Protocol for motor and language mapping by navigated TMS in patients and healthy volunteers; workshop report

Navigated transcranial magnetic stimulation (nTMS) is increasingly used for preoperative mapping of motor function, and clinical evidence for its benefit for brain tumor patients is accumulating. In respect to language mapping with repetitive nTMS, literature reports have yielded variable results, and it is currently not routinely performed for presurgical language localization. The aim of this project is to define a common protocol for nTMS motor and language mapping to standardize its neurosurgical application and increase its clinical value. The nTMS workshop group, consisting of highly experienced nTMS users with experience of more than 1500 preoperative nTMS examinations, met in Helsinki in January 2016 for thorough discussions of current evidence and personal experiences with the goal to recommend a standardized protocol for neurosurgical applications. nTMS motor mapping is a reliable and clinically validated tool to identify functional areas belonging to both normal and lesioned primary motor cortex. In contrast, this is less clear for language-eloquent cortical areas identified by nTMS. The user group agreed on a core protocol, which enables comparison of results between centers and has an excellent safety profile. Recommendations for nTMS motor and language mapping protocols and their optimal clinical integration are presented here. At present, the expert panel recommends nTMS motor mapping in routine neurosurgical practice, as it has a sufficient level of evidence supporting its reliability. The panel recommends that nTMS language mapping be used in the framework of clinical studies to continue refinement of its protocol and increase reliability.Peer reviewe

Short- and long-term reliability of language fMRI

When using functional magnetic resonance imaging (fMRI) for mapping important language functions, a high test-retest reliability is mandatory, both in basic scientific research and for clinical applications. We, therefore, systematically tested the short-and long-term reliability of fMRI in a group of healthy subjects using a picture naming task and a sparse-sampling fMRI protocol. We hypothesized that test-retest reliability might be higher for (i) speech-related motor areas than for other language areas and for (ii) the short as compared to the long intersession interval. 16 right-handed subjects (mean age: 29 years) participated in three sessions separated by 2-6 (session 1 and 2, short-term) and 21-34 days (session 1 and 3, long-term). Subjects were asked to perform the same overt picture naming task in each fMRI session (50 black-white images per session). Reliability was tested using the following measures: (i) Euclidean distances (ED) between local activation maxima and Centers of Gravity (CoGs), (ii) overlap volumes and (iii) voxel-wise intraclass correlation coefficients (ICCs). Analyses were performed for three regions of interest which were chosen based on whole-brain group data: primary motor cortex (M1), superior temporal gyrus (STG) and inferior frontal gyrus (IFG). Our results revealed that the activation centers were highly reliable, independent of the time interval, ROI or hemisphere with significantly smaller ED for the local activation maxima (6.45 +/- 1.36 mm) as compared to the CoGs (8.03 +/- 2.01 mm). In contrast, the extent of activation revealed rather low reliability values with overlaps ranging from 24% (IFG) to 56% (STG). Here, the left hemisphere showed significantly higher overlap volumes than the right hemisphere. Although mean ICCs ranged between poor (ICC0.75) were found for all ROIs. Voxel-wise reliability of the different ROIs was influenced by the intersession interval. Taken together, we could show that, despite of considerable ROI-dependent variations of the extent of activation over time, highly reliable centers of activation can be identified using an overt picture naming paradigm

Accelerated Clustered Sparse Acquisition to Improve Functional MRI for Mapping Language Functions

Background Functional magnetic resonance imaging (fMRI) is a useful method for noninvasive presurgical functional mapping. However, the scanner environment is inherently unsuitable for the examination of auditory and language functions, due to the loud acoustic noise produced by the scanner. Interleaved acquisition methods alleviate this problem by providing a silent period for stimulus presentation and/or response control (sparse sampling) but at the expense of a diminished amount of data collected. There are possible improvements to these sparse acquisition methods that increase the amount of data by acquiring several images per event (clustered sampling). We tested accelerated clustered fMRI acquisition in comparison with conventional sparse sampling in a pilot study. Methods The clustered and sparse acquisition techniques (7.4 minutes scanning time per protocol) were directly compared in 15 healthy subjects (8 men; mean age: 24 +/- 3 years) using both a motor (tongue movement) and a language (overt picture-naming) task. Functional imaging data were analyzed using Statistical Parametric Mapping software (SPM12 Wellcome Department of Imaging Neuroscience, London, UK). For both tasks, activation levels were compared and Euclidean distances (EDs) between cluster centers (i.e., local activation maxima and centers of gravity) were calculated. Overlaps and laterality indices were computed for the picture-naming task. In addition, the feasibility of the clustered acquisition protocol in a clinical setting was assessed in one pilot patient. Results For both tasks, activation levels were higher using the clustered acquisition protocol, reflected by bigger cluster sizes ( p < 0.05). Mean ED between cluster centers ranged between 9.9 +/- 5.4 mm (left superior temporal gyrus; centers of gravity) and 16.6 +/- 13.2 mm (left inferior frontal gyrus; local activation maxima) for the picture-naming task. Overlaps between sparse and clustered acquisition reached 88% (Simpson overlap coefficient). A similar activation pattern for both acquisition methods was also confirmed in the clinical case. Conclusion Despite some drawbacks inherent to the acquisition technique, the clustered sparse sampling protocol showed increased sensitivity for activation in language-related cortical regions with short scanning times. Such scanning techniques may be particularly advantageous for investigating patients with contraindications for long scans (e.g., reduced attention span)

The Treatment of Gliomas in Adulthood

Background: Gliomas are the most common intrinsic tumors of the brain, with an incidence of 6 per 100 000 persons per year. Recent years have seen marked changes in the diagnosis and treatment of gliomas, with molecular parameters now being an integral part of the diagnostic evaluation. Methods: This review is based on pertinent articles retrieved by a selective search in PubMed, with special attention to the new WHO glioma classification. Results: The classification of gliomas on the basis of additional molecular parameters enables more accurate prognostication and serves as a basis for therapeutic decision-making and treatment according to precisely specified algorithms. PET scanning with F-18-fluoroethyl tyrosine and C-11-methionine for the measurement of metabolic activity in gliomas has further refined the diagnostic evaluation. The median overall survival of patients with glioblastoma who have undergone resection of all tumor tissue with a disrupted blood-brain barrier (i.e., all contrast-enhancing tumor tissue) has been prolonged to up to 20 months. The 5-year survival of patients with WHO grade II gliomas is now as high as 97% after near-total resection. The surgical resection of all contrast-enhancing tumor tissue and subsequent radiotherapy and chemotherapy remain the key elements of treatment. New surgical strategies and new methods of planning radiotherapy have made these techniques safer and more effective. The percutaneous application of tumor-treating fields is a new therapeutic option that has gained a degree of acceptance. Accompanying measures such as psycho-oncology and palliative care are very important for patients and should be considered mandatory. Conclusion: The consistent application of the existing multimodal treatment options for glioma has led in recent years to improved survival. Areas of important current and future scientific activity include immunotherapy and targeted and combined chemotherapy, as well as altered neurocognition, modern approaches to palliative care, and complementary therapies

Focal Radiotherapy of Brain Metastases in Combination With Immunotherapy and Targeted Drug Therapy

Background: Advances in systemic treatment and in brain imaging have led to a higher incidence of diagnosed brain metastases. In the treatment of brain metastases, stereotactic radiotherapy and radiosurgery, systemic immunotherapy, and targeted drug therapy are important evidence-based options. In this review. we summarize the available evidence on the treatment of brain metastases of the three main types of cancer that give rise to them: non-small-cell lung cancer, breast cancer, and malignant melanoma. Methods: This narrative review is based on pertinent original articles. meta-analyses. and systematic reviews that were retrieved by a selective search in PubMed. These publications were evaluated and discussed by an expert panel including radiation oncologists. neurosurgeons. and oncologists. Results: There have not yet been any prospective randomized trials concerning the optimal combination of local stereotactic radiotherapy/radiosurgery and systemic immunotherapy or targeted therapy. Retrospective studies have consistently shown a benefit from early combined treatment with systemic therapy and (in particular) focal radiotherapy. compared to sequential treatment. Two meta-analyses of retrospective data from cohorts consisting mainly of patients with non-small-cell lung cancer and melanoma revealed longer overall survival after combined treatment with focal radiotherapy and checkpoint inhibitor therapy (rate of 12-month overall survival for combined versus non-combined treatment: 64.6% vs. 51.6%, p <0.001). In selected patients with small, asymptomatic brain metastases in non-critical locations. systemic therapy without focal radiotherapy can be considered, as long as follow-up with cranial magnetic resonance imaging can be performed at close intervals. Conclusion: Brain metastases should be treated by a multidisciplinary team, so that the optimal sequence of local and systemic therapies can be determined for each individual patient

Introduction to spasticity and related mouse models

Although spasticity is one of the most common causes of motor disability worldwide, its precise definition and pathophysiology remain elusive, which to date renders its experimental targeting tricky. At least in part, this difficulty is caused by heterogeneous phenotypes of spasticity-causing neurological disorders, all causing spasticity by involving upper motor neurons. The most common clinical symptoms are a series of rapid muscle contractions (clonus), an increased muscle tone (hypertonia), and augmented tendon reflex activity (hyperreflexia). This muscle overactivity is due to disturbed inhibition of spinal reflexes following upper motor neuron dysfunction. Despite a range of physical and pharmacological therapies ameliorating the symptoms, their targeted application remains difficult. Therefore, to date, spasticity impacts rehabilitative therapy, and no therapy exists that reverses the pathology completely. In contrast to the incidence and importance of spasticity, only very little pre-clinical work in animal models exists, and this research is focused on the cat or the rat spastic tail model to decipher altered reflexes and excitability of the motor neurons in the spinal cord. Meanwhile, the characterization of spasticity in clinically more relevant mouse models of neurological disorders, such as stroke, remains understudied. Here, we provide a brief introduction into the clinical knowledge and therapy of spasticity and an in-depth review of pre-clinical studies of spasticity in mice including the current experimental challenges for clinical translation

The Cologne Picture Naming Test for Language Mapping and Monitoring (CoNaT): An Open Set of 100 Black and White Object Drawings

Language assessment using a picture naming task crucially relies on the interpretation of the given verbal response by the rater. To avoid misinterpretations, a language-specific and linguistically controlled set of unambiguous, clearly identifiable and common object-word pairs is mandatory. We, here, set out to provide an open-source set of black and white object drawings, particularly suited for language mapping and monitoring, e.g., during awake brain tumour surgery or transcranial magnetic stimulation, in German language. A refined set of 100 black and white drawings was tested in two consecutive runs of randomised picture order and was analysed in respect of correct, prompt, and reliable object recognition and naming in a series of 132 healthy subjects between 18 and 84 years (median 25 years, 64% females) and a clinical pilot cohort of 10 brain tumour patients (median age 47 years, 80% males). The influence of important word- and subject-related factors on task performance and reliability was investigated. Overall, across both healthy subjects and patients, excellent correct object naming rates (97 vs. 96%) as well as high reliability coefficients (Goodman-Kruskal's gamma = 0.95 vs. 0.86) were found. However, the analysis of variance revealed a significant, overall negative effect of low word frequency (p < 0.05) and high age (p < 0.0001) on task performance whereas the effect of a low educational level was only evident for the subgroup of 72 or more years of age (p < 0.05). Moreover, a small learning effect was observed across the two runs of the test (p < 0.001). In summary, this study provides an overall robust and reliable picture naming tool, optimised for the clinical use to map and monitor language functions in patients. However, individual familiarisation before the clinical use remains advisable, especially for subjects that are comparatively prone to spontaneous picture naming errors such as older subjects of low educational level and patients with clinically apparent word finding difficulties

Assessment Practice of Patient-Centered Outcomes in Surgical Neuro-Oncology: Survey-Based Recommendations for Clinical Routine

The psycho-oncological burden related to the diagnosis of an intracranial tumor is often accompanied by neurocognitive deficits and changes in character, overall affecting health-related quality of life (HRQoL) and activities of daily living. Regular administration of adequate screening tools is crucial to ensure a timely detection of needs for support and/or specific interventions. Although efforts have been made to assure the quality of neuro-oncological care, clinical assessment practice of patient-reported outcomes (PROs) remains overall heterogeneous, calling for a concise recommendation tailored to neuro-oncological patients. Therefore, this survey, promoted by the German Society of Neurosurgery, was conducted to evaluate the status quo of health care resources and PRO/neurocognition assessment practices throughout departments of surgical neuro-oncology in Germany. 72/127 (57%) of registered departments participated in the study, including 83% of all university hospital units. A second aim was to shed light on the impact of quality assurance strategies (i.e., department certification as part of an integrative neuro-oncology cancer center; CNOC) on the assessment practice, controlled for interacting structural factors, i.e., university hospital status (UH) and caseload. Despite an overall good to excellent availability of relevant health care structures (psycho-oncologist: 90%, palliative care unit: 97%, neuropsychology: 75%), a small majority of departments practice patient-centered screenings (psycho-oncological burden: 64%, HRQoL: 76%, neurocognition: 58%), however, much less frequently outside the framework of clinical trials. In this context, CNOC affiliation, representing a specific health care quality assurance process, was associated with significantly stronger PRO assessment practices regarding psycho-oncological burden, independent of UH status (common odds ratio=5.0, p=0.03). Nevertheless, PRO/neurocognitive assessment practice was not consistent even across CNOC. The overall most commonly used PRO/neurocognitive assessment tools were the Distress Thermometer (for psycho-oncological burden; 64%), the EORTC QLQ-C30 combined with the EORTC QLQ-BN20 (for HRQoL; 52%) and the Mini-Mental Status Test (for neurocognition; 67%), followed by the Montreal Cognitive Assessment (MoCA; 33%). Accordingly, for routine clinical screening, the authors recommend the Distress Thermometer and the EORTC QLQ-C30 and QLQ-BN20, complemented by the MoCA as a comparatively sensitive yet basic neurocognitive test. This recommendation is intended to encourage more regular, adequate, and standardized routine assessments in neuro-oncological practice

Improving the efficacy and reliability of rTMS language mapping by increasing the stimulation frequency

Repetitive TMS (rTMS) with a frequency of 5–10 Hz is widely used for language mapping. However, it may be accompanied by discomfort and is limited in the number and reliability of evoked language errors. We, here, systematically tested the influence of different stimulation frequencies (i.e., 10, 30, and 50 Hz) on tolerability, number, reliability, and cortical distribution of language errors aiming at improved language mapping. 15 right-handed, healthy subjects (m = 8, median age: 29 yrs) were investigated in two sessions, separated by 2–5 days. In each session, 10, 30, and 50 Hz rTMS were applied over the left hemisphere in a randomized order during a picture naming task. Overall, 30 Hz rTMS evoked significantly more errors (20 ± 12%) compared to 50 Hz (12 ± 8%; p <.01), whereas error rates were comparable between 30/50 and 10 Hz (18 ± 11%). Across all conditions, a significantly higher error rate was found in Session 1 (19 ± 13%) compared to Session 2 (13 ± 7%, p <.05). The error rate was poorly reliable between sessions for 10 (intraclass correlation coefficient, ICC = .315) and 30 Hz (ICC = .427), whereas 50 Hz showed a moderate reliability (ICC = .597). Spatial reliability of language errors was low to moderate with a tendency toward increased reliability for higher frequencies, for example, within frontal regions. Compared to 10 Hz, both, 30 and 50 Hz were rated as less painful. Taken together, our data favor the use of rTMS-protocols employing higher frequencies for evoking language errors reliably and with reduced discomfort, depending on the region of interest

An MR technique for simultaneous quantitative imaging of water content, conductivity and susceptibility, with application to brain tumours using a 3T hybrid MR-PET scanner

Approaches for the quantitative mapping of water content, electrical conductivity and susceptibility have been developed independently. The purpose of this study is to develop a method for simultaneously acquiring quantitative water content, electrical conductivity and susceptibility maps based on a 2D multi-echo gradient echo sequence. Another purpose is to investigate the changes in these properties caused by brain tumours. This was done using a 3T hybrid magnetic resonance imaging and positron emission tomography (MR-PET) scanner. Water content maps were derived after performing T-2* and transmit-receive field bias corrections to magnitude images essentially reflecting only the H2O content contrast. Phase evolution during the multi-echo train was used to generate field maps and derive quantitative susceptibility, while the conductivity maps were retrieved from the phase value at zero echo time. Performance of the method is demonstrated on phantoms and two healthy volunteers. In addition, the method was applied to three patients with brain tumours and a comparison to maps obtained from PET using O-(2-[18F]fluoroethyl)-L-tyrosine and clinical MR images is presented. The combined information of the water content, conductivity and susceptibility may provide additional information about the tissue viability. Future studies can benefit from the evaluation of these contrasts with shortened acquisition times