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Deep brain stimulation of the thalamus has become a valuable treatment for medication-refractory essential tremor, but current targeting provides for only a limited ability to account for individual anatomic variability. We examined whether functional connectivity measurements between the motor cortex, superior cerebellum, and thalamus would allow discrimination of precise targets useful for image guidance of neurostimulator placement.
Resting BOLD images (8 minutes) were obtained in 58 healthy adolescent and adult volunteers. ROI’s were identified from an anatomic atlas and a finger movement task in each subject in the primary motor cortex and motor activation region of bilateral superior cerebellum. Correlation was measured in the time series of each thalamic voxel with the 4 seeds. An analogous procedure was performed on a single subject imaged for 10 hours to constrain time needed for single subject optimization of thalamic targets.
Mean connectivity images from 58 subjects showed precisely localized targets within the expected location of the ventral intermediate nucleus of the thalamus, within a single voxel of currently used deep brain stimulation anatomic targets. These targets could be mapped with single voxel accuracy in a single subject with 3 hours of imaging time, although targets were reproduced in different locations for the individual than for the group averages.
Interindividual variability likely exists in optimal placement for thalamic deep brain stimulation targeting of the cerebellar thalamus for essential tremor. Individualized thalamic targets can be precisely estimated for image guidance with sufficient imaging time.
Deep brain stimulation (DBS), a technique consisting of depth electrode placement in deep gray nuclei, has allowed successful treatment of patients suffering from medication-refractory essential tremor1, with fewer adverse effects than with thalamotomy2. Typically, results have been achieved by placing depth electrodes within the ventral intermediate (Vim) nucleus of the thalamus, or cerebellar thalamus1.
While anatomic atlas-based localization of Vim have been traditionally utilized, the direct method of electrode placement based on MR imaging coordinates may provide better targeting results as shown previously for Globus Pallidus Internus (Gpi) localization for dystonia3. However targeting the Vim nucleus is problematic for image guidance, since thalamic subnuclei do not show demarcation of boundaries on standard magnetic resonance imaging sequences. Post-placement outcome analysis based on the brain atlas by Schaltenbrand and Wahren4 as well as Taren et. al. diagrams for thalamic targeting5, has found that electrode location with the most effective clinical outcome was just anterior to Vim and 3 mm from the anterior border of main sensory nucleus Ventralis caudalis (Vc)6. In a study with over 2 years followup in 37 subjects, optimal lead placement was reported to be 12.3 mm lateral to midline and 6.3 mm anterior to the posterior commissure in the plane of anterior and posterior commissures6.
The lack of direct image guidance is particularly important, given that even minimal variation in lead placement may result in long-term clinical failure or less than satisfactory treatment of essential tremor7. Long-term failure rates for deep brain stimulation in essential tremor have been reported to be 13–40%, due to a hypothesized physiologic tolerance or sub-optimal lead placement8–12. In one study, even as little as a 2 mm error in placement resulted in only 17% chance of producing essential tremor control defined by criteria of greater than 66% improvement in tremors6.
A recent study by Yamada et al. showed that Vim could be approximated using diffusion tensor tractography, providing a novel way to accurately image the Vim without relying on anatomic atlases13. Utilizing directional information provided by Diffusion Tensor Imaging (DTI) for tractography and anatomic knowledge that cerebellothalamocortical tract (CTC) dentate projections intersect the spinothalamic tracts within the Vim, the authors were able to define landmarks for in vivo localization of the Vim. Yet this technique yielded approximations that were more lateral than those typically used by anatomic landmarks, and did not identify the more medial regions of the Vim nucleus. The authors suggested that given the current technical artifacts associated with DTI techniques the procedure may not be suited for individualized targeting13.
Cytoarchitectonic studies by Morel et al. have demonstrated inter-individual differences in location and size of thalamic nuclei14 that cannot be easily taken into account by standardization procedures. Furthermore, cortical connectivity parcellation of thalamic nuclei using diffusion tensor tractography in healthy individuals reveals that there is both quantitative and qualitative variation in probabilistic thalamic atlases due to individual variability in precise volumes and location of borders of different nuclei15. Interindividual variations in connectivity-defined parcellations reflect the difficulty in precisely matching variations in brain and thalamic sizes and shapes in registration of images across groups.
As an alternative for individualized preoperative image guidance, we attempted to identify the ventral intermediate nucleus by performing functional connectivity (fcMRI) measurements of thalamic connectivity to cerebellar and motor cortical brain regions. Functional connectivity uses synchrony of task or resting-state fMRI time series data to estimate quantitatively correlation between two brain regions16, 17. Such an approach has been used previously to define differential thalamocortical connectivity within the thalamus18–20, and has allowed precise identification of subtle differences in connectivity between adjacent voxels in other functional brain regions21.
BOLD fMRI data was obtained from 59 normal, healthy adolescent and adult volunteers, examined after informed consent in accordance with procedures approved by the University of Utah Institutional Review Board (mean age 18.0 +/− 4.9 years. Age range 11–35. 32 male, 26 female.) Data from these subjects have been previously reported21–23. All subjects had no DSM-IV Axis I diagnoses based on diagnostic semi-structured psychiatric interview and screening surveys as previously described22.
Additionally, one hundred 5-minute scans were obtained during 10 imaging sessions (10 scans per session) on one of the subjects (age 39, male) during a three-week period. 5 of the sessions were obtained while the subject was instructed to “keep your eyes open and remain awake” and 5 of the sessions were obtained while the subject was watching 10 5-minute clips from Bugs Bunny cartoons (Looney Tunes Golden Collection Volume 1, Warner Home Video). The same 10 clips were used for each of the 5 cartoon sessions in the same order, with the clips synchronized to the onset of the BOLD acquisition by a fiber optic trigger pulse. Images from this dataset have been previously reported in the context of reproducibility of functional connectivity measurements throughout the brain23.
In all 59 subjects, an additional BOLD sequence was obtained consisting of a 4 minute block design where the subject was instructed to alternately touch the thumbs with each of the second through fifth digits in turn for 20 seconds followed by 20 seconds of rest. 6 such blocks were obtained, with visual cues “Task” and “Rest” to switch between finger movement task and rest blocks.
Images were acquired on Siemens 3 Tesla Trio scanner with 12-channel head coil. The scanning protocol consisted of initial 1 mm isotropic MPRAGE acquisition for an anatomic template. BOLD echoplanar images (TR= 2.0 s, TE = 28 ms, GRAPPA parallel acquisition with acceleration factor = 2, 40 slices at 3 mm slice thickness, 64 × 64 matrix) were obtained during the resting state. The BOLD acquisition resolution was 3.0 mm isotropic. Prospective motion correction was performed during BOLD imaging with PACE sequence. An 8-minute resting scan (240 volumes) was obtained for each of the group subjects. 100 5-minute scans (155 volumes) were obtained for the individual subject. An additional field map scan was obtained for each subject for the purposes of distortion correction. For all BOLD sequences, simultaneous plethysmograph (pulse oximeter) and chest excursion (respiratory belt) waveforms were recorded for offline analysis.
Post-processing of BOLD images has been previously described22. Briefly, BOLD images were processed with RETROICOR24 using AFNI software package25, slice timing correction (SPM8, Wellcome Trust, London), motion and distortion correction (realign and unwarp, SPM8), coregistration to MPRAGE (SPM8), Segmentation of gray matter, white matter, and CSF (SPM8), Normalization to MNI template brain (SPM8, T1.nii), PSTCor22 allowing removal by regression of motion, physiologic, CSF, white matter, and soft tissue signals, bandpass filtering between 0.001 and 0.1 Hz26 and linear detrend at each voxel in the brain.
Four ROI’s were used to define functional connectivity, located in bilateral primary motor cortex (M1) and bilateral motor activation regions of the superior cerebellum. In the group of 58 subjects, the mean time series was extracted from left and right precentral gyrus clusters (M1) from an MNI-normalized version of the automated anatomical labeling (AAL) atlas27 packaged with the wfupickatlas toolbox software28. The ROI’s for superior cerebellar clusters were selected from group-level activation maps from 58 subjects using second level analysis in SPM with a standard general linear model after first extracting finger movement > rest activation maps for each subject. A threshold of T>9 was selected to ensure that superior cerebellar clusters were distinct, with no overlap and no voxels that extended across midline.
The superior cerebellar and primary motor ROI’s for the individual subject were obtained from a general linear model analysis of the finger movement task for this subject, with a threshold of T> 8 for M1 clusters and threshold T>4 for superior cerebellar clusters, with >10 voxels per cluster selected to achieve distinct clusters for connectivity seeds.
A mask of the bilateral thalamus was obtained from the AAL atlas27, and used to identify voxels within the thalamus. For each thalamic voxel in each subject, time series data was extracted and a Pearson correlation coefficient was measured between each voxel and the time series data from the 4 motor cortex and superior cerebellar seeds. Correlation values were Fisher transformed for improved normality by evaluating the hyperbolic arctangent29. The resulting four Z-scores were averaged for correlation measurements with each thalamic voxel and the four seed ROI’s to obtain a mean connectivity Z-score for the voxel.
We attempted to “triangulate” functional connectivity between the thalamus, motor activation regions of the superior cerebellum, and primary motor cortex by measuring correlation in each voxel of the thalamus with bilateral primary motor cortex and bilateral superior cerebellar motor areas. We used the same seed ROI’s for these 4 regions in 58 subjects, shown in Figure 1. The primary motor cortex (M1) ROI’s were defined by the AAL atlas27, whereas the superior cerebellar ROI’s represented group level activation from a bilateral finger movement task. In results for the single subject, analogous ROI’s were derived from activation in bilateral M1 and bilateral superior cerebellum from the finger movement task.
Once the relevant ROI masks were identified, Pearson correlation coefficients between each voxel in the thalamus and the ROI’s from Figure 1 were averaged, with mean correlation from 58 subjects shown in Figure 2. The group correlation results show cylindrical volumes in the bilateral thalamus that correspond to the expected location of the ventral intermediate nucleus (VIM) of the thalamus, for which peak correlation to the seeds lies at MNI coordinates (left x = −11, y = −25, z = 2; right x = −13, y = −26, z = 1) within 5 mm distance from the coordinates used for thalamic deep brain stimulation based on anatomic landmarks (x = +/−12.5, y = 22, z = 1).
When similar measurements of correlation to primary motor and superior cerebellar cortex were obtained within a single subject, nearly identical results were obtained for peak correlation coordinates. This was true for data from grouped scan sessions when the subject was in a resting state as well as for the correlations observed when the subject was watching cartoons. This result is reassuring in that it suggests the motor correlation measured in the thalamus is not dependent on the specific task the subject was performing. Moreover, reproducible targets for thalamic brain stimulation are critical if a connectivity-based method is used for image guidance. Since precise coordinates will be required for thalamic targeting, likely requiring relatively long image acquisition times, it is helpful to establish that results can be obtained during a task that patients can easily perform for an extended period, such as watching a film.
The correlation peak seen in the VIM nucleus is not the only correlation peak seen in the individual’s result. An additional peak is seen in the expected location of bilateral lateral geniculate nuclei, which might suggest that the motor regions also show specific connectivity to visual inputs necessary for coordination of movement with the subject’s visual reference frame. Although the group-level and individual results are precise, there are notable differences between the targets suggested in Figures 2 and and3.3. This may indicate interindividual variation in the optimal location of motor network connectivity in the thalamus.
The individual subject results of Figure 3 were obtained from 5 hours of imaging time each. To obtain an estimate of how much imaging time was necessary in this subject to obtain reproducible results, we examined results of a single scan session (50 minutes BOLD imaging time) for this subject. In some of the scan sessions, a clear peak was not identified that would suggest a target for deep brain stimulation. When groups of 2 scans were averaged together (100 minutes BOLD imaging time), all 5 groups of 2 scans showed a peak in the region of the VIM nucleus, but the variability in the measurements was greater than a single voxel in location, not optimal for precise image guidance.
Results are shown in Figure 4 when 10 groups of 3 scan sessions were averaged together (150 minutes BOLD imaging time). The sessions were selected randomly from among the 10 scan sessions. In all 10 cases, a clear peak was obtained in close proximity to the targets identified using all 10 sessions. The mean and standard deviation of the targets obtained from the 10 groups of 3 scan sessions were: left: x=−10.8 +/− 1.1, y=−20.1 +/− 1.0, z=−0.5 +/− 1.0; right: x=4.6 +/− 1.3, y=−20.6 +/− 1.9, z=0.0 +/− 1.1. For the 10 groups of scans evaluated, the mean distance from the target using 3 sessions compared to using all 10 sessions was less than 2 mm, less than the size of a single voxel. In all cases, the distance between the targets was less than 5 mm between different groups of 3 scans.
We have demonstrated that functional connectivity between the bilateral primary motor cortex, bilateral cerebellar motor cortex, and bilateral thalami is greatest in thalamic voxels located within 3 mm of clinically optimized targets for deep brain stimulation in essential tremor, validating these coordinates as representing the intersection of connections between the cerebellum and motor cortex in the thalamus. Additionally, we demonstrate feasibility of identifying individualized coordinates within one subject with accuracy on the order of a single voxel. Given the known variability in the size and shape of the thalamus, as well as interindividual variations in thalamic nuclei location14, 15, it is possible that functional connectivity targeting may allow improved localization of deep brain stimulator targets those obtained from conventional anatomic landmarks.
Reliability of functional connectivity measurements is directly related to imaging time. In a study assessing reliability as a function of imaging time, variability in connectivity metrics decreased with the square root of imaging time, with intersession correlation improving from 0.7 to 0.85 when 40 minutes of imaging time was used instead of 5 minutes30. The same 1/sqrt(n) relationship between test-retest reliability and imaging time has also been observed within a single individual, as well as for convergence to group means of measurements within a population of subjects23. When average correlation strengths over an entire network are examined, correlation measurements stabilize after approximately 5 minutes of imaging time, reaching asymptotic values30. Yet individual functional connectivity measurements, such as we obtained in comparing adjacent thalamic voxels, are more noisy, and high resolution thalamic targeting was only possible with imaging times in the neighborhood of 3 hours.
Deep brain stimulation targets for essential tremor have been chosen to target the “cerebellar thalamus,” or location where cerebellar motor connections arrive in the thalamus, however it remains unknown how deep brain stimulation is able to successfully mitigate tremor, or what specific neurophysiological changes are achieved during treatment in cerebellothalamocortical circuitry. Although our imaging technique allows connection-based targeting, we do not know which connections are optimal, and comparison of deep brain stimulation outcomes with functional connectivity-based targets will be required to verify whether this approach can identify high-yield targets for neurostimulator placement. Even if the location our technique identifies is not optimal, the methods suggest a systematic approach to identifying targets by comparing brain connectivity to functional outcomes.
The resolution achieved in our results, with the target identified within 2–3 mm, are on the order of the acquisition resolution, and the main reason for the long scan times used in the individual subject. It is possible to estimate BOLD targets at a resolution even finer than the sampling resolution if interpolation is used, particularly if numerous sequences are obtained allowing for meaningful differences in connectivity between neighboring voxels. In our data, the target reproducibility error was slightly smaller than the size of an individual voxel.
All of the subjects used in the above analysis had no tremor or other neurological illness. It is possible that subjects with tremor may have altered cerebellothalamocortical connectivity that may affect targeting for brain stimulator placement. Moreover, reliability results were performed in a single subject. Other subjects may vary in reproducibility of functional connectivity measurements. Further, it is possible that when the technique is applied to older individuals, obtaining sufficient high-quality BOLD imaging data may be difficult given patient motion or intolerable scan durations for patients. To mitigate these challenges, we show that similar results can be obtained when the subject is watching a video clip as during resting state acquisition, and that data from multiple scan sessions can be combined to obtain sufficient resolution for identifying thalamic targets. In our experience, patient motion is mitigated when the subject is engaged in a task such as watching a video clip. This may have additional benefit in reducing the chance a subject will fall asleep during a protracted acquisition, since it has been demonstrated that functional connectivity measurements can depend on cognitive state or task during acquisition23.
Functional connectivity measurements between bilateral motor cortex and bilateral superior cerebellar motor regions and the thalamus show peak correlation within the thalamus across subjects within 3 mm of the targets currently used for deep brain stimulation in essential tremor, validating these coordinates as a location of cerebellar and motor cortical convergence in the thalamus. With sufficient imaging time, likely in the neighborhood of 3 hours of BOLD imaging, individual subject measurements can be reproducibly obtained with precision of about 2 mm, demonstrating feasibility for individualized targeting of deep brain stimulator placement. Further work is necessary to demonstrate feasibility in tremor patients and assess effects of functional connectivity targeting on clinical outcomes.
The project described was supported by NIH grant numbers K08 MH092697 (JSA) and RO1 DA020269 (DYT) and by the Ben B. and Iris M. Margolis Foundation (JSA).
Prior Presentation: Results have been submitted for presentation to American Society of Neuroradiology 2011.