Objective: Brain–computer interfaces (BCIs) could potentially be used to interact with pathological brain signals to intervene and ameliorate their effects in disease states. Here, we provide proof-of-principle of this approach by using a BCI to interpret pathological brain activity in patients with advanced Parkinson disease (PD) and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered. Our goal was to demonstrate that by personalizing and optimizing stimulation in real time, we could improve on both the efficacy and efficiency of conventional continuous DBS.Methods: We tested BCI-controlled adaptive DBS (aDBS) of the subthalamic nucleus in 8 PD patients. Feedback was provided by processing of the local field potentials recorded directly from the stimulation electrodes. The results were compared to no stimulation, conventional continuous stimulation (cDBS), and random intermittent stimulation. Both unblinded and blinded clinical assessments of motor effect were performed using the Unified Parkinson's Disease Rating Scale.Results: Motor scores improved by 66% (unblinded) and 50% (blinded) during aDBS, which were 29% (p = 0.03) and 27% (p = 0.005) better than cDBS, respectively. These improvements were achieved with a 56% reduction in stimulation time compared to cDBS, and a corresponding reduction in energy requirements (p < 0.001). aDBS was also more effective than no stimulation and random intermittent stimulation.Interpretation BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD. Ann Neurol 2013;74:449–457

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BackgroundAlthough deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity.MethodsTo explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 μs; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides.ResultsThe authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V.ConclusionThe findings suggest that DBS can suppress pathological 11–30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective.

BackgroundStandard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma.MethodsAfter surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).ResultsFor the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.ConclusionsAddition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival.Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

Despite long-term and widespread use of deep brain stimulation (DBS) in a variety of neurological conditions, the underlying mechanisms of action have been elusive. Growing evidence suggests that DBS acts through multimodal mechanisms that are not limited to inhibition and excitation of basal ganglia circuits. DBS also seems to act over variable time spans - for example, the effects on tremor are immediate, whereas the effects on dystonia emerge over several weeks - suggesting that large networks are targeted. Studies reviewing the use of DBS in pain and obsessive-compulsive disorder have demonstrated direct involvement of axonal fibres rather than grey matter. In this Review, we draw on clinical and experimental data to examine the various hypotheses that have been put forward to explain the effects of DBS. In agreement with several other experts, we suggest that the term 'deep brain stimulation' warrants modification. A potentially more accurate term is 'deep brain neuromodulation', as the mode of action spans an array of therapeutic effects over a variable period of time, and is not just limited to 'stimulation' of the basal ganglia brain centres. Terms such as 'electrical neuro-network modulation' may be useful for applications in which deep brain structures are not the primary target.

We have examined dopaminergic cell survival after alteration of the subthalamic nucleus (STN) in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The STN was lesioned with kainic acid (B series) or underwent deep brain stimulation (DBS) at high frequency (C series). In another series, MPTP-treated and non-MPTP-treated monkeys had no STN alteration (intact animals; A series). Animals were treated with MPTP either after (B1, C1) or before (B2, C2) STN alteration. We also explored the long-term ( approximately 7 months) effect of DBS in non-MPTP-treated monkeys (D series). Brains were aldehyde-fixed and processed for routine Nissl staining and tyrosine hydroxylase immunocytochemistry. Our results showed that there were significantly more (20-24%) dopaminergic cells in the substantia nigra pars compacta (SNc) of the MPTP-treated monkeys that had STN alteration, either with kainic acid lesion or DBS, compared to the non-MPTP-treated monkeys (intact animals). We suggest that this saving or neuroprotection was due to a reduction in glutamate excitotoxicity, as a result of the loss or reduction of the STN input to the SNc. Our results also showed that SNc cell number in the B1 and C1 series were very similar to those in the B2 and C2 series. In the cases that had long-term DBS of the STN (D series), there was no adverse impact on SNc cell number. In summary, these results indicated that STN alteration offered neuroprotection to dopaminergic cells that would normally die as part of the disease process.

Making the right decision from conflicting information takes time. Recent computational, electrophysiological, and clinical studies have implicated two brain areas as being crucial in assuring sufficient time is taken for decision-making under conditions of conflict: the medial prefrontal cortex and the subthalamic nucleus (STN). Both structures exhibit an elevation of activity at low frequencies (Ͻ10 Hz) during conflict that correlates with the amount of time taken to respond. This suggests that the two sites could become functionally coupled during conflict. To establish the nature of this interaction we recorded from deep-brain stimulation electrodes implanted bilaterally in the STN of 13 Parkinson's disease patients while they performed a sensory integration task involving randomly moving dots. By gradually increasing the number of dots moving coherently in one direction, we were able to determine changes in the STN associated with response execution. Furthermore, by occasionally having 10% of the dots move in the opposite direction as the majority, we were able to identify an independent increase in STN theta-delta activity triggered by conflict. Crucially, simultaneous midline frontal electroencephalographic recordings revealed an increase in the theta-delta band coherence between the two structures that was specific to high-conflict trials. Activity over the midline frontal cortex was Granger causal to that in STN. These results establish the corticosubcortical circuit enabling successful choices to be made under conditions of conflict and provide support for the hypothesis that the brain uses frequency-specific channels of communication to convey behaviorally relevant information.