Pretherapeutic Motor Thalamus Resting-State Functional Connectivity with Visual Areas Predicts Tremor Arrest After Thalamotomy for Essential Tremor: Tracing the Cerebello-thalamo-visuo-motor Network.

BACKGROUND: Essential tremor (ET) is a common movement disorder. Resting-state functional magnetic resonance imaging is a noninvasive neuroimaging method acquired in absence of task. OBJECTIVE: Our study aimed to correlate pretherapeutic ventrolateral thalamus functional connectivity (FC) with clinical results 1 year after stereotactic radiosurgical thalamotomy (SRS-T) for drug-resistant ET. Data from 12 healthy control individuals were additionally included. METHODS: Resting state was acquired for 17 consecutive (right-handed) patients, before and 1 year after left unilateral SRS-T. Standard tremor scores were evaluated pretherapeutically and 1 year after SRS-T. Tremor network was investigated using region of interest, left ventrolateral ventral (VLV) cluster, obtained from pretherapeutic diffusion magnetic resonance imaging. Seed-based FC was obtained as correlations between the time courses of the VLV and that of every other voxel. The seed-connectivity maps were obtained pretherapeutically and correlated across all patients with clinical outcome 1 year after SRS-T. One-year magnetic resonance signature volume was always located inside VLV and did not correlate with reported seed-FC measures (P > 0.05). RESULTS: We report statistically significant correlations between pretherapeutic VLV FC with clinical outcome for 1) right visual association area (Brodmann area, BA19) predicting 1 year activities of daily living decrease (Punc = 0.02); 2) left fusiform gyrus (BA37) predicting 1 year head tremor score improvement (Punc = 0.04); and 3) posterior cingulate (left BA23, Puncor = 0.009), lateral temporal cortex (right BA21, Punc = 0.02) predicting time to tremor arrest. CONCLUSIONS: Our results suggest that pretherapeutic resting-state seed-FC of left VLV predicts tremor arrest after SRS-T for ET. Visual areas are identified as the main regions in this correlation.

Ventrolateral Motor Thalamus Abnormal Connectivity in Essential Tremor Before and After Thalamotomy: A Resting-State Functional Magnetic Resonance Imaging Study.

OBJECTIVE: To evaluate functional connectivity (FC) of the ventrolateral thalamus, a common target for drug-resistant essential tremor (ET), resting-state data were analyzed before and 1 year after stereotactic radiosurgical thalamotomy and compared against healthy controls (HCs). METHODS: In total, 17 consecutive patients with ET and 10 HCs were enrolled. Tremor network was investigated using the ventrolateral ventral (VLV) thalamic nucleus as the region of interest, extracted with automated segmentation from pretherapeutic diffusion magnetic resonance imaging. Temporal correlations of VLV at whole brain level were evaluated by comparing drug-naïve patients with ET with HCs, and longitudinally, 1 year after stereotactic radiosurgical thalamotomy. 1 year thalamotomy MR signature was always located inside VLV and did not correlate with any of FC measures (P > 0.05). This suggested presence of longitudinal changes in VLV FC independently of the MR signature volume. RESULTS: Pretherapeutic ET displayed altered VLV FC with left primary sensory-motor cortex, pedunculopontine nucleus, dorsal anterior cingulate, left visual association, and left superior parietal areas. Pretherapeutic negative FC with primary somatosensory cortex and pedunculopontine nucleus correlated with poorer baseline tremor scores (Spearman = 0.04 and 0.01). Longitudinal study displayed changes within right dorsal attention (frontal eye-fields and posterior parietal) and salience (anterior insula) networks, as well as areas involved in hand movement planning or language production. CONCLUSIONS: Our results demonstrated that patients with ET and HCs differ in their left VLV FC to primary somatosensory and supplementary motor, visual association, or brainstem areas (pedunculopontine nucleus). Longitudinal changes display reorganization of dorsal attention and salience networks after thalamotomy. Beside attentional gateway, they are also known for their major role in facilitating a rapid access to the motor system.

Pretherapeutic Functional Imaging Allows Prediction of Head Tremor Arrest After Thalamotomy for Essential Tremor: The Role of Altered Interconnectivity Between Thalamolimbic and Supplementary Motor Circuits.

OBJECTIVE: To correlate pretherapeutic resting-state functional magnetic resonance imaging (rs-fMRI) measures with pretherapeutic head tremor presence and/or further improvement 1 year after stereotactic radiosurgical thalamotomy (SRS-T) for essential tremor (ET). METHODS: We prospectively collected head tremor scores (range, 0-3) and rs-fMRI data for a cohort of 17 consecutive ET patients in pretherapeutic and 1 year after SRS-T states. We additionally acquired rs-fMRI data for a healthy control (HC) group (n = 12). Group-level independent component analysis (n = 17 for pretherapeutic rs-fMRI) was applied to decompose neuroimaging data into 20 large-scale brain networks using a standard approach. Through spatial regression, we projected 1 year after SRS-T and HC rs-fMRI time points, on the same 20 brain networks. RESULTS: Pretherapeutic interconnectivity (IC) strength between the network including bilateral thalamus and limbic system with left supplementary motor area predicted head tremor improvement at 1 year after SRS-T (family-wise corrected P < 0.001, cluster size Kc = 146). For the statistically significant cluster, IC strength was strongest in HCs (mean, 4.6; median, 3.8) compared with pre- (mean, 0.1; median, 0.2) or posttherapeutic (mean, -0.2; median, 0.09) states. CONCLUSIONS: Baseline measures of IC between bilateral thalamus and limbic system with left supplementary motor area may predict head tremor arrest after thalamotomy. However, procedures such as SRS-T, for this particular clinical feature, do not align patients to HCs in terms of functional brain connectivity. We postulate that supplementary motor area is modulating head tremor appearance, by abnormal connectivity with the thalamolimbic system.

Clinical response to Vim's thalamic stereotactic radiosurgery for essential tremor is associated with distinctive functional connectivity patterns.

INTRODUCTION: Essential tremor (ET) is the most common movement disorder. Drug-resistant ET can benefit from standard surgical stereotactic procedures (deep brain stimulation, thalamotomy) or minimally invasive high-intensity focused ultrasound (HIFU) or stereotactic radiosurgical thalamotomy (SRS-T). Resting-state fMRI (rs-fMRI) is a non-invasive imaging method acquired in absence of a task. We examined whether rs-fMRI correlates with tremor score on the treated hand (TSTH) improvement 1 year after SRS-T. METHODS: We included 17 consecutive patients treated with left unilateral SRS-T in Marseille, France. Tremor score evaluation and rs-fMRI were acquired at baseline and 1 year after SRS-T. Resting-state data (34 scans) were analyzed without a priori hypothesis, in Lausanne, Switzerland. Based on degree of improvement in TSTH, to consider SRS-T at least as effective as medication, we separated two groups: 1, ≤ 50% (n = 6, 35.3%); 2, > 50% (n = 11, 64.7%). They did not differ statistically by age (p = 0.86), duration of symptoms (p = 0.41), or lesion volume at 1 year (p = 0.06). RESULTS: We report TSTH improvement correlated with interconnectivity strength between salience network with the left claustrum and putamen, as well as between bilateral motor cortices, frontal eye fields and left cerebellum lobule VI with right visual association area (the former also with lesion volume). Longitudinal changes showed additional associations in interconnectivity strength between right dorsal attention network with ventro-lateral prefrontal cortex and a reminiscent salience network with fusiform gyrus. CONCLUSIONS: Brain connectivity measured by resting-state fMRI relates to clinical response after SRS-T. Relevant networks are visual, motor, and attention. Interconnectivity between visual and motor areas is a novel finding, revealing implication in movement sensory guidance.

Right Brodmann area 18 predicts tremor arrest after Vim radiosurgery: a voxel-based morphometry study.

INTRODUCTION: Drug-resistant essential tremor (ET) can benefit from open standard stereotactic procedures, such as deep-brain stimulation or radiofrequency thalamotomy. Non-surgical candidates can be offered either high-focused ultrasound (HIFU) or radiosurgery (RS). All procedures aim to target the same thalamic site, the ventro-intermediate nucleus (e.g., Vim). The mechanisms by which tremor stops after Vim RS or HIFU remain unknown. We used voxel-based morphometry (VBM) on pretherapeutic neuroimaging data and assessed which anatomical site would best correlate with tremor arrest 1 year after Vim RS. METHODS: Fifty-two patients (30 male, 22 female; mean age 71.6 years, range 49-82) with right-sided ET benefited from left unilateral Vim RS in Marseille, France. Targeting was performed in a uniform manner, using 130 Gy and a single 4-mm collimator. Neurological (pretherapeutic and 1 year after) and neuroimaging (baseline) assessments were completed. Tremor score on the treated hand (TSTH) at 1 year after Vim RS was included in a statistical parametric mapping analysis of variance (ANOVA) model as a continuous variable with pretherapeutic neuroimaging data. Pretherapeutic gray matter density (GMD) was further correlated with TSTH improvement. No a priori hypothesis was used in the statistical model. RESULTS: The only statistically significant region was right Brodmann area (BA) 18 (visual association area V2, p = 0.05, cluster size Kc = 71). Higher baseline GMD correlated with better TSTH improvement at 1 year after Vim RS (Spearman's rank correlation coefficient = 0.002). CONCLUSIONS: Routine baseline structural neuroimaging predicts TSTH improvement 1 year after Vim RS. The relevant anatomical area is the right visual association cortex (BA 18, V2). The question whether visual areas should be included in the targeting remains open.

Assessing the clinical outcome of Vim radiosurgery with voxel-based morphometry: visual areas are linked with tremor arrest!

INTRODUCTION: Radiosurgery (RS) is an alternative to open standard stereotactic procedures (deep-brain stimulation or radiofrequency thalamotomy) for drug-resistant essential tremor (ET), aiming at the same target (ventro-intermediate nucleus, Vim). We investigated the Vim RS outcome using voxel-based morphometry by evaluating the interaction between clinical response and time. METHODS: Thirty-eight patients with right-sided ET benefited from left unilateral Vim RS. Targeting was performed using 130 Gy and a single 4-mm collimator. Neurological and neuroimaging assessment was completed at baseline and 1 year. Clinical responders were considered those with at least 50% improvement in tremor score on the treated hand (TSTH). RESULTS: Interaction between clinical response and time showed the left temporal pole and occipital cortex (Brodmann area 19, including V4, V5 and the parahippocampal place area) as statistically significant. A decrease in gray matter density (GMD) 1 year after Vim RS correlated with higher TSTH improvement (Spearman = 0.01) for both anatomical areas. Higher baseline GMD within the left temporal pole correlated with better TSTH improvement (Spearman = 0.004). CONCLUSIONS: Statistically significant structural changes in the relationship to clinical response after Vim RS are present in remote areas, advocating a distant neurobiological effect. The former regions are mainly involved in locomotor monitoring toward the local and distant environment, suggesting the recruiting requirement in targeting of the specific visuomotor networks.

Total reference air kerma can accurately predict isodose surface volumes in cervix cancer brachytherapy. A multicenter study.

PURPOSE: To demonstrate that V60 Gy, V75 Gy, and V85 Gy isodose surface volumes can be accurately estimated from total reference air kerma (TRAK) in cervix cancer MRI-guided brachytherapy (BT). METHODS AND MATERIALS: 60 Gy, 75 Gy, and 85 Gy isodose surface volumes levels were obtained from treatment planning systems (VTPS) for 239 EMBRACE study patients from five institutions treated with various dose rates, fractionation schedules and applicators. An equation for estimating VTPS from TRAK was derived. Furthermore, a surrogate Point A dose (Point A*) was proposed and tested for correlation with V75 Gy. RESULTS: Predicted volumes Vpred = 4965 (TRAK/dref) 3/2 + 170 (TRAK/dref) - 1.5 gave the best fit to VTPS. The difference between VTPS and predicted volumes was 0.0% ± 2.3%. All volumes were predicted within 10%. The prediction was valid for (1) high-dose rate and pulsed dose rate, (2) intracavitary vs. intracavitary/interstitial applicators, and (3) tandem-ring, tandem-ovoid, and mold. Point A* = 14 TRAK was converted to total EQD2 and showed high correlation with V75 Gy. CONCLUSIONS: TRAK derived Isodose surface volumes may become a tool for assessment of treatment intensity. Furthermore, surrogate Point A∗ doses can be applied for both intracavitary and intracavitary/interstitial BT and can be used to compare treatments across fractionation schedules.

Jaw Immobilization for Gamma Knife Surgery in Patients with Mandibular Lesions: A Newly, Innovative Approach.

BACKGROUND: The purpose of our report is to describe an innovative system used for mandibular immobilization during Gamma Knife surgery (GKS) procedures. It is based on an approach originally developed in Marseille in extracranial lesions, close to or involving the mandible, which may imply a certain degree of movement during the therapeutic image acquisitions and/or GKS treatment. METHODS: The maxillofacial surgeon applied bone titanium self-tapping monocortical screws (4; 2 mm diameter, 10 mm length) between roots of the teeth in the fixed gingiva (upper and lower maxillae) the day before GKS (local anesthesia, 5-10 min time). Two rubber bands were sufficient for the desired tension required to undergo GKS. We further proceeded with application of the Leksell stereotactic G frame and carried out the usual GKS procedure. RESULTS: The mean follow-up period was 2.3 years (range 0.6-3). Three patients have been treated with this approach: 2 cases with extracranial trigeminal schwannomas involving the mandibular branch, with decrease in tumor size on MR follow-up; 1 case with residual paracondylian mandibular arteriovenous malformation following partial embolization, completely obliterated at 7 months (digital subtraction angiography programmed 1 year after treatment). CONCLUSIONS: Jaw immobilization appears to be a quick, minimally invasive, safe and accurate adjunctive technique to enhance GKS targeting precision.

Intrafractional organs movement in three-dimensional image-guided adaptive pulsed-dose-rate cervical cancer brachytherapy: assessment and dosimetric impact.

PURPOSE: To prospectively evaluate the intrafractional movements of organs at risk (OARs) and their dosimetric impact during the delivery of pulsed-dose-rate brachytherapy in cervical cancer. PATIENTS AND METHODS: An MRI on Day 1 was used for treatment planning in 19 patients. CT scans were acquired at Days 1, 2, and 3 with delineation of the OARs. The MRI plan was transferred to each CT. The intersection volume between the 10 Gy isodose and the OARs were monitored, reflecting movement. Lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ and lower dose evaluated in the maximally exposed 2 cm(3) of an organ (D(2cm3)) were evaluated on each CT and compared. Results were averaged considering that each CT reflected one-third of the treatment course to evaluate the delivered dose. RESULTS: No major movements of the sigmoid and bladder were observed, whereas the rectum got significantly closer to the implant at Day 2. The consequence was an increase of 6% ± 5.3 (3.7 Gy, α/ß = 3 Gy) of the delivered D(2cm3) from the planned dose, in contrast to 0.2% ± 6.1 for the bladder and 1.1% ± 6.4 for the sigmoid. The increase of the D(2cm3) of the rectum was reported in 17 patients, ranging from 0.4 to 9.4 Gy, leading to a 10.5% overcoming of the dose constraint (75 Gy). Similar tendencies were reported for lower dose evaluated in the maximally exposed 0.1 cm(3) of an organ. CONCLUSIONS: A significant systematic variation was observed for the rectum (+3.7 Gy). As significant random variations were observed, caution should be exercised when the planned D(2cm3) is close to the dose constraints.

Functional data analysis in NTCP modeling: a new method to explore the radiation dose-volume effects.

PURPOSE/OBJECTIVE(S): To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. METHODS AND MATERIALS: Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principal components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). RESULTS: The incidence rate of grade ≥2 RB was 14%. V65Gy was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade ≥2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03-1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. CONCLUSION: Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy.

Adaptive 3D image-guided brachytherapy: a strong argument in the debate on systematic radical hysterectomy for locally advanced cervical cancer.

PURPOSE: To evaluate the outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy (IGABT) after concomitant chemoradiation (CCRT). MATERIALS AND METHODS: Data from patients treated with CCRT followed by magnetic resonance imaging-guided or computed tomography-guided pulsed-dose-rate brachytherapy, performed according to the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology guidelines, were reviewed. At first, stage I or II patients systematically underwent radical hysterectomy or were offered a randomized study evaluating hysterectomy. Then, hysterectomy was limited to salvage treatment. RESULTS: Of 163 patients identified, 27% had stage IB, 57% had stage II, 12% had stage III, and 3% had stage IVA disease. The mean dose delivered (in 2-Gy dose equivalents) to 90% of the high-risk clinical target volume was 78.1 ± 9.6 Gy, whereas the doses delivered to organs at risk were maintained under the usual thresholds. Sixty-one patients underwent a hysterectomy. Macroscopic residual disease was found in 13 cases. With a median follow-up of 36 months (range, 5-79 months), 45 patients had relapsed. The 3-year overall survival rate was 76%. Local and pelvic control rates were 92% and 86%, respectively. According to the Common Toxicity Criteria 3.0, 7.4% of patients experienced late grade 3 or 4 toxicity. Most of those had undergone postradiation radical surgery (2.9% vs. 14.8; p = .005). CONCLUSION: IGABT combined with CCRT provides excellent locoregional control rates with low treatment-related morbidity, justifying the elimination of hysterectomy in the absence of obvious residual disease. Distant metastasis remains an important first relapse and may warrant more aggressive systemic treatment.

[Postoperative vaginal brachytherapy in endometrial cancer]. / Curiethérapie vaginale postopératoire dans les cancers de l'endomètre.

Several randomized studies published in recent years have greatly changed the management of postoperative endometrial cancer, especially for lesions of intermediate prognosis. Vaginal brachytherapy is now standard treatment for these lesions at the expense of external beam radiation, which, despite an improvement in locoregional control, has no impact on overall survival. This review aims to take stock of new indications for vaginal brachytherapy detailing the trials that led to change standards or care.