualise the centromedian and parafascicular complex using widely available methods.

Finally, the focus of the current study was limited to centromedian/parafascicular targeting; however, EDGE-MICRA holds promise for multiple other applications in DBS. DBS of the anterior nucleus of the thalamus (ANT) is the most recently approved DBS indication by the US Food and Drug Administration. The ANT is located in the anterior dorsal thalamus along the medial border with a Y-shaped internal medullary lamina separating it from the adjacent nuclei.36,37 Grewal et al. have previously shown that the location of ANT at the termination of the mammillothalamic tract, as well as the adjacent lamina, can be exploited to visualise ANT by using white matter suppression in the FGATIR sequence. 26 The FGATIR sequence is a fast and easily implementable sequence with superb visualisation of ANT; however, other key nuclei, such as the centromedian and parafascicular, are not well resolved. EDGE-MICRA allows similar to improved visualisation of the mammillothalamic tract and ANT (Figure 5), but with the added advantage of simultaneously visualising other emerging thalamic targets. In addition, the globus pallidus internus, a common target in disorders such as Parkinson’s disease, dystonia and Tourette’s syndrome, is exquisitely delineated by this technique (Figure 6(a)). The lateral boundary with the globus pallidus externus is clearly defined by the medial medullary lamina. In addition, an accessory medullary lamina within the globus pallidus internus can be easily visualised and has not been previously reported with conventional clinical imaging. Thalamic targets for the treatment of tremor, namely the ventral intermedius nucleus, are also well visualised by a hypointense band (Figure 6(b)) that presumably reflects increased myelin content from the traversing dentato–rubro–thalamic tract.

Figure 6.

Figure 6.

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(a) Axial EDGE-MICRA image showing the globus pallidus externus (GPe) and globus pallidus internus (GPi) separated by the medial medullary lamina (MML). The GPi also contains an accessory medullary lamina (aML). (b) Sagittal EDGE-MICRA images showing the location of the ventral intermedius nucleus (VIM) that can be visualised by an area of slight hypointensity that is presumably related to increased myelin content from the traversing dentate–rubro–thalamic tract. EDGE-MICRA: three-dimensional edge-enhancing gradient echo multi-image co-registration and averaging.

Several limitations are noteworthy. First, the base MPRAGE sequence used for EDGE-MICRA is more widely available than other reported techniques, such as MP2RAGE, application 3D-EDGE contrast has not yet been reported using other variations of 3D inversion-recovery gradient echo schemes, and further validation is needed to determine if it can be reproduced on similar base sequences. Second, although the scan time for EDGE-MICRA is clinically feasible, with acquisition times similar to slightly longer than some MP2RAGE protocols, scan times between 13 and 18 minutes may be required to get the desired SNR. Newly described techniques for image acceleration, such as WaveCAIPI 38 and compressed sensing (CS), 39 have the potential dramatically to reduce imaging times of EDGE-MICRA with minimal SNR penalty. It is worth noting that the EDGE-MICRA technique may be more valuable in situations in which imaging acceleration is not possible (e.g. single-channel transmit/receive coil) and would create excessively long single scan times with MP2RAGE that are susceptible to patient motion.

Conclusion

We have described a novel application of the recently described 3D-EDGE sequence, EDGE-MICRA, as a promising method for direct targeting in DBS. EDGE-MICRA can be easily adapted to widely available scan equipment and a common base sequence (MPRAGE). Further studies are needed to assess the added benefit in targeting accuracy and outcomes with the use of direct targeting using EDGE-MICRA.

Supplementary Material

Supplemental Video 1
Download video file (61.5MB, mov)
Supplemental Video 2
Download video file (57.7MB, mov)

Conflict of interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: EHM receives unrelated research support from Boston Scientific Corp. and Varian Medical Systems, Inc. The remaining author(s) have no conflicts of interest to declare.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: EHM receives unrelated research support from Boston Scientific Corp. and Varian Medical Systems, Inc., as well as unrelated consultant to Boston Scientific Corp. SSG is a consultant for Medtronic, Inc. and Boston Scientific Corp.

Supplemental material: Supplemental material for this article is available online.

ORCID iD

Lela Okromelidze https://orcid.org/0000-0002-1296-0522

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