Adaptive deep brain stimulation in advanced Parkinson disease
TL;DR: This work uses a BCI to interpret pathological brain activity in patients with advanced Parkinson disease and to use this feedback to control when therapeutic deep brain stimulation (DBS) is delivered to improve on both the efficacy and efficiency of conventional continuous DBS.
Abstract: 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. 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. 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. BCI-controlled DBS is tractable and can be more efficient and efficacious than conventional continuous neuromodulation for PD. Copyright © 2013 American Neurological Association.
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TL;DR: It is proposed that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons.
Abstract: Deep brain stimulation (DBS) is increasingly applied for the treatment of brain disorders, but its mechanism of action remains unknown. Here we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients, neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the beta rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as that of the reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons.
511 citations
TL;DR: LFADS, a deep learning method for analyzing neural population activity, can extract neural dynamics from single-trial recordings, stitch separate datasets into a single model, and infer perturbations, for example, from behavioral choices to these dynamics.
Abstract: Neuroscience is experiencing a revolution in which simultaneous recording of thousands of neurons is revealing population dynamics that are not apparent from single-neuron responses. This structure is typically extracted from data averaged across many trials, but deeper understanding requires studying phenomena detected in single trials, which is challenging due to incomplete sampling of the neural population, trial-to-trial variability, and fluctuations in action potential timing. We introduce latent factor analysis via dynamical systems, a deep learning method to infer latent dynamics from single-trial neural spiking data. When applied to a variety of macaque and human motor cortical datasets, latent factor analysis via dynamical systems accurately predicts observed behavioral variables, extracts precise firing rate estimates of neural dynamics on single trials, infers perturbations to those dynamics that correlate with behavioral choices, and combines data from non-overlapping recording sessions spanning months to improve inference of underlying dynamics.
455 citations
TL;DR: Deep brain stimulation is widely used for the treatment of movement disorders including Parkinson's disease, essential tremor, and dystonia and, to a lesser extent, certain treatment-resistant neuropsychiatric disorders including obsessive-compulsive disorder.
Abstract: Deep brain stimulation (DBS) is widely used for the treatment of movement disorders including Parkinson's disease, essential tremor, and dystonia and, to a lesser extent, certain treatment-resistant neuropsychiatric disorders including obsessive-compulsive disorder. Rather than a single unifying mechanism, DBS likely acts via several, nonexclusive mechanisms including local and network-wide electrical and neurochemical effects of stimulation, modulation of oscillatory activity, synaptic plasticity, and, potentially, neuroprotection and neurogenesis. These different mechanisms vary in importance depending on the condition being treated and the target being stimulated. Here we review each of these in turn and illustrate how an understanding of these mechanisms is inspiring next-generation approaches to DBS.
375 citations
Cites background from "Adaptive deep brain stimulation in ..."
...Delivery of high-frequency STN DBS triggered on an STN beta power threshold set to achieve 50% stimulation on time resulted in a 50% improvement in blinded motor ratings compared with traditional, continuous high-frequency stimulation and was superior to an randomly delivered stimulation with a similar on time (Little et al. 2013) (Fig....
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...…on an STN beta power threshold set to achieve 50% stimulation on time resulted in a 50% improvement in blinded motor ratings compared with traditional, continuous high-frequency stimulation and was superior to an randomly delivered stimulation with a similar on time (Little et al. 2013) (Fig....
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...In adaptive or closed-loop stimulation, electrical stimulation (bottom) is delivered only when a control signal, in this case beta-band power (middle), is elevated above a threshold (Little et al. 2013)....
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TL;DR: The results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.
Abstract: The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.
340 citations
Cites background from "Adaptive deep brain stimulation in ..."
...Real-time behavioral prediction may also aid in the development of therapeutic interventions such as adaptive deep brain stimulation, which uses measures of neural activity to improve stimulation efficacy (Little et al., 2013)....
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TL;DR: Tinkhauser et al. show that adaptive DBS regulates pathological beta synchronisation in the subthalamic nucleus by selectively limiting long duration beta bursts, which are related to clinical impairment.
Abstract: Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson's disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could be more efficacious than conventional continuous deep brain stimulation in the treatment of Parkinson's disease, and helps inform how adaptive deep brain stimulation might best be delivered.
308 citations
References
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TL;DR: High-frequency deep brain stimulation of the subthalamic nucleus is a powerful method that is currently unchallenged in the management of Parkinson's disease, but its long-term effects must be thoroughly assessed.
Abstract: High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN-HFS) is the preferred surgical treatment for advanced Parkinson's disease. In the 15 years since its introduction into clinical practice, many studies have reported on its benefits, drawbacks, and insufficiencies. Despite limited evidence-based data, STN-HFS has been shown to be surgically safe, and improvements in dopaminergic drug-sensitive symptoms and reductions in subsequent drug dose and dyskinesias are well documented. However, the procedure is associated with adverse effects, mainly neurocognitive, and with side-effects created by spread of stimulation to surrounding structures, depending on the precise location of electrodes. Quality of life improves substantially, inducing sudden global changes in patients' lives, often requiring societal readaptation. STN-HFS is a powerful method that is currently unchallenged in the management of Parkinson's disease, but its long-term effects must be thoroughly assessed. Further improvements, through basic research and methodological innovations, should make it applicable to earlier stages of the disease and increase its availability to patients in developing countries.
1,107 citations
TL;DR: Local potentials from the globus pallidus interna and subthalamic nucleus are recorded in four awake patients after neurosurgery for Parkinson's disease to demonstrate synchronization of activity does occur between pallidum and STN, and its pattern is critically dependent on the level of dopaminergic activity.
Abstract: The extent of synchronization within and between the nuclei of the basal ganglia is unknown in Parkinson's disease. The question is an important one because synchronization will increase postsynaptic efficacy at subsequent projection targets. We simultaneously recorded local potentials (LPs) from the globus pallidus interna (GPi) and subthalamic nucleus (STN) in four awake patients after neurosurgery for Parkinson's disease. Nuclei from both sides were recorded in two patients so that a total of six ipsilateral GPi–STN LP recordings were made. Without medication, the power within and the coherence between the GPi and STN was dominated by activity with a frequency <30 Hz. Treatment with the dopamine precursor levodopa reduced the low-frequency activity and resulted in a new peak at ∼70 Hz. This was evident in the power spectrum from STN and GPi and in the coherence between these nuclei. The phase relationship between the nuclei varied in a complex manner according to frequency band and the presence of exogenous dopaminergic stimulation. Synchronization of activity does occur between pallidum and STN, and its pattern is critically dependent on the level of dopaminergic activity.
1,064 citations
TL;DR: In this article, a procedure for estimating the reliability of sets of ratings, test scores, or other measures is described and illustrated, based upon analysis of variance, which may be applied both in the special case where a complete set of ratings from each ofk sources is available for each ofn subjects, and in the general case wherek 1,k 2,k 3,k 4,k 5,k 6,k 7,k 8,k 9,k 10,k 11,k 12,
Abstract: A procedure for estimating the reliability of sets of ratings, test scores, or other measures is described and illustrated. This procedure, based upon analysis of variance, may be applied both in the special case where a complete set of ratings from each ofk sources is available for each ofn subjects, and in the general case wherek
1,k
2, ...,k
n ratings are available for each of then subjects. It may be used to obtain either a unique estimate or a confidence interval for the reliability of either the component ratings or their averages. The relations of this procedure to others intended to serve the same purpose are considered algebraically and illustrated numerically.
1,033 citations
TL;DR: A link between levodopa‐induced improvements in bradykinesia and rigidity and reductions in population synchrony at frequencies < 35 Hz in the region of the STN in patients with PD is supported.
Abstract: Strong synchronization of neuronal activity occurs in the 8-35 Hz band in the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) and is evident as oscillatory local field potential (LFP) activity. To test whether such synchronization may contribute to bradykinesia and rigidity, we sought correlations between the suppression of synchronization at 8-35 Hz in STN and the reduction in Parkinsonism with levodopa. LFPs were recorded on and off medication from STN deep-brain stimulation electrodes in nine PD patients. LFP power was calculated over the frequencies of the most prominent spectral peak within the 8-35 Hz frequency band on each of 17 sides (off medication), and over the frequencies of any peak in the 60-90 Hz band, if present (seven sides, on medication). Levodopa-induced reduction of LFP power over these two frequency ranges was then correlated with improvement in motor impairment as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). The reduction in peak activity in the 8-35 Hz band with levodopa positively correlated with the improvement in the contralateral hemibody motor UPDRS score with levodopa (r = 0.811, P < 0.001) as well as with hemibody subscores of akinesia-rigidity (r = 0.835, P < 0.001), but not tremor. A trend for negative correlations was found between peak 60-90 Hz LFP power and UPDRS hemibody score, suggesting that positive correlations were relatively frequency-specific. Our results support a link between levodopa-induced improvements in bradykinesia and rigidity and reductions in population synchrony at frequencies < 35 Hz in the region of the STN in patients with PD.
735 citations
TL;DR: Closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD.
719 citations
"Adaptive deep brain stimulation in ..." refers background in this paper
...Equally, our intervention, discontinuous but regular stimulation at high frequency, may be bettered in time by stimulation regimes that specifically target patho- logical rhythms through phase cancellation or disruption.36,37 Nevertheless, our simple and tractable system was able to outperform standard continuous stimulation in efficacy and power consumption, potentially offering a major advance in electrical neuromodulation therapy for PD....
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...If it were feasible to track these fluctuations with a suitable feedback signal and stimulate only when necessary, it might be possible to improve therapeutic efficacy while preserving battery life and limiting side effects.3–5 A recent study in nonhuman primates suggested that adaptively controlled DBS triggered by feedback from the spikes of a single motor cortical neurone was even more effective than standard continuous high-frequency stimulation in a model of PD.6 In developing adaptive DBS (aDBS) for clinical use, two challenges must be overcome....
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...A recent study in nonhuman primates suggested that adaptively controlled DBS triggered by feedback from the spikes of a single motor cortical neurone was even more effective than standard continuous high-frequency stimulation in a model of PD.(6) In developing adaptive DBS (aDBS) for clinical use, two challenges must be overcome....
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...In particular, periods of nearly normal functioning will not be compromised by DBS when the delivery of this is controlled by a BCI.27 Such periods of normal functioning include those induced by antiparkinsonian medication, which when effective is associated with suppression of beta activity in the STN.28–33 We have demonstrated that it is possible to track an LFP biomarker from the site of stimulation and use this to successfully control stimulation in patients with a continuously fluctuating neurological condition such as PD. Power savings were substantial, and efficacy was found to be superior to standard stimulation....
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...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 Deep brain stimulation (DBS) is an established treat-ment for severe Parkinson disease (PD), dystonia, and tremor, and has an emerging role in a range of other neurological and neuropsychiatric conditions.1 However, its widespread adoption is at present limited by cost, side effects, and partial efficacy.2 In many brain disorders, for example PD, symptoms fluctuate on a moment-bymoment basis depending on factors such as cognitive and motor load and concurrent drug therapy....
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