[Show abstract][Hide abstract] ABSTRACT: Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of non-invasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multi-day repetitive TMS (rTMS) can induce long-lasting, potentially therapeutic, brain plasticity. Nearby ferromagnetic or electronic implants are contraindications, and adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. TMS devices are marketed for depression and migraine in the U.S. and for multiple indications elsewhere. Although multiple studies report that high-frequency rTMS of motor cortex reduces neuropathic pain, their quality has been insufficient to support FDA application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters, and improve strategies for sham and double-blinding. Subjects should have common, well-characterized pain conditions amenable to motor-cortex rTMS and samples should be adequately powered. They recommended standardized assessment tools (e.g., NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (e.g. IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion/exclusion criteria, baseline and post-treatment means and standard deviations, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months post-initiation with pre-specified statistical analyses. Multi-group collaborations or registry studies may be needed for pivotal trials.
[Show abstract][Hide abstract] ABSTRACT: To study the temporal dynamics of tissue impedance after deep brain stimulation (DBS).
DBS therapy commonly employs a constant voltage approach, and current delivery to the tissue is a function of electrode-tissue impedance. It is presumed that impedance fluctuates early postimplantation, with implications for variations in current delivery and therapeutic efficacy. We hypothesised that the largest variation will be recorded early after surgery, followed by stabilisation.
Review of impedance checks of implanted DBS systems at standard parameters during the first five months postimplantation. All measurement time points were binned into 1-week periods, and we used repeated measures analysis of variance with Tukey pairwise multiple comparisons correction. The analysis was repeated after normalising impedance values for each subject to that patient's baseline value.
There was an initial (non-significant) drop in impedance at week 1, followed by significant increase at week 3 (p=0.0002). There were no further significant differences in impedance values at subsequent time points. Analysis of normalised data showed a significant difference between the initial measurement in postoperative week 1 (normalised value 1) and week 3 (normalised value 1.73, p<0.0001), with no further difference among the subsequent weekly points during the 5-month follow-up. No significant hourly variations were found at any time points.
We found major changes in impedance within the first month postimplantation, with no further variation. This is an important confirmation in patients of this temporal dynamics of the impedance of implanted DBS hardware, with potential therapeutic implications.
Journal of neurology, neurosurgery, and psychiatry 11/2013; 85(7). DOI:10.1136/jnnp-2013-306066 · 6.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Injectable botulinum neurotoxin (BoNT) is the principal effective treatment for blepharospasm (BSP). This trial explores the safety and efficacy of topical acetyl hexapeptide-8 (AH8), a competitive SNAP25 inhibitor, as a potential new therapy in BSP.
Double-blind, placebo-controlled, randomized trial of daily topical application of AH8 in 24 patients with BSP. The primary outcome was time to return to baseline Jankovic Blepharospasm Rating Scale (JBRS) after a BoNT injection simultaneously with the initiation of AH8. Patients displaying a strictly regular pattern of response to 3-monthly injections of BoNT were included.
There were no significant adverse events. There was a trend for longer time until return to baseline JBRS after injection in the active group compared to placebo (3.7 months vs. 3.0 months), and for better scores in the active group. One-third (4/12) of the patients in the active group had a considerable extension of symptom control after BoNT (range: 3.3-7.1 months).
Topical AH8 is safe and promising for extending the duration of action of BoNT therapy for BSP.
European Journal of Neurology 11/2012; 20(3). DOI:10.1111/ene.12009 · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Subthalamic nucleus deep brain stimulation (STN DBS) is an effective surgical treatment for Parkinson's disease (PD). Recent studies demonstrated that pathological oscillations are seen largely within the dorsolateral portion of the STN, which is the same location that predicts optimal therapeutic benefit with DBS; however, the precise nature of the relationship between these two phenomena remains unclear. The purpose of this study was to explore localization of oscillatory activity in relation to the optimal contacts of DBS which results in the best motor improvement. We studied 23 PD patients who underwent electrode implantation into the STN for motor symptoms. Microelectrode recordings were taken from the STN during surgery and neuronal activity was analyzed offline. Spectral characteristics were calculated. Clinical outcomes were evaluated pre- and post-STN DBS implantation using the Unified Parkinson's Disease Rating Scale (UPDRS III). The position of optimal electrode contacts was assessed by postoperative magnetic resonance imaging (MRI) and was compared to the location of oscillatory activity within the STN as well as its dorsal margin (where STN neuronal activity was first detected). Of the total 188 neurons obtained, 51 (27.1%) neurons showed significant oscillatory activity. Of those, 47 (92.2%) were localized in the dorsal portion of the STN. Furthermore, there was no significant difference between the averaged coordinates of the position of 40 optimal contacts and the coordinates of the dorsal margin of the STN. The data indicate that the positions of the best contacts correlate with the locations of the oscillatory neurons supporting the prediction that stimulation of the dorsolateral oscillatory region leads to an effective clinical outcome for STN DBS surgery.
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation (DBS) is a highly promising therapy for Parkinson's disease (PD). However, most patients do not get full therapeutic benefit from DBS, due to its critical dependence on electrode location in the Subthalamic Nucleus (STN). For this reason, we believe that the development of a novel surgical tool for DBS placement, i.e., an automated intraoperative closed-loop DBS localization system, is essential. In this paper, we analyze single unit spiking activity of 120 neurons in different STN locations collected from 4 PD patients. Specifically, for each neuron, we estimate a point process model (PPM) of the spiking activity for different depths within the STN by which we are able to detect pathological bursting and oscillations. Our results suggest that these signatures are more prominent in the dorsolateral part of the STN. Therefore, accurately placing the DBS electrode in this target may result in maximal therapeutic benefit with less power effort required by DBS. Furthermore, PPMs might be an effective tool for modeling of the STN neuronal activities as a function of location within the STN, which may pave the way towards developing a closed-loop navigation tool for optimal DBS electrode placement.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2012; 2012:2539-42. DOI:10.1109/EMBC.2012.6346481
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation (DBS) is a highly promising therapy for Parkinson's disease (PD). However, most patients do not get full therapeutic benefit from DBS yet, due to its critical dependence on electrode location. For this reason, we believe that the investigation of a neural modeling, estimation and control framework for the STN is an interesting research problem. This would pave the way for the development of a novel surgical tool for the DBS placement standardization, i.e., an automated intraoperative closed-loop DBS localization system. A fundamental problem to be solved for the realization of a such framework is the neurophysiologic characterization of the STN activity. Indeed, this would allow to understand if the modeling of the sweet spot is feasible. In this paper an effort towards the modeling of the neuronal activity near the stimulation target is made: first we analyze single unit spiking activity of 120 STN neurons collected from four PD patients at different distances from the sweet spot and, for each neuron, we estimate a point process model (PPM). Then, we see that PPMs capture the stochastic effects of the distance from the sweet spot on the STN spiking activity, and characterize the impact of local neuronal networks on the single neurons. Our results suggest that PPMs might be an effective tool for modeling of the STN neuronal activities accounting for the depth within it.
Control Applications (CCA), 2012 IEEE International Conference on; 01/2012
[Show abstract][Hide abstract] ABSTRACT: Valid assessment of apraxia in usually non-apraxic Parkinson's disease helps to delineate atypical parkinsonism frequently associated with apraxia. Furthermore, in a subgroup of late Parkinson's disease apraxia, typically the ideomotor subtype, may gradually superimpose onto parkinsonian motor symptoms contributing to defective manual skill. Here we evaluate the utility of a brief, standardized test, the apraxia screen of TULIA (AST).
Seventy five Parkinson's disease patients were tested with the AST. Parkinsonian motor deficits were measured using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III and difficulties in activities of daily living (ADL) by modified MDS-UPDRS part II (eating, dressing, personal hygiene, and writing).
No association was found between the AST and MDS-UPDRS part III, indicating that AST discriminates well (discriminative validity) between apraxia and parkinsonism. Furthermore, AST was associated with ADL and Hoehn & Yahr stage (convergent validity).
AST is a short and valid test to rule out or detect apraxia in Parkinson's disease.