Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Stimulus modality influences session-to-session transfer of training effects in auditory and tactile streaming-based P300 brain-computer interfaces.

Despite recent successes, patients suffering from locked-in syndrome (LIS) still struggle to communicate using vision-independent brain-computer interfaces (BCIs). In this study, we compared auditory and tactile BCIs, regarding training effects and cross-stimulus-modality transfer effects, when switching between stimulus modalities. We utilized a streaming-based P300 BCI, which was developed as a low workload approach to prevent potential BCI-inefficiency. We randomly assigned 20 healthy participants to two groups. The participants received three sessions of training either using an auditory BCI or using a tactile BCI. In an additional fourth session, BCI versions were switched to explore possible cross-stimulus-modality transfer effects. Both BCI versions could be operated successfully in the first session by the majority of the participants, with the tactile BCI being experienced as more intuitive. Significant training effects were found mostly in the auditory BCI group and strong evidence for a cross-stimulus-modality transfer occurred for the auditory training group that switched to the tactile version but not vice versa. All participants were able to control at least one BCI version, suggesting that the investigated paradigms are generally feasible and merit further research into their applicability with LIS end-users. Individual preferences regarding stimulus modality should be considered.

Week-long visuomotor coordination and relaxation trainings do not increase sensorimotor rhythms (SMR) based brain-computer interface performance.

Brain-computer interfaces (BCI) translate brain activity into control signals or commands for a device. Motor imagery of the limbs allows for modulating the sensorimotor rhythms (SMR), but there are up to 30% of the participants for whom electroencephalography (EEG) based SMR-BCI cannot detect any imagery-related changes. Individual variables, such as ability to concentrate on a task and error duration in a two-hand visuomotor coordination (VMC) task have been previously found to predict accuracy in an SMR-BCI. A first study attempted to substantiate those predictors by introducing a 30 min relaxation or VMC training period prior to an SMR-BCI session, but performance did not increase when compared to a control group. As the predictor training may have been too short, we applied 4 such training sessions on consecutive days in the current study. In a pre-post design, SMR-BCI accuracy of n = 39 participants increased from session 1 before to session 2 after the predictor training. While the manipulation of the predictor variables was successful, there was no effect on SMR-BCI performance. BCI accuracy correlated positively with the neurophysiological SMR predictor identified by Blankertz et al. [3], consolidating its predictive value, and with the state mindfulness scale. No other psychological predictor could be identified or replicated. Further studies should therefore focus more on delineating (partially) replicated or potential predictors such as VMC or mindfulness to help refining a sound model to predict SMR-BCI accuracy.

Short progressive muscle relaxation or motor coordination training does not increase performance in a brain-computer interface based on sensorimotor rhythms (SMR).

Brain computer interfaces (BCIs) allow for controlling devices through modulation of sensorimotor rhythms (SMR), yet a profound number of users is unable to achieve sufficient accuracy. Here, we investigated if visuo-motor coordination (VMC) training or Jacobsen's progressive muscle relaxation (PMR) prior to BCI use would increase later performance compared to a control group who performed a reading task (CG). Running the study in two different BCI-labs, we achieved a joint sample size of N=154 naïve participants. No significant effect of either intervention (VMC, PMR, control) was found on resulting BCI performance. Relaxation level and visuo-motor performance were associated with later BCI performance in one BCI-lab but not in the other. These mixed results do not indicate a strong potential of VMC or PMR for boosting performance. Yet further research with different training parameters or experimental designs is needed to complete the picture.

Effects of training and motivation on auditory P300 brain-computer interface performance.

OBJECTIVES: Brain-computer interface (BCI) technology aims at helping end-users with severe motor paralysis to communicate with their environment without using the natural output pathways of the brain. For end-users in complete paralysis, loss of gaze control may necessitate non-visual BCI systems. The present study investigated the effect of training on performance with an auditory P300 multi-class speller paradigm. For half of the participants, spatial cues were added to the auditory stimuli to see whether performance can be further optimized. The influence of motivation, mood and workload on performance and P300 component was also examined. METHODS: In five sessions, 16 healthy participants were instructed to spell several words by attending to animal sounds representing the rows and columns of a 5 × 5 letter matrix. RESULTS: 81% of the participants achieved an average online accuracy of ⩾ 70%. From the first to the fifth session information transfer rates increased from 3.72 bits/min to 5.63 bits/min. Motivation significantly influenced P300 amplitude and online ITR. No significant facilitative effect of spatial cues on performance was observed. CONCLUSIONS: Training improves performance in an auditory BCI paradigm. Motivation influences performance and P300 amplitude. SIGNIFICANCE: The described auditory BCI system may help end-users to communicate independently of gaze control with their environment.

Training leads to increased auditory brain-computer interface performance of end-users with motor impairments.

OBJECTIVE: Auditory brain-computer interfaces are an assistive technology that can restore communication for motor impaired end-users. Such non-visual brain-computer interface paradigms are of particular importance for end-users that may lose or have lost gaze control. We attempted to show that motor impaired end-users can learn to control an auditory speller on the basis of event-related potentials. METHODS: Five end-users with motor impairments, two of whom with additional visual impairments, participated in five sessions. We applied a newly developed auditory brain-computer interface paradigm with natural sounds and directional cues. RESULTS: Three of five end-users learned to select symbols using this method. Averaged over all five end-users the information transfer rate increased by more than 1800% from the first session (0.17 bits/min) to the last session (3.08 bits/min). The two best end-users achieved information transfer rates of 5.78 bits/min and accuracies of 92%. CONCLUSIONS: Our results show that an auditory BCI with a combination of natural sounds and directional cues, can be controlled by end-users with motor impairment. Training improves the performance of end-users to the level of healthy controls. SIGNIFICANCE: To our knowledge, this is the first time end-users with motor impairments controlled an auditory brain-computer interface speller with such high accuracy and information transfer rates. Further, our results demonstrate that operating a BCI with event-related potentials benefits from training and specifically end-users may require more than one session to develop their full potential.

The effect of multimodal and enriched feedback on SMR-BCI performance.

OBJECTIVE: This study investigated the effect of multimodal (visual and auditory) continuous feedback with information about the uncertainty of the input signal on motor imagery based BCI performance. A liquid floating through a visualization of a funnel (funnel feedback) provided enriched visual or enriched multimodal feedback. METHODS: In a between subject design 30 healthy SMR-BCI naive participants were provided with either conventional bar feedback (CB), or visual funnel feedback (UF), or multimodal (visual and auditory) funnel feedback (MF). Subjects were required to imagine left and right hand movement and were trained to control the SMR based BCI for five sessions on separate days. RESULTS: Feedback accuracy varied largely between participants. The MF feedback lead to a significantly better performance in session 1 as compared to the CB feedback and could significantly enhance motivation and minimize frustration in BCI use across the five training sessions. CONCLUSION: The present study demonstrates that the BCI funnel feedback allows participants to modulate sensorimotor EEG rhythms. Participants were able to control the BCI with the funnel feedback with better performance during the initial session and less frustration compared to the CB feedback. SIGNIFICANCE: The multimodal funnel feedback provides an alternative to the conventional cursorbar feedback for training subjects to modulate their sensorimotor rhythms.

The auditory p300-based SSBCI: a door to minimally conscious patients?

In this study we report on the evaluation of a novel auditory single-switch BCI in nine patients diagnosed with MCS. The task included a simple and a complex oddball paradigm, the latter uses the tone stream segregation phenomenon. In all patients a significant difference between deviant and frequent tones could be observed in EEG. However, in some cases the deviant tones produce a significant negative peak and in some a very late positive peak. These preliminary findings are relevant in order to address future customization of this auditory ssBCI-based paradigm for unresponsive patients.

Neural mechanisms of brain-computer interface control.

Brain-computer interfaces (BCIs) enable people with paralysis to communicate with their environment. Motor imagery can be used to generate distinct patterns of cortical activation in the electroencephalogram (EEG) and thus control a BCI. To elucidate the cortical correlates of BCI control, users of a sensory motor rhythm (SMR)-BCI were classified according to their BCI control performance. In a second session these participants performed a motor imagery, motor observation and motor execution task in a functional magnetic resonance imaging (fMRI) scanner. Group difference analysis between high and low aptitude BCI users revealed significantly higher activation of the supplementary motor areas (SMA) for the motor imagery and the motor observation tasks in high aptitude users. Low aptitude users showed no activation when observing movement. The number of activated voxels during motor observation was significantly correlated with accuracy in the EEG-BCI task (r=0.53). Furthermore, the number of activated voxels in the right middle frontal gyrus, an area responsible for processing of movement observation, correlated (r=0.72) with BCI-performance. This strong correlation highlights the importance of these areas for task monitoring and working memory as task goals have to be activated throughout the BCI session. The ability to regulate behavior and the brain through learning mechanisms involving imagery such as required to control a BCI constitutes the consequence of ideo-motor co-activation of motor brain systems during observation of movements. The results demonstrate that acquisition of a sensorimotor program reflected in SMR-BCI-control is tightly related to the recall of such sensorimotor programs during observation of movements and unrelated to the actual execution of these movement sequences.

An auditory oddball brain-computer interface for binary choices.

OBJECTIVE: Brain-computer interfaces (BCIs) provide non-muscular communication for individuals diagnosed with late-stage motoneuron disease (e.g., amyotrophic lateral sclerosis (ALS)). In the final stages of the disease, a BCI cannot rely on the visual modality. This study examined a method to achieve high accuracies using auditory stimuli only. METHODS: We propose an auditory BCI based on a three-stimulus paradigm. This paradigm is similar to the standard oddball but includes an additional target (i.e. two target stimuli, one frequent stimulus). Three versions of the task were evaluated in which the target stimuli differed in loudness, pitch or direction. RESULTS: Twenty healthy participants achieved an average information transfer rate (ITR) of up to 2.46 bits/min and accuracies of 78.5%. Most subjects (14 of 20) achieved their best performance with targets differing in pitch. CONCLUSIONS: With this study, the viability of the paradigm was shown for healthy participants and will next be evaluated with individuals diagnosed with ALS or locked-in syndrome (LIS) after stroke. SIGNIFICANCE: The here presented BCI offers communication with binary choices (yes/no) independent of vision. As it requires only little time per selection, it may constitute a reliable means of communication for patients who lost all motor function and have a short attention span.

An auditory oddball (P300) spelling system for brain-computer interfaces.

This study was designed to develop and test an auditory event-related potential (ERP) based spelling system for a brain-computer interface (BCI) and to compare user's performance between the auditory and visual modality. The spelling system, where letters in a matrix were coded with acoustically presented numbers, was tested on a group of healthy volunteers. The results were compared with a visual spelling system. Nine of the 13 participants presented with the auditory ERP spelling system scored above a predefined criterion level control for communication. Compared to the visual spelling system, users' performance was lower and the peak latencies of the auditorily evoked ERPs were delayed. It was concluded that auditorily evoked ERPs from the majority of the users could be reliably classified. High accuracies were achieved in these users, rendering item selection with a BCI based on auditory stimulation feasible for communication.

A brain-computer interface tool to assess cognitive functions in completely paralyzed patients with amyotrophic lateral sclerosis.

OBJECTIVE: Brain-computer interface methodology based on self-regulation of slow-cortical potentials (SCPs) of the EEG was used to assess cognitive abilities of two late-stage ALS patients. METHODS: A monitor presented visual information in two targets. Patients used their SCPs to steer a cursor to one of the targets. Within-subject methodology tested the ability to differentiate odd/even numbers, consonants/vowels, nouns/verbs, large/small numbers, and the ability to perform simple computations. One patient had a short-term memory task with delays up to 15s. RESULTS: Both patients reached accuracy near 90% correct on simple tasks showing that they understood the instructions, discriminated the visual stimuli, and could use the SCP to control the cursor. Both patients showed some deficit on the task that involved computations. The patient with the short-term memory task showed a large reduction in accuracy on delay trials but retained high accuracy on non-delay trials. CONCLUSION: The fully computerized method is a useful tool for presenting a variety of two-choice tasks to assess certain cognitive functions in the severely paralyzed patient. SIGNIFICANCE: The task can potentially be used to examine maintenance or decline of cognitive abilities in individual ALS patients.

[EEG-based communication--a new concept for rehabilitative support in patients with severe motor impairment]. / "EEG-basierende Kommunikation"--ein neues Konzept zur rehabilitativen Unterstützung von Patienten mit schwerer motorischer Beeinträchtigung.

This paper describes a paralyzed patient diagnosed with severe infantile cerebral palsy, trained over a period of several months to use an EEG-based brain-computer interface (BCI) for verbal communication. The patient learned to "produce" two distinct EEG patterns by mental imagery and to use this skill for BCI-controlled spelling. The EEG feedback training was conducted at a clinic for Assisted Communications, supervised from a distant laboratory with the help of a telemonitoring system. As a function of training sessions significant learning progress was found, resulting in an average accuracy level of 70% correct responses for letter selection. At present, "copy spelling" can be performed with a rate of approximately one letter per minute. The proposed communication device, the "Virtual Keyboard", may improve actual levels of communication ability in completely paralyzed patients. "Telemonitoring-assisted" training facilitates clinical application in a larger number of patients.

Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients--a report of a thirty year retrospective review.

This retrospective study aimed to demonstrate the incidence and the aetiological factors involved in osteoradionecrosis (ORN) in a group of 830 head and neck tumour patients who received radiotherapy between 1969 and 1999. The data showed an over all incidence of 8.2% and a 3-fold higher incidence for men than for women. Osteoradionecrosis was most commonly located in the body of the mandible. Concerning the risk factors, a negative influence was shown for advanced tumours, segmental resections of the mandible and pre-/post-radiation tooth extractions. Tooth extractions were found to be responsible for 50% of all cases. The osteoradionecroses were observed significantly earlier in patients who received pre-surgical radiotherapy than those who received post-surgical radiotherapy. Combined pre-surgical radio- and chemotherapy significantly hastened the appearance of osteoradionecrosis compared to pre-surgical radiotherapy alone. Only 40% of patients with osteoradionecrosis could be healed completely by means of surgery and antibiotic medication. Hyperbaric oxygenation (HBO) therapy was performed only in individual cases. The data suggest that osteoradionecrosis has a multifactorial aetiology. Therefore, a very close follow-up of tumour patients and a strict prophylactic management are required.

Clinical application of an EEG-based brain-computer interface: a case study in a patient with severe motor impairment.

OBJECTIVE: This case study describes how a completely paralyzed patient, diagnosed with severe cerebral palsy, was trained over a period of several months to use an electroencephalography (EEG)-based brain-computer interface (BCI) for verbal communication. METHODS: EEG feedback training was performed in the patient's home (clinic), supervised from a distant laboratory with the help of a 'telemonitoring system'. Online feedback computation was based on single-trial analysis and classification of specific band power features of the spontaneous EEG. Task-related changes in brain oscillations over the course of training steps was investigated by quantifying time-frequency maps of event-related (de-)synchronization (ERD/ERS). RESULTS: The patient learned to 'produce' two distinct EEG patterns, beta band ERD during movement imagery vs. no ERD during relaxing, and to use this for BCI-controlled spelling. Significant learning progress was found as a function of training session, resulting in an average accuracy level of 70% (correct responses) for letter selection. 'Copy spelling' was performed with a rate of approximately one letter per min. CONCLUSIONS: The proposed BCI training procedure, based on electroencephalogram (EEG) biofeedback and concomitant adaptation of feature extraction and classification, may improve actual levels of communication ability in locked-in patients. 'Telemonitoring-assisted' BCI training facilitates clinical application in a larger number of patients.

A non-invasive communication device for the paralyzed.

An EEG-based communication system has been developed to re-establish communication in severely paralyzed patients who operate the device by generating shifts of their slow cortical potentials. Training to gain control over slow cortical potentials was based on visual feedback and operant conditioning strategies. The vertical movement of a graphic signal on a computer screen informs the patients about the course of their slow cortical potential amplitude. Positive slow cortical potential shifts move the cursor up, negative shifts move it down. These shifts are then translated into binary responses. When a patient has achieved reliable control over his/her slow cortical potential shifts, these responses can be used to select or reject items presented at the bottom of the screen. As learning processes and applications differ considerably between patients, the present paper describes the data from one patient with amyotrophic lateral sclerosis. After about three months of training, this patient gained stable, near-perfect control over his slow cortical potentials. This skill enabled him to operate a specially designed program to communicate messages to his caregivers.

Brain-computer communication: self-regulation of slow cortical potentials for verbal communication.

OBJECTIVE: To test a training procedure designed to enable severely paralyzed patients to communicate by means of self-regulation of slow cortical potentials. DESIGN: Application of the Thought Translation Device to evaluate the procedure in patients with late-stage amyotrophic lateral sclerosis (ALS). SETTING: Training sessions in the patients' homes. PARTICIPANTS: Two male patients with late-stage ALS. INTERVENTIONS: Patients learned voluntary control of their slow cortical potentials by means of an interface between the brain and a computer. Training was based on visual feedback of slow cortical potentials shifts and operant learning principles. The learning process was divided into small steps of increasing difficulty. MAIN OUTCOME MEASURES: Accuracy of self-control of slow cortical potentials (percentage of correct responses). Learning progress calculated as a function of training session. RESULTS: Within 3 to 8 weeks, both patients learned to self-regulate their slow cortical potentials and to use this skill to select letters or words in the Language Support Program. CONCLUSIONS: This training schedule is the first to enable severely paralyzed patients to communicate without any voluntary muscle control by using self-regulation of an electroencephalogram potential only. The protocol could be a model for training patients in other brain-computer interface techniques.

Self-initiation of EEG-based communication in paralyzed patients.

OBJECTIVES: Severely paralyzed patients could learn to voluntarily generate slow cortical potential (SCP) shifts in their electroencephalogram and to use these signals to operate a communication device. To enhance the patients' autonomy, the present study describes the development of a permanently available communication system that can be turned on and off by locked-in patients without external assistance. A skill necessary for turning the system on is the ability to regulate one's slow potentials in the absence of continuous feedback. METHODS: A stepwise learning approach was employed to train two paralyzed patients to regulate their SCPs without continuous feedback. Elements of the original communication system were gradually removed and elements of the new stand-by mode were introduced. RESULTS: At the end of the learning procedure, both patients achieved correct response rates of above 84% in training sessions without continuous feedback. This skill enabled them to turn the communication device on and off without assistance from others. CONCLUSIONS: These findings suggest that severely paralyzed individuals can learn to operate an EEG-based communication device autonomously.

The thought translation device (TTD) for completely paralyzed patients.

The thought translation device trains locked-in patients to self-regulate slow cortical potentials (SCP's) of their electroencephalogram (EEG). After operant learning of SCP self-control, patients select letters, words or pictograms in a computerized language support program. Results of five respirated, locked-in-patients are described, demonstrating the usefulness of the thought translation device as an alternative communication channel in motivated totally paralyzed patients with amyotrophic lateral sclerosis.

The thought translation device: a neurophysiological approach to communication in total motor paralysis.

A thought translation device (TTD) for brain-computer communication is described. Three patients diagnosed with amyotrophic lateral sclerosis (ALS), with total motor paralysis, were trained for several months. In order to enable such patients to communicate without any motor activity, a technique was developed where subjects learn to control their slow cortical potentials (SCP) in a 2-s rhythm, producing either cortical negativity or positivity according to the task requirement. SCP differences between a baseline interval and an active control interval are transformed into vertical or horizontal cursor movements on a computer screen. Learning SCP self regulation followed an operant-conditioning paradigm with individualized shaping procedures. After prolonged training over more than 100 sessions, all patients achieved self-control, leading to a 70-80% accuracy for two patients. The learned cortical skill enabled the patients to select letters or words in a language-supporting program (LSP) developed for inter-personal communication. The results demonstrate that the fast and stable SCP self-control can be achieved with operant training and without mediation of any muscle activity. The acquired skill allows communication even in total locked-in states.