The spacing principle for unlearning abnormal neuronal synchrony
Oleksandr V. Popovych1 , Markos N. Xenakis1 and Peter A. Tass1;2;3
1Institute of Neuroscience and Medicine — Neuromodulation, Jülich Research Center, Jülich, Germany
2Department of Neurosurgery, Stanford University, Stanford, California, United States of America
3Department of Neuromodulation, University of Cologne, Cologne, Germany
Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, learning effects can be enhanced by means of the spacing principle, i.e. by delivering repeated stimuli spaced by pauses as opposed to delivering a massed stimulus (in a single long stimulation session). To illustrate that the spacing principle may also be used for unlearning abnormally up-regulated synaptic connectivity, in particular, to boost the anti-kindling effect of CR neuromodulation, in this computational study we carry this approach to extremes. To this end, we deliver spaced CR neuromodulation at particularly weak intensities which render permanently delivered CR neuromodulation ineffective. Intriguingly, spaced CR neuromodulation at these particularly weak intensities effectively induces an anti-kindling. In fact, the spacing principle enables the neuronal population to successively hop from one attractor to another one, finally approaching attractors characterized by down-regulated synaptic connectivity and synchrony. Our computational results might open up novel opportunities to effectively induce sustained desynchronization at particularly weak stimulation intensities, thereby avoiding side effects, e.g., in the case of deep brain stimulation.
- PMID: 25714553
Abnormal neuronal synchronization may severely impair brain function and is a hallmark of several neurological disorders such as Parkinson’s disease (PD) [1, 2], essential tremor , epilepsy , and tinnitus [5–7]. The standard therapy for the treatment of medically refractory PD is high frequency (HF) deep brain stimulation (DBS), where electrical HF pulse trains are administered at frequencies >100 Hz via depth electrodes chronically implanted in target areas like the thalamic ventralis intermedius (VIM) nucleus or the subthalamic nucleus (STN) [8, 9]. HF DBS has been developed empirically, and the clinical and electrophysiological mechanisms of the symptom suppression by HF DBS are still a matter of intensive research [10–12]. HF DBS only has acute effects, i.e., neither clinical  nor electrophysiological [14, 15] effects persist after cessation of stimulation.
To specifically counteract the abnormal neuronal synchronization, based on a computational approach  several desynchronizing methods have been developed, where one of these methods, coordinated reset (CR) stimulation [17, 18], received solid support from numerous computational, pre-clinical and clinical studies [19–29]. By taking into account that the neurons continuously adapt the strength of their synaptic connections governed by spike timing-dependent plasticity (STDP), computationally it was shown that desynchronizing CR stimulation reduces the rate of coincidences and, hence, down-regulates abnormal synaptic weights and neuronal synchronization [19, 30]. CR stimulation can thus induce anti-kindling, i.e., it can initiate a process, where neuronal networks “unlearn” pathologically strong interactions and synchronization. This is achieved by the neural network being shifted from a state characterized by abnormal synaptic connectivity and abnormal neuronal synchrony to a stable regime with physiological connectivity and synchrony, where the system remains after the stimulation is switched off. This constitutes long-lasting therapeutic aftereffects which persist after stimulation cessation.
In accordance with modeling studies, long-lasting CR-induced desynchronization was confirmed in vitro in rat hippocampal slices rendered epileptic by magnesium withdrawal . In monkeys rendered parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), CR stimulation causes beneficial therapeutic long-lasting after-effects which may last for at least 30 days after only 5 consecutive days of short-epoch (2 hours per day) CR DBS of the STN . Long-lasting after-effects of CR-DBS as well as cumulative effects of CR-DBS of the STN in MPTP monkeys were also shown by Wang et al . . Lasting clinical and electrophysiological after-effects of CR DBS of the STN were also confirmed in PD patients  already within 3 consecutive days of short-epoch CR stimulation (with two daily sessions of up to 2 hours of each session). Based on the same principles of desynchronization-induced unlearning of abnormal synaptic connectivity and neuronal synchrony, i.e., anti-kindling, the initially invasive CR approach was later on extended to non-invasive stimulation modalities [22, 23]. Non-invasive, acoustic CR stimulation was successively applied in a clinical proof of concept study in tinnitus patients [25, 26, 32]. Acoustic CR stimulation can significantly counteract both tinnitus symptoms and the underlying pathological neuronal synchronization by normalizing the effective connectivity and restoring the functional patterns of activity [25, 26, 32].
For an efficient and safe treatment a proper dosage of drug or stimulation administration is of crucial importance. The intensity of the stimulation is a key factor. For standard HF DBS, the therapeutic window of the stimulation intensity is bounded from below by the values necessary to obtain the required clinical effect and bounded from above by the side effect threshold . It is thus of clinical relevance to reduce the stimulation intensity as much as possible without losing the therapeutic benefit of the stimulation, in this way reducing the risk of side effects.
It is known that CR stimulation works at much lower stimulation intensities than the standard HF DBS [24, 29]. In this study we suggested further improvement of desynchronizing CR stimulation by modulating the timing of the stimulation. We considered the case of a very weak stimulation where the conventional CR stimulation becomes ineffective in inducing anti-kindling irrespectively of the stimulation duration if permanently delivered [Fig. 1A, blue curve]. However, if the course of the stimulation is spaced by long enough pauses, which constitutes the spaced CR stimulation, the anti-kindling can be initiated, and the stimulated neuronal population converges to a regime of normalized weak coupling and desynchronized dynamics [Fig. 1, red curves]. Such an approach takes advantage of a principle playing an important role in different research traditions including psychology, neuroscience and education, where it was shown that learning effects can be enhanced by means of the spacing principle, i.e., by delivering repeated stimuli spaced by pauses as opposed to delivering a massed stimulus (in a single long stimulation session).
We illustrated the efficacy and robustness of the spaced CR stimulation on a population of model neurons and show that the spacing principle utilizes the pronounced multistability arising due to STDP. During the delivery of spaced CR stimulation the neuronal population successively bounces from one attractor to another one, and finally approaches an attractor characterized by down-regulated synaptic connectivity and synchrony [Fig. 1, red curves]. The lengths of the stimulation (Lstim) and pause (Lpause) epochs play an important role at this, and a certain balance between Lstim and Lpause is required for a pronounced decoupling and desynchronization [Fig. 2]. In particular, anti-kindling does not occur for insufficiently long stimulation- and pause-epochs [Fig. 2, red circles]. Too long stimulation-epochs with respect to pause-epochs will also lead to failure of the stimulation in inducing anti-kindling, and the neuronal population remains strongly coupled and synchronized. Even for very long pause-epochs, but short stimulation-epochs only a weak suppression of the coupling and synchronization can be achieved [Fig. 2, blue squares and violet diamonds]. The weak spaced CR stimulation reliably induces an anti-kindling, decouples and desynchronizes stimulated neurons when both stimulation- and pause-epochs are of sufficient duration [Fig. 2, magenta asterisks and green triangles].
Our computational results show that the spacing principle may also be used for unlearning abnormally up-regulated synaptic connectivity. In particular, spaced CR is a strategy which might be favorable whenever weak stimulation intensities are required, for instance, in the case of side effects, such as speech and gait impairment in patients with Parkinson’s disease receiving deep brain stimulation  or in tinnitus patients suffering from hyperacusis . In the field of deep brain stimulation a substantial reduction of the integral stimulation current is relevant since side effects may not only be caused by excessive current spread to areas neighboring the target area, but also by stimulation of the target area itself [36, 37].
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