Abstracts and biosketches BCN Symposium 2017: Plenary Session - morning

Prof. Peter Brown
Nuffield department of clinical Neurosciences
Medical Sciences Division
University of Oxford, United Kingdom

Prof. Peter Brown obtained his medical degree from Cambridge University and thereafter joined the Medical Research Council Human Movement and Balance Unit before moving to the Institute of Neurology, London, where he also worked as a neurologist at the affiliated National Hospital for Neurology and Neurosurgery, London. He moved to the University of Oxford as Professor of Experimental Neurology in 2010, and in 2015 became director of the Medical Research Council Brain Network Dynamics Unit at the University of Oxford.

Towards adaptive DBS in Parkinson’s Disease
Examples of the application of adaptive DBS in Parkinson’s Disease are growing [1-6]. These have demonstrated symptom improvement despite substantial power savings, and/or reduction in the side-effects attributable to stimulation. The feedback substrates and closed-loop control algorithms involved have varied, but hitherto most have relied on the amplitude of beta activity directly recorded in the basal ganglia-cortical loop. The amplitude of such beta activity correlates with bradykinesia and rigidity, and is suppressed by both dopaminergic medication and high frequency DBS [7]. Thus far adaptive control algorithms have switched between on and off, or involved a more gradual, proportional control policy. One important consideration is the optimal reactivity of the adaptive system, which may impact on its efficacy, efficiency and upon the ultimate therapeutic window. In healthy primates, and in patients with Parkinson’s disease, beta activity is phasic [8]. Longer busts attain higher amplitudes, indicative of more pervasive oscillatory synchronisation within the neural circuit. Shorter bursts predominate in health, and in patients the relative proportions of short and long bursts negatively and positively correlate with motor impairment, respectively. Hence it might be best to selectively terminate longer, bigger, pathological beta bursts through closed-loop deep brain stimulation to both maximise power savings and to spare the ability of underlying neural circuits to engage in more physiological processing, which may involve shorter bursts [8].

The role of more complex feedback signals, including multidimensional central and peripheral inputs, remains to be explored, as do the advantages of more sophisticated control algorithms. On the other hand, one of the factors holding back the development of closed-loop DBS is the very range of possible feedback signals, control policies and stimulation patterns, and, arguably, the field needs to focus on demonstrating an unequivocal step gain over conventional DBS before closed-loop DBS techniques are further nuanced. Key here is to shift from acute trials in post-operative patients where studies are confounded by stun effects and temporal constraints, to acute then chronic trials in patients who have already undergone conventional DBS. The latter allows resolution of the stun effect and time for optimisation of conventional DBS so that fair comparisons can be made. Such chronic trials will require the further development of enabling technology, together with a more informed understanding of the dynamics of target circuits.

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Dr. Freek Hoebeek
Department of Neuroscience
Erasmus University, the Netherlands

After receiving his doctoral degree in 2000 from University of Amsterdam and his PhD in 2005 from Erasmus Medical Center, dr. Freek Hoebeek’s postdoctoral research focused on the output of the cerebellum, which is generated by the often neglected cerebellar nuclei. He based his hypotheses on data gathered during his PhD, which highlighted the importance of the regularity of neuronal firing. Currently, his research group focusses on the potential impact of the cerebellum on thalamo-cortical networks and how information processing in this neuronal tract influences the behaviour encoded in the various cerebral cortices. They have three key objectives: development of neuronal connections, motor control, and epilepsy, each of which has an obvious translational focus. Already in the motor control (ataxia) and epilepsy fields they published several manuscripts on the potential therapeutic value of pharmacological, electrical and optogenetic interventions at the level of cerebellar output. To ensure an optimal translation of our research findings Freek Hoebeek is actively directing a multi-disciplinary taskforce consisting of neurosurgeons, neurologists, bioengineers and neuroscientists from Leiden UMC, TU Delft and Erasmus MC. Their findings guide ongoing preclinical studies in the fields of neurodevelopment and epilepsy.

C erebral impact of cerebellar neurostimulation: from basic neuroscience to seizure control
Treatment options for in-operable epilepsy patients suffering from drug-resistant seizures are sparse. Currently the last-resort treatment for these patients is deep brain stimulation (DBS). Despite that this local intervention has been refined since the 1970s and that various sites have been probed (Fisher and Velasco, 2014, Nat Rev Neurol) the currently reported seizure reduction and responder rates underline the need for further developments in this field (see for instance, Salanova et al., 2015, Neurology). Based upon the previous clinical use of cerebellar stimulation to treat epilepsy patients in the 1970s and novel insights about the anatomical and physiological connectivity of the neural networks underlying generalized seizures, we recently identified the cerebellar nuclei (CN), which connect to various thalamo-cortical networks, as an ideal candidate to reliably stop generalized seizures. Using an on-demand stimulation paradigm shortly increasing the activity of CN neurons resulted in acute cessation of all epileptic neuronal activity throughout the mouse brain (Kros et al., 2015, Ann Neurol; Kros et al., 2015, TiNS). In my talk I will review these remarkable results and will highlight unpublished findings about how single pulse stimulation in CN can desynchronize thalamo-cortical network activity. These results provide new insights that can help to build a better frame of reference for the therapeutic use of DBS for epilepsy patients.

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Prof.dr. Yasin Temel
Department of Neurosurgery
Maastricht University Medical Center, the Netherlands

Prof. Yasin Temel is a Neurosurgeon with a strong interest in understanding the basis of behaviour. He holds a chair in Experimental Neurosurgery and is the director of the Interuniversity DBS center (Maastricht UMC and Radboud UMC). His research focuses on the basal ganglia and related systems, utilizing clinical and preclinical methods.

DBS in psychiatric disorders: a mechanism-based approach
Deep brain stimulation (DBS) is effective in patients with severe obsessive-compulsive disorders and Tourette syndrome. In other psychiatric disorders, DBS is experimental. The approach of linking specific symptoms, such as compulsions and tics to dysfunction of specific (sub)circuits is the rationale for DBS. This rationale is based on key findings from neuroanatomical, neurophysiological and behavioural studies, both in humans as well as in animal models. In this presentation, this rationale will be outlined with key findings from own studies and from the literature.

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Prof.dr. John Rothwell
Institute of Neurology
University College London, United Kingdom

Prof. John Rothwell is currently Professor of Human Neurophysiology at UCL Institute of Neurology and an Honorary Professor at the University of Adelaide. His main interests are in the pathophysiology of human Movement Disorders and in basic mechanisms of restoration of function after brain injury, particularly stroke. Current research projects include using neurophysiological techniques to study the mechanisms of neural plasticity that underpin motor learning, and using this knowledge to devise new therapeutic interventions for rehabilitation after stroke.

He is an elected Fellow of the Academy of Medical Sciences and Editor-in-Chief of the journal Experimental Brain Research. He has received the Adrian Award of the International Clinical Neurophysiology Society, the Sherrington Medal of the Royal Society of Medicine, the Gloor Award from the American Clinical Neurophysiology Society and the Caruso Award of the Italian Society for Clinical Neurophysiology.

TMS: from basic mechanisms towards clinical applications
Transcranial magnetic stimulation (TMS) uses a magnetic field to “carry” an electrical stimulating pulse into the brain. In the motor cortex, TMS activates neurones that have synaptic inputs onto corticospinal neurones, which then can produce contralateral muscle contraction via their projections to the spinal cord. Initial clinical use of TMS used this to calculate the speed of conduction in corticospinal axons, and detect slowing in conditions such as multiple sclerosis. The recent development of repetitive TMS (rTMS) devices allows us to activate the same set of synapses repetitively, and studies show that this leads to short term changes in synaptic efficiency that outlast the period of stimulation. These produce sustained increases/decrease in the amplitude of the evoked muscle twitches that are probably due to early stages of long term potentiation/depression of cortical synapses. I will describe how these lasting effects can be harnessed for therapy of neurological disease and stroke, and highlight the challenges that still need to be overcome to make the methods reproducible and effective.