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Time series analysis with delay differential equations (DDEs) reveals nonlinear properties of the underlying dynamical system and can serve as a non-linear time-domain classification tool. Here global DDE models were used to analyze short segments of simulated time series from a known dynamical system, the Rössler system, in high noise regimes. In a companion paper, we apply the DDE model developed here to classify short segments of encephalographic (EEG) data recorded from patients with Parkinson's disease and healthy subjects. Nine simulated subjects in each of two distinct classes were generated by varying the bifurcation parameter b and keeping the other two parameters (a and c) of the Rössler system fixed. All choices of b were in the chaotic parameter range. We diluted the simulated data using white noise ranging from 10dB to -30dB signal-to-noise ratios (SNR). Structure selection was supervised by selecting the number of terms, delays, and order of nonlinearity of the model DDE model that best linearly separated the two classes of data. The distances d from the linear dividing hyperplane was then used to assess the classification performance by computing the area A' under the ROC curve. The selected model was tested on untrained data using repeated random sub-sampling validation. DDEs were able to accurately distinguish the two dynamical conditions, and moreover, to quantify the changes in the dynamics. There was a significant correlation between the dynamical bifurcation parameter b of the simulated data and the classification parameter d from our analysis. This correlation still held for new simulated subjects with new dynamical parameters selected from each of the two dynamical regimes. Furthermore, the correlation was robust to added noise, being significant even when the noise was greater than the signal. We conclude that DDE models may be used as a generalizable and reliable classification tool for even small segments of noisy data.

Objective To evaluate the safety and assess the different symptom improvements found after a combined low frequency primary motor cortex and high frequency prefrontal cortex stimulation using the deep TMS (dTMS) H-coil, as an add-on treatment for Parkinson´s disease (PD). Methods: 45 PD patients underwent 14 dTMS sessions; each consisting of 1Hz stimulation of the primary motor cortex for 15 min, followed by 10Hz stimulation of the prefrontal cortex for 15 min. Clinical assessments were performed, at the START, MIDDLE, and END of therapy as well as at FOLLOW-UP after 30 days, using MDS-UPDRS, TINETTI, UP&GO, SCOPA, HDRS21, BDI and self-applied daily motor assessment scales. Results: Treatment was well tolerated, without serious adverse effects. Treatment induced significant PD symptom improvements at END and at FOLLOW-UP, in all subscales of the UPDRS, gait speed, depressive symptoms, balance, autonomic symptoms and a 73% increase in daily ON time. Conclusions: In the cohort of PD patients treated, dTMS was well tolerated with only minor adverse effects. The dTMS induced significant improvements in motor, postural, and motivational symptoms of PD patients and may potentiate concurrent levodopa treatment. Significance: The present study demonstrates that dTMS may have a much wider spectrum of beneficial effects than previously reported for TMS, including enhancement of levodopa effects, suggesting that future clinical trials with dTMS should include a broader range of symptom measurements.

(1)Context: Despite its widespread use, the precise mechanism of action of Deep Brain Stimulation (DBS) therapy remains unknown. The modern urgency to publish more and new data can obscure previously learned lessons by the giants who have preceded us and whose shoulders we now stand upon. Wilder Penfield extensively studied the effects of artificial electrical brain stimulation and his comments on the subject are still very relevant today. In particular, he noted two very different (and seemingly opposite) effects of stimulation within the human brain. In some structures, artificial electrical stimulation has an effect which mimics ablation, while, in other structures, it produces a stimulatory effect on that tissue. (2)Hypothesis:The hypothesis of this paper is fourfold. First, it proposes that some neural circuits are widely synchronized with other neural circuits, while some neural circuits are unsynchronized and operate independently. Second, it proposes that artificial high frequency electrical stimulation of a synchronized neural circuit results in an ablative effect, but artificial high frequency electrical stimulation of an unsynchronized neural circuit results in a stimulatory effect. Third, it suggests a part of the mechanism by which large scale physiologic synchronization of widely distributed independently processed information streams may occur. This may be the neural mechanism underlying Penfield’s centrencephalic system which he emphasized so many years ago. Fourth, it outlines the specific anatomic distribution of this physiologic synchronization, which Penfield has already clearly delineated as the distribution of his centrencephalic system. (3)Evidence:This paper draws on a brief overview of previous theory regarding the mechanism of action of DBS and on historical, as well as widely known modern clinical data regarding the observed effects of stimulation delivered to various targets within the brain. Basic science in

Background: Movement disorders in Huntington´s disease are often medically refractive. The aim of the trial was assessment of procedure safety of deep brain stimulation, equality of internal- and external-pallidal stimulation and efficacy followed-up for 6 months in a prospective pilot trial.Methods: In a conrolled double-blind phase 6 patients (4 chorea-dominant, 2 Westphal-variant) with predominant movement disorder were randomly assigned to either the sequence of 6 week internal-/6 week external-pallidal stimulation, or vice versa, followed by further 3 months chronic pallidal stimulation at the target with best effect-side-effect ratio. Primary endpoints were changes in the Unified Huntington´s Disease Rating Scale motor-score, chorea subscore and total motor-score 4 (blinded video ratings), comparing internal- versus external-pallidal stimulation, and 6 month versus baseline. Secondary endpoints assessed scores on dystonia, hypokinesia, cognition, mood, functionality/disability and quality-of-life. Results: Intention-to-treat analysis of all patients (n=3 in each treatment sequence): Both targets were equal in terms of efficacy. Chorea subscores decreased significantly over 6 months (-5.3 (60.2%), p=0.037). Effects on dystonia were not significant over the group due to it consisting of three responders (>50% improvement) and three non-responders. Westphal patients did not improve. Cognition was stable. Mood and some functionality/disability and quality-of-life scores improved significantly. 8 adverse events and 2 additional serious adverse events - mostly internal-pallidal stimulation-related - resolved without sequalae. No procedure-related complications occurred.Conclusion: Pallidal deep brain stimulation was demonstrated to be a safe treatment option for the reduction of chorea in Huntington´s disease. Their effects on chorea and dystonia and on quality-of-life, should be examined in larger controlled trials.

In recent years there has been a significant increase in the use of electroencephalography (EEG) and magnetoencephalography (MEG) to investigate changes in oscillatory brain activity associated with tinnitus with many conflicting results. Current view of the underlying mechanism of tinnitus is that it results from changes in brain activity in various structures of the brain as a consequence of sensory deprivation. This in turn gives rise to increased spontaneous activity and/or synchrony in the auditory centres but also involves modulation from non-auditory processes from structures of the limbic and paralimbic system. Some of the neural changes associated with tinnitus may be assessed non-invasively in humans with MEG and EEG (M/EEG) in ways which are superior to animal studies and other non-invasive imaging techniques. However, both MEG and EEG have their limitations and research results can be misinterpreted in the absence of sufficient understanding of these limitations. In this article, I intend to provide a brief review of these techniques, describe what the recorded signals reflect in terms of the underlying neural activity, and their strengths and limitations. I also discuss some pertinent methodological issues involved in tinnitus related studies and concludes with suggestions to minimise possible discrepancies between results. The overall message is that while MEG and EEG are extremely useful techniques, the interpretation of results from tinnitus studies requires much caution given the individual variability in oscillatory activity and the limits of these techniques.

There is increasing evidence supporting dietary and alternative therapies for epilepsy, including the ketogenic diet, modified Atkins diet, and omega-3 fatty acids. Vitamin D is actively under investigation as a potential intervention for epilepsy. Vitamin D is fat soluble steroid which shows promise in animal models of epilepsy. Basic research has shed light on the possible mechanisms by which Vitamin D may reduce seizures, and animal data support the efficacy of Vitamin D in rat and mouse models of epilepsy. Very little clinical data exists to support the treatment of human epilepsy with Vitamin D, but positive findings from preliminary clinical trials warrant larger Phase I and II clinical trials in order to more rigorously determine the potential therapeutic value of Vitamin D as a treatment for human epilepsy.

IntroductionAging and age-associated disorders such as Parkinson’s disease (PD) are often associated with turning difficulties, which can lead to falls and fractures. Valid assessment of turning and turning deficits specifically in non-standardized environments may foster specific treatment and prevention of consequences.MethodsRelative orientation, obtained from 3D-accelerometer and 3D-gyroscope data of a sensor worn at the lower back, was used to develop an algorithm for turning detection and qualitative analysis in PD patients and controls in non-standardized environments. The algorithm was validated with a total of 2,304 turns ≥90° extracted from an independent dataset of 20 PD patients during medication ON- and OFF-conditions and 13 older adults. Video observation by two independent clinical observers served as gold standard.ResultsIn PD patients under medication OFF, the algorithm detected turns with a sensitivity of 0.92, a specificity of 0.89, and an accuracy of 0.92. During medication ON, values were 0.92, 0.78, and 0.83. In older adults, the algorithm reached validation values of 0.94, 0.89, and 0.92. Turning magnitude (difference, 0.06°; SEM, 0.14°) and duration (difference, 0.004 s; SEM, 0.005 s) yielded high correlation values with gold standard. Overall accuracy for direction of turning was 0.995. Intra class correlation of the clinical observers was 0.92.ConclusionThis wearable sensor- and relative orientation-based algorithm yields very high agreement with clinical observation for the detection and evaluation of ≥90° turns under non-standardized conditions in PD patients and older adults. It can be suggested for the assessment of turning in daily life.