Advanced MRI techniques for transcranial high intensity focused ultrasound targeting

Abstract

Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson’s disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T₁ inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.

deep brain stimulation, dentatorubrothalamic tract, globus pallidus, MRgHIFU, ventral intermediate nucleus

Introduction

From 1980 to 2000 several case reports were published that described the abatement of tremor in patients with essential tremor following stroke (Duncan et al., 1988; Dupuis et al., 1989; Im et al., 1996; Barbaud et al., 2001; Constantino and Louis, 2003; Le Pira et al., 2004; Kim et al., 2006). Neuroscientists studying these cases worked to elucidate the circuit biology underlying movement disorders. Concurrently, neuro-anatomists were working on a new parcellation of the human thalamus based on advances in histochemical staining (Hirai and Jones, 1989). While the function and interconnectivity of the human thalamus remained ambiguous, the input-output connections of thalamic nuclei of the non-human primate had been well characterized (Hirai and Jones, 1989). In an effort to harmonize human thalamic anatomy with function, neuroanatomists attempted to redefine thalamic nomenclature based on that of the non-human primate (Hirai and Jones, 1989).

Classification of the thalamic nuclei in humans has undergone numerous iterations. While this iterative growth has been an attempt to reclassify nuclei based on both anatomy and function, it has led to a considerable challenge in realizing a unified thalamic nomenclature. Despite these limitations and an incomplete understanding of the connectivity of the thalamus, thalamotomy was performed as early as the 1950s (Miocinovic et al., 2013). As a result, patients who underwent bilateral thalamotomy frequently developed speech and swallowing deficits as well as sensory abnormalities. These adverse effects likely resulted from inadvertent injury to adjacent thalamic nuclei, interconnecting structures, and white matter bundles. The risks associated with bilateral thalamotomy led most surgeons to perform unilateral surgeries. Although unilateral thalamotomy aimed to reduce adverse effects, patients still experienced a debilitating postoperative course. To address the shortcomings of conventional thalamotomy, deep brain stimulation (DBS) was FDA approved in 1997 (Gardner, 2013).

The development of CT and MRI have improved preoperative targeting. However, the inability to identify specific targets by conventional MRI remains a significant limitation. This limitation is best exemplified by the failure to visualize the ventral intermediate (VIM) nucleus of the thalamus using traditional neuroimaging techniques. Stimulation of the incorrect target can lead to patient discomfort, gait abnormalities, weakness, and sensory alterations (Gardner, 2013). Although microelectrode recording can be performed intraoperatively, accurate spatial localization remains a significant technical challenge, and the use of microelectrode recording substantially increases the cost and time required for DBS lead implantation. As a result, both conventional thalamotomy and DBS often still result in unintended postoperative complications.

Magnetic resonance guided high intensity focused ultrasound (MRgHIFU) is a non-invasive, image-guided therapy that can ablate tissue with millimetre precision. However, the efficacy of this procedure remains limited by subjective targeting methods. This manuscript aims to describe the limitations of these methods and to demonstrate the role of emerging advanced imaging targeting methods.

Tremor

Tremor imposes a significant limitation on basic activities of daily living and reduces the quality of life. Essential tremor and tremor-predominant Parkinson’s disease are the most common movement disorders and are increasing in prevalence. The first-line treatment of tremor is medication, yet ∼30% of patients with essential tremor and Parkinson’s disease discontinue their medication or have a tremor that is refractory to medication (Louis et al., 2010). Medication-resistant tremor has typically been treated with thalamotomy or DBS of the VIM in essential tremor (Anderson et al., 2017).

Pertinent thalamic anatomy and histopathology

As first described by Hassler, the VIM is an approximately 4 mm × 4 mm × 6 mm thalamic nucleus (Dormont et al., 1997). The VIM primarily sends and receives projections to and from the motor cortex and the cerebellum (Dormont et al., 1997). This relay network serves an obligatory role in the generation of electrical impulses that control movement. The widely used Schaltenbrand-Wahren and Talairach-Tournoux stereotactic atlases are based on Hassler’s classification scheme (Niemann et al., 1994; Nowinski, 1998). Significant limitations of Hassler’s classification system are that it is based on a small number of subjects and Nissl staining alone (Niemann et al., 1994; Nowinski, 1998). Nissl-stained sections of the human thalamus led Hassler to believe that transition zones between the different nuclei of the lateral thalamus were additional thalamic nuclei.

Given the differences between the human thalamus and that of the non-human primate, Hirai and Jones (1989) proposed a new parcellation of the human thalamus based on histochemical techniques. This new method overcame the limitations of Hassler’s classification by incorporating acetylcholinesterase staining. They demonstrated that, while the human thalamus was much larger, it was organized similar to the non-human primate. The human thalamus has only three ventrolateral thalamic nuclei: the ventrolateral anterior nucleus (VLa), ventrolateral posterior nucleus (VLp), and ventroposterolateral nucleus (VPL) (Hirai and Jones, 1989).

The VLa and VPL serve as thalamic relays for the globus pallidus and the medial lemniscus, respectively, and project without overlap to the premotor and somatosensory cortices, respectively. The ventral portion of the VLp represents what Hassler had first described as the VIM and is the thalamic relay for the dentate nucleus that projects to the motor cortex. The ventral VLp receives excitatory glutamatergic afferents from the deep cerebellar nuclei and from the cerebral cortex, but inhibitory GABAergic inputs from the reticular nucleus of the thalamus. The ventral portion of the VLp demonstrates a strictly somatotopic organization: face (medial), followed by hand, followed by the leg (lateral).

An understanding of this microstructural organization is relevant to both DBS and MRgHIFU. For example, inferolateral lesioning of the VLp during MRgHIFU is often associated with gait disturbances (Reich et al., 2016; Boutet et al., 2018). As such, some institutions advocate creating more dorsal HIFU lesions ∼1–2 mm superior to the AC-PC plane to avoid ataxia although data supporting this practice are limited. Historically, the negative functional consequences of bilateral surgical thalamotomy were largely attributed to unrefined surgical techniques, imprecise targeting, and human variability. The ability to ablate tissue with millimetre precision coupled with significant advancements in MRI technology and our understanding of thalamic anatomy could allow for more precise lesioning of the intended targets and thereby substantially reduce adverse effects.

MRgHIFU precision thalamotomy

MRgHIFU is a non-invasive, image-guided procedure that is able to ablate tissue with millimetre precision while preserving the surrounding tissue integrity and function. The deposition of ultrasound energy to ablate tissue has a long history. In 1950, Lars Leksell created a focused-ultrasound stereotactic frame and attempted to treat psychiatric disease. Early attempts at using focused ultrasound to treat intracranial disease suffered two significant limitations: (i) a craniotomy was required to deliver sufficient ultrasound energy; and (ii) the lack of real-time imaging to identify targets and monitor energy deposition exposed the patient to a high risk of adverse effects. Since then, there have been significant technical advances in the field of therapeutic ultrasound. The most significant advancement in focused-ultrasound technology is the development of phased-array ultrasound transducers. Phased-array ultrasound systems have numerous elements that can each be pulsed at varying time intervals. The resultant summation of these interference patterns can be combined by the operator to steer and shape the intensity of the focused ultrasound beam effectively. This has made it possible to overcome the intact skull as a barrier to transmitting intracranial focused ultrasound. To correct additional distortions from variable skull thickness, bone thickness measurements and skull composition are determined using CT of the head. These measurements are then used to calculate appropriate phase corrections and the CT scan is registered to the magnetic resonance images during treatment (Hynynen and Jolesz, 1998; Sun and Hynynen, 1998; Tanter et al., 1998).

An advantage of focused ultrasound thalamotomy is the ability to overcome human anatomic variability by refining target selection prior to tissue ablation. After the initial target selection, subablative thermal energy is deposited in the expected location of the VIM. During the biofeedback stage of the treatment, the patient is monitored for neurological changes. Subablative thermal neuromodulation results in tremor suppression when the VIM is accurately targeted. However, off-target sonication can result in somatosensory thalamus neuromodulation and will elicit transient sensory changes and paraesthesia in the contralateral fingers, hand, lips, and tongue. Once the location of the VIM has been refined with biofeedback, thermal ablation can proceed. Despite the ability to perform a precision medicine thalamotomy, the most common transient adverse effects after MRgHIFU are lip and hand paraesthesia and gait abnormalities such as ataxia (Elias et al., 2016). Occasionally, paraesthesia and gait abnormalities may persist at 12 months (Elias et al., 2016). While transient side effects likely represent inadvertent neuromodulation of surrounding structures, permanent deficits or adverse effects probably reflect thermal injury to surrounding structures. To avoid the permanent adverse effects associated with conventional bilateral thalamotomy, current MRgHIFU guidelines advocate unilateral procedures. However, clinical trials are already underway to establish the safety and efficacy of bilateral MRgHIFU. Bilateral therapy will require improved targeting methods to limit adverse effects. While there have been significant advances in focused ultrasound technology and imaging techniques, established targeting methods remain mostly unchanged and vary between clinical sites.

Established targeting methods

Established targeting methods can broadly be classified as indirect or direct (Yamada et al., 2010). Indirect targeting methods attempt to register a stereotactic brain atlas to the patient’s brain MRI. Accurate co-registration is critical to targeting accuracy (Nowinski, 1998, 2008; Yamada et al., 2010). Although various registration and warping techniques have been developed, poor registration can introduce errors up to 5 mm (Nowinski, 1998; Yamada et al., 2010). Errors of this magnitude can be associated with unacceptable adverse effects (Nowinski, 1998). Direct targeting methods attempt to either visualize the target on the patient’s MRI or use anatomic landmarks to generate image-based coordinates for the target. An example of one of the earliest methods of direct targeting is Guiot’s parallelogram (Guiot et al., 1968). Guiot’s parallelogram was a technique used in conjunction with air ventriculography to predict the location of the VIM based on specific anatomical landmarks (Dormont et al., 2004). Guiot’s method has subsequently evolved to include applying approximate predetermined distances to anatomical landmarks identified on the patient’s MRIs. Although this technique is expeditious, the methods of selecting landmarks and the distances used often vary. Additionally, adjustments are usually made for differing morphologies or sizes of anatomic landmarks. For example, if the third ventricle is enlarged, then the distance used to measure from the lateral wall of the third ventricle is subjectively decreased by the physician.

Limitations of established targeting methods

Conventional targeting methods suffer from inaccuracies based on human anatomic variation, subjectivity, and experience of the physician. Inaccuracies may also occur because of underlying pathological derangement of the thalamus and surrounding structures. Direct targeting methods also regard the VIM as a point in space, whereas in actuality, the VIM is a complex region of interest with a highly organized somatotopic microstructure. Indirect targeting methods are even more limited because they identify stereotactic coordinates based on human brain atlases. These atlases are two-dimensional, created from a limited number of samples, and are inherently prone to tissue processing distortions (Nowinski, 2008; Calabrese, 2016). Additionally, these atlases use an outdated thalamic nomenclature and have no method for identifying connecting white matter tracts (Calabrese, 2016). As such, there is ample evidence that current methods for targeting have been incompletely validated (Nowinski, 1998; Calabrese, 2016). In light of these considerations, there is a significant interest in using advanced MRI techniques for targeting.

Advanced MRI techniques for targeting the VIM encompass sequences such as susceptibility weighted imaging (SWI)/quantitative susceptibility mapping (QSM), fast grey matter acquisition T₁ inversion recovery (FGATIR), and diffusion tractography (Table 1). Prior attempts to visualize the VIM with MRI sequences have lacked the contrast and resolution needed for direct targeting. While these recent technical advances offer potential, they will still require histological and physiological validation. Currently, diffusion tractography is the technique that has demonstrated the most promise with multiple studies showing its clinical utility in both DBS and MRgHIFU (Sudhyadhom et al., 2013; Coenen et al., 2014; Calabrese, 2016; Krishna et al., 2019).

Table 1

Synoptic table listing the targeting method, advantages, disadvantages, the MRI vendor, our specific sequence parameters, its current FDA approval status, and if and how the targeting method has been validated

Targeting method	Advantages	Disadvantages	MRI vendor	Sequence parameters	MRI sequence FDA approval status	How targeting methods have been validated
Guiot's method/landmark-based method	Expeditious. Can be performed with 1.5 T or 3 T MRI. Widely used for DBS.	Subjective methodology. Often associated with off-target effects. Unreliable for bilateral procedures. Cannot account for underlying pathological derangement of the thalamus and surrounding structures. Treats the VIM as a point instead of a region of interest. Cannot target white matter structures.	GE, Siemens, Philips	3D T2 FSE: 0.9 mm isotropic (TR = 3500; TE = 90) 3D T1: 0.9 mm isotropic, (TR = 1900; TE = 2.93)	Yes	Method used in clinical practice without significant validation. Adverse effects have limited utility. Limited histological validation.
Atlas co-registration method	Expeditious. Can be performed with 1.5 T or 3 T MRI.	Black-box registration methods. Tissue processing artefacts during atlas generation result in inaccuracies. Based on limited number of samples. Cannot account for individual variability. Cannot account for underlying pathological derangement of the thalamus and surrounding structures. Cannot target white matter structures.	GE, Siemens, Philips	3D T2 FSE: 0.9 mm isotropic (TR = 3500; TE = 90); 3D T1: 0.9 mm isotropic, (TR = 1900; TE = 2.93)	Yes	Method used in clinical practice without significant validation. Adverse effects have limited utility
Quantitative susceptibility mapping (QSM)	Direct targeting is based on differences in intrinsic susceptibility. Increased contrast easily delineates grey matter structures. Clear thalamic nuclei boundaries correspond well to histological atlases.	Prone to artefacts. Require longer scan times in multiple head positions. Require extensive post-processing. Require 3T or higher field strength.	GE, Siemens, Philips	3D Multi-echo TFE: 1 x 1 x 2 mm3 (TR = 25; TE1 = 4.6; flip angle = 20°) 4 echoes	Yes	No physiological or histological validation.
Fast grey and white T1 inversion recovery (FGATIR)	Direct targeting method. Increased image contrast easily delineates grey matter structures. Specific white matter tracts and surrounding nuclei can be targeted. No post-processing required.	Requires expertise with expected location of white matter tracts and nuclei to be identified.	GE, Siemens, Philips	3D FGATIR: 0.7 mm isotropic (TR = 3000; TE = 4.39; TI = 400; inversion pulse angle = 180°)	Yes	Early DBS physiological validation data. No histological validation.
Diffusion tractography	Direct targeting method that can allow for targeting of specific white matter tracts. Determines not only the location but also the shape of the DRT and VIM. Easy to incorporate in treatment planning software.	Historically diffusion tractography targeting has been limited by MRI artefacts. Requires post-processing. Requires a priori knowledge of white matter tracts targeted is necessary.	GE, Siemens, Philips	2.0–2.5 mm isotropic voxel size, b-value 1000, 32 diffusion directions.	Yes	Early published DBS and MRgHIFU physiological validation data. No histological validation.

FSE = fast spin echo; TE = echo time; TFE = turbo field echo; TI = inversion time; TR = repetition time.

Quantitative susceptibility mapping and susceptibility weighted imaging

The presence of highly paramagnetic substances such as iron and myelin accelerate the decay of local magnetic resonance signals and result in local magnetic field inhomogeneities. Gradient echo (GRE) sequences such as SWI and QSM are exquisitely sensitive to these local alterations in the magnetic field. The local alterations in the magnetic field create a signal void on GRE and therefore appear hypointense on SWI (Viswanathan and Chabriat, 2006). This effect has been termed ‘susceptibility’. SWI sequences are more sensitive to ‘susceptibility’ than standard GRE imaging because they generate an additional type of image contrast by utilizing the phase information of the GRE images (Viswanathan and Chabriat, 2006). QSM is a similar technique that uses the phase of the magnetic resonance signal to generate a map of susceptibility distribution (Fig. 1). This technique is FDA approved and has higher contrast resolution and a spatial resolution of 0.9 × 0.9 × 0.9 mm. Recent studies have shown that QSM can delineate thalamic nuclei with superior detail when compared to other MRI sequences (Deistung et al., 2013). However, when susceptibility mapping algorithms are performed from a single data source, they produce image artefacts. To overcome this limitation, multiple datasets are obtained with the subject’s head in various orientations (Liu et al., 2009). This results in prolongation of scan time that currently limits the utility of QSM.

Figure 1

Unannotated (A) and annotated (B) images from a quantitative susceptibility mapping (QSM) scan performed on a healthy 52-year-old male on a 3 T Phillips MRI. Varying degrees of susceptibility can be used to clearly differentiate thalamic nuclei when comparing it to a histological atlas. CM = centromedian.

Fast grey matter acquisition T₁ inversion recovery

FGATIR sequences represent a method to optimize T₁ contrast by nullifying the white matter signal (Sudhyadhom et al., 2009). This technique is FDA approved and provides excellent delineation of grey matter structures that are surrounded by highly myelinated white matter tracts. As such, the VLp, globus pallidus, red nucleus, and substantia nigra are better delineated than on standard T₁- and T₂-weighted images (Sudhyadhom et al., 2009). To label the VIM on this sequence reliably, first the dentatorubrothalamic tract (DRT) is identified coursing from the red nucleus superiorly towards the thalamus. The DRT appears as a circular, linear hypointensity. At the level of the AC-PC plane, the DRT can be directly visualized within the VIM (Fig. 2). Similar methods of identifying the VIM using the DRT have been previously described and validated physiologically in a small cohort (Morishita et al., 2019).

Figure 2

Unannotated (A) and annotated (B) images from a fast grey matter acquisition T₁ inversion recovery (FGATIR) scan. Performed on a previously healthy 61-year-old unfixed cadaver, <6 h after death on a 3 T Phillips MRI. The VIM of the thalamus is delineated by identifying the DRT as a small, circular, hypointense structure surrounded by the VIM. AC = anterior commissure; CM = centromedian; GPe = globus pallidus externa; IC = internal capsule; MTT = mammillothalamic tract; PC = posterior commissure; Put = putamen.

The DRT connects the three regions classically targeted in tremor surgery: the caudal zona incerta (cZi), the posterior subthalamic region (pSTR), and the VIM/VLp (Calabrese, 2016). There is convincing evidence that tremor is caused by aberrant electrical activity within the DRT (Calabrese, 2016). As a result, there has been significant interest in using advanced imaging techniques to target white matter tracts, such as the DRT.

Diffusion tractography

While reports of the aforementioned advanced imaging techniques to facilitate direct VIM targeting are limited, reports of the utility of diffusion tractography for targeting with both DBS and MRgHIFU are emerging as the current method of choice. As such, diffusion tractography has been implemented in some clinical practices. Diffusion tractography is an FDA approved method to generate three-dimensional white matter maps from diffusion weighted imaging (DWI). DWI is a type of MRI sequence that is uniquely sensitive to water movement within tissues (Basser et al., 1994a, b; Soares et al., 2013). DWI can be performed with a variety of methods. The underlying premise of all of these methods is that water molecules diffuse differently in various tissue types (Basser et al., 1994a, b; Soares et al., 2013). The variable diffusion of water is a function of tissue microstructure, tissue integrity, and degree of myelination. Diffusion tractography is a three-step process: data acquisition, data processing, and fibre tracking (Soares et al., 2013; Calabrese, 2016).

Data acquisition is largely predetermined by the post-processing algorithm to be used. Image resolution, number of diffusion measurements, and b-values are important acquisition parameters for diffusion tractography studies. In DWI every voxel contains directional information regarding three-dimensional diffusion of water molecules. The diffusion of water molecules in white matter is predominantly anisotropic and less restricted along the axon. Therefore, DWI can serve as an indirect measurement of anisotropy and structural organization of white matter. Given scan time limitations, DTI with 12–60 diffusion directions and a b-value of 1000 s/mm² are widely used in the existing DBS literature (Coenen et al., 2014; Calabrese, 2016).

Data processing can be subdivided into two methods: direct fibre estimation methods and orientation distribution function-based methods. Orientation distribution function-based methods reconstruct diffusion propagators for each voxel to infer fibre orientation (Calabrese, 2016). Alternatively, direct fibre estimation determines fibre orientation directly based on diffusion MRI data (Soares et al., 2013; Coenen et al., 2014; Calabrese, 2016).

Fibre tracking can also be divided into two methods: probabilistic or deterministic fibre tracking. Deterministic fibre tracking utilizes calculated fibre tract orientations assuming a single diffusion orientation from each voxel, whereas probabilistic algorithms generate tracts based on probability density functions of diffusion orientation at each voxel. Deterministic tractography is substantially more common for DBS applications (Soares et al., 2013; Coenen et al., 2014; Calabrese, 2016).

Anatomical accuracy has been a significant criticism of diffusion tractography (Calabrese, 2016). Diffusion tractography is generated using echo-planar images, which are prone to significant image distortion (Zhuang et al., 2006). To address these inherent limitations, eddy current and distortion correction methods have been incorporated into standard tractography methods (Zhuang et al., 2006). Anatomic precision in DTI is largely dependent on data acquisition techniques, post-processing methods, and fibre tracking algorithms. A priori knowledge of the anatomic course of a white matter tract combined with standardized DTI algorithms can provide anatomically precise targets (King et al., 2017). For example, deterministic diffusion tractography MRI has been used to predict the location of the VIM (King et al., 2017). The authors demonstrated that the predicted location of the VIM corresponded to microelectrode recordings characteristic of the VIM in patients with tremor (King et al., 2017). Furthermore, this diffusion tractography-based targeting method was used for MRgHIFU of the VIM and showed good efficacy (Krishna et al., 2019). In this study, no patients experienced sensory deficits or motor weakness at 6 months (Krishna et al., 2019). Three of the nine patients developed transient ataxia after treatment, which resolved during follow-up (1–6 months) (Krishna et al., 2019). Although the acknowledged limitations of the study were a small cohort and limited follow-up, when compared to a multi-institutional landmark paper that used conventional targeting methods, the risk of adverse effects was substantially less (Elias et al., 2016; Krishna et al., 2019).

While Krishna et al. (2019) used a two tract (somatosensory and pyramidal) method with inference of the DRT location, Chazen et al. (2018) report a single tract (DRT only) method in four patients for targeting with MRgHIFU. The authors have developed a three-fibre diffusion tractography algorithm that can directly target the DRT and facilitate avoidance of the somatosensory and pyramidal tracts. Additionally, the DRT tractography not only determines the location of the VIM but also its orientation, size, and shape (Yamada et al., 2010; Tournier et al., 2012; Chazen et al., 2018). This technique underscores the clinical significance of histological considerations by attempting to identify the VIM as well as surrounding nuclei and white matter structures. Tractography of the medial lemniscus, corticospinal tracts, and DRT is performed to delineate the VPL, the internal capsule, and the ventral VLp/VIM, respectively (Fig. 3) (Yamada et al., 2010; Chazen et al., 2018).

Figure 3

MRIs from a diffusion tractography scan performed on a 63-year-old male with essential tremor on a 3 T Siemens MRI. The somatosensory fibres (bright red), corticospinal/pyramidal tract (yellow), and DRT (blue) project to the primary sensory cortex, primary motor cortex, and hand region within the primary motor cortex, respectively. Note seeding of the precentral (maroon) and postcentral gyri (turquoise). 3D tractography image showing the relative position of the white matter tracts at the level of the anterior-posterior commissure plane.

Similar methodology has also been adopted by the authors for use with the Insightec Exablate Treatment Planning Software (Insightec, Haifa, Israel) for targeting the motor thalamus (VIM) while avoiding the adjacent sensory thalamus (Vc) and pyramidal tract. A 30-direction DTI sequence with 2.0–2.5 mm isotropic voxels and parallel imaging at 3 T is acquired along with a T₂-weighted or FGATIR structural imaging series. Guided by a fused structural image, four ipsilateral brain regions are delineated on the B0 image: mid-third of the cerebral peduncle, red nucleus and surrounding posterolateral midbrain, precentral gyrus and postcentral gyrus. Probabilistic tractography is performed using the MRTrix3 software (version 3.0RC2) (Tournier et al., 2012). Streamlines through the VIM are generated by seeding the red nucleus region and precentral gyrus and selecting streamlines connecting both regions. Similarly, the pyramidal tract is mapped by streamlines connecting the mid-third of the cerebral peduncle to the precentral gyrus, and sensory tracts in the thalamus (medial lemniscus, anterolateral system, trigeminothalamic tract) by streamlines connecting the posterolateral midbrain region with the postcentral gyrus. Streamlines are verified visually, rendered and composited on the anatomical images (Renderman, Pixar). To mitigate concerns surrounding a non-FDA approved technique, the locations of generated streamlines for tract estimation are compared with standard FDA approved morphological images and fractional anisotropy maps for verification. Because of the limitations of the Insightec planning software, streamlines are ‘burned-in’ on the anatomic DICOM images in greyscale, rather than represented as secondary capture DICOM colour overlays. Final DICOM images are sent via network to the Insightec system and used in planning ablations. Although there is a growing body of evidence that suggests a superior result is obtained with DBS or MRgFUS when guided by diffusion tractography imaging, more detailed studies of the spatial errors associated with this approach are warranted.

Bilateral MRgHIFU thalamotomy clinical trials, now underway, will rely on improved targeting methodologies to reduce adverse effects and improve patient outcomes.

Conclusion

Transcranial MRgHIFU is a non-invasive, image-guided procedure that is able to focally ablate tissue while preserving surrounding tissue integrity and function. Clinical centres performing MRgHIFU target the VIM using a range of methods, with no consensus on optimal targeting strategy. Advancements in MRI technology offer a promising alternative to subjective landmark-based methods. These advancements should lead to improved clinical efficacy, a reduction of adverse effects, and a new era of non-invasive neural modulation based on the principles of circuit biology.

Funding

No funding was received towards this work.

Competing interests

The authors report no competing interests.

 
• DBS =

  deep brain stimulation

 
• DRT =

  dentatorubrothalamic tract

 
• MRgHIFU =

  magnetic resonance guided high intensity focused ultrasound

 
• VIM =

  ventral intermediate nucleus