Original ArticleTractography Study of Deep Brain Stimulation of the Anterior Cingulate Cortex in Chronic Pain: Key to Improve the Targeting
Introduction
Deep brain stimulation (DBS) for severe pharmacoresistant pain was first introduced more than 60 years ago.1 Different brain structures have been targeted, including the periaqueductal gray area (PAG)2 and the ventral posterior medial and lateral nuclei of the sensory thalamus.3 As described in a recent case series,4 DBS of these areas can alleviate pain of various etiologies. Even though DBS is widely used, most commonly in the subthalamic nucleus (STN) for Parkinson disease, its mechanism of action remains incompletely understood.5, 6, 7 DBS probably modulates a large network of interconnected brain regions.8, 9 We hypothesized that the optimum target in the anterior cingulate cortex (ACC) to relieve pain might be determined by the connectivity of the stimulated site rather than simply its location.10
Pain is a multifaceted sensation with 3 main dimensions: sensory (pain intensity), affective (pain unpleasantness), and cognitive.11 We recently demonstrated that some patients who are unsuitable for DBS of sensory thalamus and PVG/PAG (e.g., because their pain is too widespread) may benefit from targeting a specific part of the ACC,12, 13 an area of the brain that is particularly involved in the affective dimension of pain.14, 15 Unlike targets in the basal ganglia, the volume of activated tissue (VAT) surrounding the active contacts in the ACC predominantly contains white matter.
The cingulate cortex is a structure of the limbic system, and it is divided into an anterior part (ACC) and a posterior part (posterior cingulate cortex [PCC]). The ACC consists of Broadmann's area 32, 24 and 25, and the PCC of areas 29, 30, 23, and 31. Even though they are parts of the same structure, they seem to perform different functions.16 The ACC is a large heterogeneous area with complex connectivity patterns17, 18, 19 lying in the anterior part of the cingulum, dorsal to the corpus callosum and ventral to the superior frontal gyrus. It seems to be involved in both emotional reactions and executive functions. Thus there is a nociceptive region in the ACC, responsible for the affective responses to noxious stimuli.20 Patients with lesions in this area report that they can still localize their pain but are not bothered by it anymore.21, 22 In 1952, MacLean defined the ACC as “a visceral brain that interprets and gives expression to its incoming information in terms of feeling”.23 Its involvement in the affective component of pain is what suggested that it might be a potential target to relieve pain.12, 13 Several studies have also found a link between the PCC and pain. Brain imaging showed that nociceptive inputs reach the caudal part of the cingulate cortex first, before further projection to the ACC.24, 25, 26
The landmark used for targeting ACC DBS electrodes (the tip of the frontal horn of the lateral ventricle) is likely to be subject to significant interindividual variability. Furthermore, unlike DBS of the thalamus or periaqueductal gray area (PAG), the optimal location within the ACC cannot be defined intraoperatively using test stimulation because the analgesic effect can take a few days to develop.
This pilot study offers insights into the mechanism of action of ACC DBS and suggests how that might help determine optimal targeting in the future.
Diffusion magnetic resonance imaging (MRI) tractography is a technique that quantifies the anisotropy of water diffusion in brain tissues.27 Under the assumption that diffusion is less hindered along, rather than across, axon bundles, tractography algorithms use local modelling of diffusion to provide estimates of white matter bundles by following the direction of least hindrance to diffusion.28 Even though these connection probabilities do not provide real counts of axon numbers per se, they are thought, at least, to be modulated by connection strength.29, 30 In our study, for every patient, putative connectivity was computed from the tissue around the electrodes likely to be activated by the stimulation (VAT). Because we used bipolar stimulation, unlike in most other DBS tractography studies, we used the area surrounding the whole electrode as the seed region.
We report here our diffusion MRI tractography31 results tracing the white matter connectivity of tissue adjacent to active electrode contacts in patients undergoing DBS of the ACC. We focused our analysis on areas known to be involved in pain pathways and the precuneus, recently found to be involved in pain processing.32
Section snippets
Patients
Eight patients (2 females) with chronic pain were included in the study (Table 1). Mean age of patients (±standard deviation) was 53.4 ± 6.1 years, and their mean preoperative visual analog scale (VAS) pain score was 8.4 (range, 6–10). Patients were referred by clinicians nationally to a single-center, multidisciplinary team consisting of pain specialists, neuropsychologists, and neurosurgeons. Neuropsychological evaluation excluded psychiatric disorders. Pain refractory to medication for at
Surgical Procedure and Evaluation of Electrode Position
The surgical technique has been described previously.6, 13 Briefly, a Cosman-Roberts-Wells (CRW) stereotactic frame was applied to the patient's head and a stereotactic CT scan was performed presurgically; this was volumetrically fused with the preoperative MRI using Renishaw Neuroinspire software (Renishaw, Gloucestershire, United Kingdom). The ACC was targeted in a coronal plane 20 mm posterior to the tip of the frontal horn of the lateral ventricle. After surgery, patients had a second
Acquisition
Before DBS surgery, patients underwent a T1-and T2 -weighted MRI scan on a Philips Achieva 1.5 Tesla magnet. Diffusion-weighted data were acquired using a single-shot echo planar sequence. The scanning parameters were as follows: echo time (TE), 65 ms, repetition time (TR), 9390 ms, 176 × 176 reconstructed matrix, voxel size of 1.8 × 1.8 × 2 mm, and slice thickness of 2 mm. DTI data were acquired with 33 optimal nonlinear diffusion gradient directions (b = 1200 s/mm2) and one
Probabilistic Tractography
For each subject, we ran probabilistic tractography using the DBS electrode VAT as a seed area and the ROIs included in the parcellation template as target areas.42 Five thousand sample streamlines were seeded from each voxel of the seed region (VAT), and a spatial histogram representing the probability of streamline location was built up by recording the number of streamlines passing through each voxel of the brain. This histogram is hereafter referred to as the “connection probability map.”
Spatial Localization of Electrode Contacts
Electrodes were placed bilaterally in the supragenual anterior part of the cingulate cortex (ACC). During postoperative programming sessions, the most effective configuration was found to be with the deepest contact, “C0,” as the cathode and “C3,” the shallowest, as the anode. Individual brain images were transformed into a common coordinate space, the MNI space. Subsequent coordinates are in millimeters (Supplementary Table 1). In patients A, D, E, F, G, and H, who were relieved by the
Remote Connections
We computed correlations between connectivity strengths to the different studied areas for each of the 8 patients (Supplementary Table 2). Statistically significant correlations were found between the cingulate cortex and the right vmPFC (R2 = 0.76; P = 0.029). Thalamic connectivity was strongly correlated with that to the left SMF (R2 > 0.97; P < 0.001) and particularly its anterior part (R2 > 0.99; P < 0.001). Brainstem connectivity was also greatly correlated with the insula one (R2 > 0.93; P
Main Findings
In order to improve the optimal location of DBS electrodes, we compared tractography of successful and unsuccessful ACC DBS patients with chronic pain, in whom electrode placements were seemingly similar. We used diffusion tensor imaging to investigate which fibers might be differentially modulated by the DBS electrodes in different patients. This suggested that in patients with unsuccessful outcomes, the connectivity of the VAT around the DBS electrodes with the precuneus was stronger. On the
Brainstem and Medial Forebrain Bundle
According to the Oxford thalamic connectivity atlas, ACC DBS activates the dorsomedial nucleus of the thalamus and the ATR. Actually, this tract probably also includes the MFB.44 The MFB is part of the reward-seeking system and involved in euphoric feelings, whereas the ATR carries the projections from the anterior nucleus of the thalamus to the cingulate and from the dorso-medial nucleus to the lateral prefrontal cortex. Thus as observed in the SO patients, the brainstem can be remotely
Frontal Cortex
We studied the connectivity to some parts of the frontal cortex because of its role in affective aspects of pain.58, 59, 60 Beckman et al. found a high connectivity between the cingulate cortex and the vmPFC,17 which we have confirmed. We focused on 2 particular areas, the vmPFC and SMF. However, we could not find any statistical difference between SO and UO outcomes in their connectivity, even after subdividing the SMF into separate anterior and posterior portions. Nevertheless, it is notable
Insula
We investigated the connectivity to the insula because of its contribution to the pain matrix. Indeed, it is part of the lateral neuroanatomic components of pain and is activated during an acute pain experience.61 Moreover, the insular cortex, and more specifically its anterior part, is involved in the integration of sensory information.62, 63 It is also necessary to feel empathy for others.64 Finally, descending pathways from ACC and insula have some influences on the pain transmission via the
Study Limitations
To our knowledge, this is the first study investigating differences in tractography between efficacious and nonefficacious DBS. However, we are aware of a number of limitations regarding this work, the most obvious being the small patient population with marked differences in the size of SO and UO groups. Our conclusions must be treated with caution, and data from more patients will be needed to confirm and refine them.
Clinical Implication
This study lends support to the hypothesis that DBS modulates fiber pathways and particular networks. The global effect of ACC stimulation probably consists of the sum of functional inactivation of target cell bodies together with stimulation of axons passing by,65 and this may explain why DBS may have greater effects than initially expected. We can hypothesize that even though stimulating the ACC induces a “reversible cingulotomy” by commandeering neurons in the VAT, activation of surrounding
Conclusion
We have previously reported that ACC stimulation can have a beneficial effect on pain.13 This seems to depend on not only stimulating ACC neurons but also tracts passing by. In patients with stronger connectivity from the VAT to the precuneus than to the thalamus and brainstem, the patient's pain appears less likely to be relieved. These results provide important clues to the global effect of ACC DBS. Once confirmed with more patient data, we hope that by incorporating preoperative DTI into the
Acknowledgement
The authors thank Professor Carlo Chiorri, Ph.D., Lecturer in Psychometrics at the University of Genoa, Italy (DISFOR, Department of Educational Sciences, Psychology Unit) for advising in statistical analyses.
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2021, NeuroImageCitation Excerpt :Polanski et al., 2019, Kovanlikaya et al., 2014) The anterior cingulate and the periaqueductal gray have also served as potential targets; and interestingly, may both impart their efficacy through modulation of the medial forebrain bundle. ( Coenen et al., 2015, Boccard et al., 2016) Lesion studies have provided the foundation for localization of most neurological and psychiatric symptoms because they provide a causal link between the lesion location and the resulting symptom. (
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2017, World NeurosurgeryCitation Excerpt :Moreover, we cannot exclude the possibility that brain plasticity might lead to changes in the electrode surrounding as shown in DBS for Parkinson disease.65 The variability of efficacy between patients led to a tractography study to investigate the difference in connectivity between good and bad outcome patients and found a small cohort in whom strong connectivity to the precuneus was correlated with an unsuccessful outcome.66 This result, if confirmed on a larger cohort, may help in defining the best electrode placement in future patients.
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2016, World NeurosurgeryCitation Excerpt :Connectivity strength was measured between the VAT around the electrodes and several cortical or subcortical brain areas involved in movement disorders and/or highlighted by the connectivity map. For details regarding the data processing and tractography procedure, please refer to our previous publication.22 Mapping the electrode location onto the preoperative DTI scans, we confirmed a strong connectivity along the corticothalamic tract, leading mainly to the superior frontal gyrus (n = 69.2) and precentral gyrus (n = 7.6) (Table 1).
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Supplementary digital content available online.
Conflict of interest statement: The research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.