Advanced clinical MRI for better outcome in epilepsy surgery. Focusing on fMRI and prediction of verbal memory decline.

Abstract Aim: The aim of the thesis was to evaluate the use of advanced MRI technology to improve results of epilepsy surgery, with focus on language and memory functions. Methods: In paper I, 25 patients with drug-resistant epilepsy were retrospectively included in the study for having been referred to high resolution 3T MRI with and without surface coils. The surface coils were placed over the suspected epileptogenic zone. The efficacy of the coils was assessed and graded in relation to their placement. In papers II, III and IV, a functional MRI (fMRI) paradigm, including both a verbal encoding task and a visuospatial task, was designed and implemented. The medial temporal lobe (MTL) for memory and the anterior language area were studied. In paper III, a standard word generation fMRI paradigm was also included. In these three studies, the test was performed in 15 healthy right handed subjects (paper II), 6 patients with drug-resistant temporal lobe epilepsy (TLE) with mixed handedness and 10 controls (paper III) and 14 TLE patients eligible for resective surgery (paper IV), respectively. A bootstrap algorithm was used to calculate lateralization indices (LI) and LI-curves. In paper IV, a clinical risk assessment score was created from collected clinical data. Additional value from fMRI LI was correlated to post-surgical memory decline. Results: Surface coil 3T MRI did not contribute to detection of previously undiagnosed lesions. In 20% of patients, 3T MRI, compared with previous 1.0-1.5T MRI, provided new information about cortical lesions. The fMRI paradigm visualized memory-related activity in the MTL and provided information regarding language processes. LI and LI-curves for memory at group level were consistent with previous studies, but a variety of activation effects were found at the individual level. LI-curves added complementary information for individual subjects with uncharacteristic results. The verbal encoding task provided information on verbal memory, which had equal lateralization as language in right-handed subjects, but not always in left-handed subjects and TLE patients. Bilateral fMRI language representation was seen in 2 right TLE patients who later suffered verbal memory decline post-operatively. Conclusion: High resolution 3T MRI is valuable for lesion detection, but surface coils do not provide further crucial information. The fMRI paradigm activates memory and language areas that can be studied at an individual level using LIcurves. Analysis of language patterns seems to be important for prediction of memory outcome in both left and right TLE. fMRI indices may identify an unexpected high risk for post-operative verbal memory decline in right TLE patients

The Role of the Primary Sensory Cortices in Early Language Processing.

The results of this magnetoencephalography study challenge two long-standing assumptions regarding the brain mechanisms of language processing: First, that linguistic processing proper follows sensory feature processing effected by bilateral activation of the primary sensory cortices that lasts about 100 msec from stimulus onset. Second, that subsequent linguistic processing is effected by left hemisphere networks outside the primary sensory areas, including Broca's and Wernicke's association cortices. Here we present evidence that linguistic analysis begins almost synchronously with sensory, prelinguistic verbal input analysis and that the primary cortices are also engaged in these linguistic analyses and become, consequently, part of the left hemisphere language network during language tasks. These findings call for extensive revision of our conception of linguistic processing in the brain

A Functional MRI Paradigm Suitable for Language and Memory Mapping in Pediatric Temporal Lobe Epilepsy

Functional Magnetic Resonance Imaging (fMRI) is a technique frequently used to determine the territories of eloquent tissue that serve critical functions, such as language. This can be particularly useful as part of the pre-surgical assessment for temporal lobe epilepsy (TLE) in order to predict cognitive outcome and guide surgical decision-making. Whereas language fMRI is widely used, memory fMRI is less frequently employed in adult TLE, and lacking in childhood TLE. We have developed a combined language/memory fMRI paradigm that is suitable for children, to provide clinically useful information for surgical planning in pediatric TLE. We evaluated this paradigm in 28 healthy children, aged 8 to 18 years. The advantages of this paradigm are: (a) it examines the functional mapping of language and memory networks within one scanning session, (b) provides assessment of both memory encoding- and retrieval-related neural networks, (c) examines recall-based retrieval to engage hippocampal involvement compared to recognition-based retrieval, and (d) provides overt verbal responses to monitor in-scanner memory performance. This novel fMRI paradigm was designed for language and memory mapping in pediatric TLE and could provide clinically useful information for surgical planning. Finally, parallel versions of the paradigm allow the comparison of brain activations pre- and post-surgical intervention

Spectrotemporal modulation provides a unifying framework for auditory cortical asymmetries

The principles underlying functional asymmetries in cortex remain debated. For example, it is accepted that speech is processed bilaterally in auditory cortex, but a left hemisphere dominance emerges when the input is interpreted linguistically. The mechanisms, however, are contested, such as what sound features or processing principles underlie laterality. Recent findings across species (humans, canines and bats) provide converging evidence that spectrotemporal sound features drive asymmetrical responses. Typically, accounts invoke models wherein the hemispheres differ in time-frequency resolution or integration window size. We develop a framework that builds on and unifies prevailing models, using spectrotemporal modulation space. Using signal processing techniques motivated by neural responses, we test this approach, employing behavioural and neurophysiological measures. We show how psychophysical judgements align with spectrotemporal modulations and then characterize the neural sensitivities to temporal and spectral modulations. We demonstrate differential contributions from both hemispheres, with a left lateralization for temporal modulations and a weaker right lateralization for spectral modulations. We argue that representations in the modulation domain provide a more mechanistic basis to account for lateralization in auditory cortex

Computer-Assisted Planning and Robotics in Epilepsy Surgery

Epilepsy is a severe and devastating condition that affects ~1% of the population. Around 30% of these patients are drug-refractory. Epilepsy surgery may provide a cure in selected individuals with drug-resistant focal epilepsy if the epileptogenic zone can be identified and safely resected or ablated. Stereoelectroencephalography (SEEG) is a diagnostic procedure that is performed to aid in the delineation of the seizure onset zone when non-invasive investigations are not sufficiently informative or discordant. Utilizing a multi-modal imaging platform, a novel computer-assisted planning (CAP) algorithm was adapted, applied and clinically validated for optimizing safe SEEG trajectory planning. In an initial retrospective validation study, 13 patients with 116 electrodes were enrolled and safety parameters between automated CAP trajectories and expert manual plans were compared. The automated CAP trajectories returned statistically significant improvements in all of the compared clinical metrics including overall risk score (CAP 0.57 +/- 0.39 (mean +/- SD) and manual 1.00 +/- 0.60, p < 0.001). Assessment of the inter-rater variability revealed there was no difference in external expert surgeon ratings. Both manual and CAP electrodes were rated as feasible in 42.8% (42/98) of cases. CAP was able to provide feasible electrodes in 19.4% (19/98), whereas manual planning was able to generate a feasible electrode in 26.5% (26/98) when the alternative generation method was not feasible. Based on the encouraging results from the retrospective analysis a prospective validation study including an additional 125 electrodes in 13 patients was then undertaken to compare CAP to expert manual plans from two neurosurgeons. The manual plans were performed separately and blindly from the CAP. Computer-generated trajectories were found to carry lower risks scores (absolute difference of 0.04 mm (95% CI = -0.42-0.01), p = 0.04) and were subsequently implanted in all cases without complication. The pipeline has been fully integrated into the clinical service and has now replaced manual SEEG planning at our institution. Further efforts were then focused on the distillation of optimal entry and target points for common SEEG trajectories and applying machine learning methods to develop an active learning algorithm to adapt to individual surgeon preferences. Thirty-two patients were prospectively enrolled in the study. The first 12 patients underwent prospective CAP planning and implantation following the pipeline outlined in the previous study. These patients were used as a training set and all of the 108 electrodes after successful implantation were normalized to atlas space to generate ‘spatial priors’, using a K-Nearest Neighbour (K-NN) classifier. A subsequent test set of 20 patients (210 electrodes) were then used to prospectively validate the spatial priors. From the test set, 78% (123/157) of the implanted trajectories passed through both the entry and target spatial priors defined from the training set. To improve the generalizability of the spatial priors to other neurosurgical centres undertaking SEEG and to take into account the potential for changing institutional practices, an active learning algorithm was implemented. The K-NN classifier was shown to dynamically learn and refine the spatial priors. The progressive refinement of CAP SEEG planning outlined in this and previous studies has culminated in an algorithm that not only optimizes the surgical heuristics and risk scores related to SEEG planning but can also learn from previous experience. Overall, safe and feasible trajectory schema were returning in 30% of the time required for manual SEEG planning. Computer-assisted planning was then applied to optimize laser interstitial thermal therapy (LITT) trajectory planning, which is a minimally invasive alternative to open mesial temporal resections, focal lesion ablation and anterior 2/3 corpus callosotomy. We describe and validate the first CAP algorithm for mesial temporal LITT ablations for epilepsy treatment. Twenty-five patients that had previously undergone LITT ablations at a single institution and with a median follow up of 2 years were included. Trajectory parameters for the CAP algorithm were derived from expert consensus to maximize distance from vasculature and ablation of the amygdalohippocampal complex, minimize collateral damage to adjacent brain structures whilst avoiding transgression of the ventricles and sulci. Trajectory parameters were also optimized to reduce the drilling angle to the skull and overall catheter length. Simulated cavities attributable to the CAP trajectories were calculated using a 5-15 mm ablation diameter. In comparison to manually planned and implemented LITT trajectories,CAP resulted in a significant increase in the percentage ablation of the amygdalohippocampal complex (manual 57.82 +/- 15.05% (mean +/- S.D.) and unablated medial hippocampal head depth (manual 4.45 +/- 1.58 mm (mean +/- S.D.), CAP 1.19 +/- 1.37 (mean +/- S.D.), p = 0.0001). As LITT ablation of the mesial temporal structures is a novel procedure there are no established standards for trajectory planning. A data-driven machine learning approach was, therefore, applied to identify hitherto unknown CAP trajectory parameter combinations. All possible combinations of planning parameters were calculated culminating in 720 unique combinations per patient. Linear regression and random forest machine learning algorithms were trained on half of the data set (3800 trajectories) and tested on the remaining unseen trajectories (3800 trajectories). The linear regression and random forest methods returned good predictive accuracies with both returning Pearson correlations of ρ = 0.7 and root mean squared errors of 0.13 and 0.12 respectively. The machine learning algorithm revealed that the optimal entry points were centred over the junction of the inferior occipital, middle temporal and middle occipital gyri. The optimal target points were anterior and medial translations of the centre of the amygdala. A large multicenter external validation study of 95 patients was then undertaken comparing the manually planned and implemented trajectories, CAP trajectories targeting the centre of the amygdala, the CAP parameters derived from expert consensus and the CAP trajectories utilizing the machine learning derived parameters. Three external blinded expert surgeons were then selected to undertake feasibility ratings and preference rankings of the trajectories. CAP generated trajectories result in a significant improvement in many of the planning metrics, notably the risk score (manual 1.3 +/- 0.1 (mean +/- S.D.), CAP 1.1 +/- 0.2 (mean +/- S.D.), p<0.000) and overall ablation of the amygdala (manual 45.3 +/- 22.2 % (mean +/- S.D.), CAP 64.2 +/- 20 % (mean +/- S.D.), p<0.000). Blinded external feasibility ratings revealed that manual trajectories were less preferable than CAP planned trajectories with an estimated probability of being ranked 4th (lowest) of 0.62. Traditional open corpus callosotomy requires a midline craniotomy, interhemispheric dissection and disconnection of the rostrum, genu and body of the corpus callosum. In cases where drop attacks persist a completion corpus callosotomy to disrupt the remaining fibres in the splenium is then performed. The emergence of LITT technology has raised the possibility of being able to undertake this procedure in a minimally invasive fashion and without the need for a craniotomy using two or three individual trajectories. Early case series have shown LITT anterior two-thirds corpus callosotomy to be safe and efficacious. Whole-brain probabilistic tractography connectomes were generated utilizing 3-Tesla multi-shell imaging data and constrained spherical deconvolution (CSD). Two independent blinded expert neurosurgeons with experience of performing the procedure using LITT then planned the trajectories in each patient following their current clinical practice. Automated trajectories returned a significant reduction in the risk score (manual 1.3 +/- 0.1 (mean +/- S.D.), CAP 1.1 +/- 0.1 (mean +/- S.D.), p<0.000). Finally, we investigate the different methods of surgical implantation for SEEG electrodes. As an initial study, a systematic review and meta-analysis of the literature to date were performed. This revealed a wide variety of implantation methods including traditional frame-based, frameless, robotic and custom-3D printed jigs were being used in clinical practice. Of concern, all comparative reports from institutions that had changed from one implantation method to another, such as following the introduction of robotic systems, did not undertake parallel-group comparisons. This suggests that patients may have been exposed to risks associated with learning curves and potential harms related to the new device until the efficacy was known. A pragmatic randomized control trial of a novel non-CE marked robotic trajectory guidance system (iSYS1) was then devised. Before clinical implantations began a series of pre-clinical investigations utilizing 3D printed phantom heads from previously implanted patients was performed to provide pilot data and also assess the surgical learning curve. The surgeons had comparatively little clinical experience with the new robotic device which replicates the introduction of such novel technologies to clinical practice. The study confirmed that the learning curve with the iSYS1 devices was minimal and the accuracies and workflow were similar to the conventional manual method. The randomized control trial represents the first of its kind for stereotactic neurosurgical procedures. Thirty-two patients were enrolled with 16 patients randomized to the iSYS1 intervention arm and 16 patients to the manual implantation arm. The intervention allocation was concealed from the patients. The surgical and research team could be not blinded. Trial management, independent data monitoring and trial steering committees were convened at four points doing the trial (after every 8 patients implanted). Based on the high level of accuracy required for both methods, the main distinguishing factor would be the time to achieve the alignment to the prespecified trajectory. The primary outcome for comparison, therefore, was the time for individual SEEG electrode implantation. Secondary outcomes included the implantation accuracy derived from the post-operative CT scan, infection, intracranial haemorrhage and neurological deficit rates. Overall, 32 patients (328 electrodes) completed the trial (16 in each intervention arm) and the baseline demographics were broadly similar between the two groups. The time for individual electrode implantation was significantly less with the iSYS1 device (median of 3.36 (95% CI 5.72 to 7.07) than for the PAD group (median of 9.06 minutes (95% CI 8.16 to 10.06), p=0.0001). Target point accuracy was significantly greater with the PAD (median of 1.58 mm (95% CI 1.38 to 1.82) compared to the iSYS1 (median of 1.16 mm (95% CI 1.01 to 1.33), p=0.004). The difference between the target point accuracies are not clinically significant for SEEG but may have implications for procedures such as deep brain stimulation that require higher placement accuracy. All of the electrodes achieved their respective intended anatomical targets. In 12 of 16 patients following robotic implantations, and 10 of 16 following manual PAD implantations a seizure onset zone was identified and resection recommended. The aforementioned systematic review and meta-analysis were updated to include additional studies published during the trial duration. In this context, the iSYS1 device entry and target point accuracies were similar to those reported in other published studies of robotic devices including the ROSA, Neuromate and iSYS1. The PAD accuracies, however, outperformed the previously published results for other frameless stereotaxy methods. In conclusion, the presented studies report the integration and validation of a complex clinical decision support software into the clinical neurosurgical workflow for SEEG planning. The stereotactic planning platform was further refined by integrating machine learning techniques and also extended towards optimisation of LITT trajectories for ablation of mesial temporal structures and corpus callosotomy. The platform was then used to seamlessly integrate with a novel trajectory planning software to effectively and safely guide the implantation of the SEEG electrodes. Through a single-blinded randomised control trial, the ISYS1 device was shown to reduce the time taken for individual electrode insertion. Taken together, this work presents and validates the first fully integrated stereotactic trajectory planning platform that can be used for both SEEG and LITT trajectory planning followed by surgical implantation through the use of a novel trajectory guidance system

Median and Ulnar Nerve Injuries in Children and Adolescents- Long-term outcome and Cerebral reorganisation

A peripheral nerve injury may lead to serious disability and influence the individual´s quality of life. It is considered that children can regain better sensory and motor function after a peripheral nerve injury, but the exact mechanism behind such superior recovery is not known. The aim of the thesis was to study the long-term clinical outcome after a peripheral nerve injury in patients injured in childhood and adolescence and to relate the clinical outcome to changes in the central and peripheral nervous systems. In addition, the consequences of the nerve injury for the patient´s life were explored. A short-term pilot study with four patients showed remaining clinical and electrophysiological abnormalities and functional Magnetic Resonance Imaging (fMRI) showed that the cerebral activation pattern after tactile stimulation of the injured hand was different compared to the pattern of the healthy hand. In a larger study, the long-term functional outcome after nerve repair in those injured in childhood was compared to the outcome of those injured in adolescence. Patients below the age of 21 years, operated on at our hospital for a complete median or ulnar nerve injury at the level of the forearm 1970-1989, were followed up at a median of 31 years. Outcome was significantly better in those injured in childhood, i.e. below the age of 12 years, with almost full sensory and motor recovery. No significant differences in recovery were seen between patients with median and ulnar nerve injuries, or even when both nerves were injured. The median DASH scores (i.e. questionnaire; Disability Arm Shoulder and Hand) were within normal limits and cold sensitivity was not a problem in either age group. Those injured in adolescence (i.e. above the age of 12 years) had a significantly higher impact on their profession, education, and leisure activities. Electrophysiological evaluation (amplitude, conduction velocity and distal motor latency) showed pathology in all parameters and in all patients, irrespective of age at injury. This suggests that the mechanisms behind the superior clinical outcome in children are not located in the peripheral nervous system. With fMRI it was shown that patients injured in childhood had a cortical activation pattern similar to that of healthy controls and it was observed that cerebral changes in both hemispheres may explain differences in clinical outcome following a nerve injury in childhood or adolescence. Finally, fifteen patients injured in adolescence, who were interviewed to explore the experiences after a nerve injury and its consequences for daily life, described emotional reactions to trauma. Even symptoms related to post-traumatic stress disorder were mentioned and the patients described different adaptation strategies used. Educational and professional life had changed completely for some. The present thesis shows that age is an important factor that influences outcome after a peripheral nerve injury. The reason for the age-related difference in outcome is alterations in the central nervous system. In addition, a nerve injury had a severe impact on the individuals´ life. By further exploring the mechanisms of plasticity and by modifying the rehabilitation, we might eventually improve the outcome after a peripheral nerve injury

Mapping &amp; decoding cortical engagement during motor imagery, mental arithmetic, and silent word generation using MEG

Accurate quantification of cortical engagement during mental imagery tasks remains a challenging brain-imaging problem with immediate relevance to developing brain–computer interfaces. We analyzed magnetoencephalography (MEG) data from 18 individuals completing cued motor imagery, mental arithmetic, and silent word generation tasks. Participants imagined movements of both hands (HANDS) and both feet (FEET), subtracted two numbers (SUB), and silently generated words (WORD). The task-related cortical engagement was inferred from beta band (17–25 Hz) power decrements estimated using a frequency-resolved beamforming method. In the hands and feet motor imagery tasks, beta power consistently decreased in premotor and motor areas. In the word and subtraction tasks, beta-power decrements showed engagements in language and arithmetic processing within the temporal, parietal, and inferior frontal regions. A support vector machine classification of beta power decrements yielded high accuracy rates of 74 and 68% for classifying motor-imagery (HANDS vs. FEET) and cognitive (WORD vs. SUB) tasks, respectively. From the motor-versus-nonmotor contrasts, excellent accuracy rates of 85 and 80% were observed for hands-versus-word and hands-versus-sub, respectively. A multivariate Gaussian-process classifier provided an accuracy rate of 60% for the four-way (HANDS-FEET-WORD-SUB) classification problem. Individual task performance was revealed by within-subject correlations of beta-decrements. Beta-power decrements are helpful metrics for mapping and decoding cortical engagement during mental processes in the absence of sensory stimuli or overt behavioral outputs. Markers derived based on beta decrements may be suitable for rehabilitation purposes, to characterize motor or cognitive impairments, or to treat patients recovering from a cerebral stroke

Micro-, Meso- and Macro-Connectomics of the Brain

Neurosciences, Neurolog

Transcranial magnetic stimulation in assessment of cortical network properties

This Thesis demonstrates the way to combine navigated transcranial magnetic stimulation (nTMS) with electrophysiological techniques, such as electroencephalography (EEG) and magnetoencephalo­graphy (MEG). This technical and neurophysiological possibility allows the assessment of cortical excitability and functional connectivity with the advantage of high spatiotemporal resolution. Investigation of these cortical network properties can lead in deeper understanding of sensorimotor and speech networks and bridge the gap between basic research and clinical applications by means of TMS. First, we examined whether nTMS–EEG can be used as a marker of cortical excitability changes by investigating the reproducibility of EEG after TMS. We showed that reproducibility is a feature of TMS-evoked EEG responses if the parameters of the stimulation and coil orientation are kept the same. Utilization of navigation is crucial for such test–retest paradigms. The second part of the thesis elaborated the effect of neuronal state prior to TMS on cortico–cortical excitability. We demonstrated modulation of excitability not only of the contra- but also of the ipsilateral hemisphere during preparation and execution of unilateral movements. We also tested the methodology to measure the time onset of cortical activation by grading the levels of its modulation with TMS–EEG. Next, we utilized MEG to detect sensorimotor cortical sources. nTMS was used to target these sources and modulate their activity during a motor task after a sensory stimulation. We demonstrated that stimulation of the secondary somatosensory cortex can influence the primary one and amplify somatosensory processing. By this study, we set the methodological standards on how to use nTMS and MEG in mapping the sensorimotor cortex. Therefore, we applied our experience in presurgical mapping of epileptic patients before cortical resection. By combining the nTMS and MEG advantages, we created a noninvasive methodology to map the sensorimotor cortex. The results were as accurate as electrical cortical stimulation in most patients. Thus, it may be possible to replace costly invasive standard procedures, which pose a high risk for the patient, when the epileptic focus is near sensorimotor cortex and accessible to MEG. This motivated us to create another nTMS paradigm for mapping speech-related areas. We combined an object naming paradigm and repetitive TMS to find cortical sites sensitive to interference during the task. We recorded video of the experiment to evaluate the effect of TMS on the subjects’ performance. The results show that this method may map speech-related areas successfully. All in all, we show that recent advances in TMS set new standards in basic research and clinical applications, such as preoperative work- up and test–retest pharmacological studies. Cross-modal nTMS applications open new avenues in studying cortical network parameters