Recent experimental literature has revealed that GABAergic interneurons exhibit increased activity prior to seizure onset, alongside additional evidence that such activity is synchronous and may arise abruptly. These findings have led some to hypothesize that this interneuronal activity may serve a causal role in driving the sudden change in brain activity that heralds seizure onset. However, the mechanisms predisposing an inhibitory network toward increased activity, specifically prior to ictogenesis, without a permanent change to inputs to the system remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyperexcitable interneurons modeled to mimic treatment with 4-Aminopyridine (4-AP), an agent commonly used to model seizures in vivo and in vitro. Our in silico study demonstrates that model inhibitory networks with 4-AP interneurons are more prone than their control counterparts to exist in a bistable state in which asynchronously firing networks can abruptly transition into synchrony driven by a brief perturbation. This transition into synchrony brings about a corresponding increase in overall firing rate. We further show that perturbations driving this transition could arise in vivo from background excitatory synaptic activity in the cortex. Thus, we propose that bistability explains the increase in interneuron activity observed experimentally prior to seizure via a transition from incoherent to coherent dynamics. Moreover, bistability explains why inhibitory networks containing hyperexcitable interneurons are more vulnerable to this change in dynamics, and how such networks can undergo a transition without a permanent change in the drive. We note that while our comparisons are between networks of control and ictogenic neurons, the conclusions drawn specifically relate to the unusual dynamics that arise prior to seizure, and not seizure onset itself. However, providing a mechanistic explanation for this phenomenon specifically in a pro-ictogenic setting generates experimentally testable hypotheses regarding the role of inhibitory neurons in pre-ictal neural dynamics, and motivates further computational research into mechanisms underlying a newly hypothesized multi-step pathway to seizure initiated by inhibition.

Objective: Epilepsy is one of the most common neurological disorders . Many individuals continue to have seizures despite medical and surgical treatments, suggesting adjunctive management strategies are required. Promising effects of daily listening to Mozart on reducing seizure frequency in individuals with epilepsy have been demonstrated over the last 20 years, but not in a rigorously controlled manner.In this study, we compared the effect on seizure frequency of daily listening to either Mozart K.448 or a spectrally similar, yet non-rhythmic control piece. We hypothesized that there would be no difference in seizure counts when participants listened to Mozart K.448 vs when they listened to the control piece. Methods: We employed a randomized crossover design, in which each participant was exposed to both three months of daily listening to the first six minutes of Sonata for two pianos in D major by Mozart (Mozart K.448; treatment period) and three months of daily listening to phase-scrambled version (control period). There was a three-month baseline and a three-month follow-up period before and after the sixmonth listening period, respectively. Change in seizure counts obtained from the seizure diaries was considered as the main study outcome. Results: Using three methodologies to investigate the existence of the treatment effect (paired t test, estimation statistics and plots, and Cohen's d), our results revealed a reduction in seizure counts during the treatment period, which was not observed for the control period (P-value < .001). Significance: Using a spectrally similar control piece, our study advances previous reports that were limited by a "no music" control condition. Daily listening to Mozart K.448 was associated with reducing seizure frequency in adult individuals with epilepsy. These results suggest that daily Mozart listening may be considered as an adjunctive therapeutic option to reduce seizure burden in individuals with epilepsy. |

Epilepsy is the most common serious neurological disorder in the world. Despite medical and surgical treatment, many individuals continue to have seizures, suggesting adjunctive management strategies are required. Promising effects of daily listening to Mozart K.448 on reducing seizure frequency in individuals with epilepsy have been demonstrated. In our recent randomized control study, we reported the positive effect of daily listening to Mozart K.448 on reducing seizures compared to daily listening to a control piece with an identical power spectrum to the Mozart piece yet devoid of rhythmic structure. Despite the promising effect of listening to Mozart K.448 on reducing seizure in individuals with epilepsy, the mechanism(s) underlying such an effect is largely unknown. In this paper, we specifically review how auditory stimulation alters brain dynamics, in addition to computational approaches to define the structural features of classical music, to then propose a plausible mechanism for the underlying anticonvulsant effects of listening to Mozart K.448. We review the evidence demonstrating that some Mozart pieces in addition to compositions from other composers such as Joplin contain less predictable rhythmic structure in comparison with other composers such as Beethoven. We propose through both entrainment and 1/f resonance mechanisms that listening to musical pieces containing the least predictable rhythmic structure, might reduce the self similarity of brain activity which in turn modulates low frequency power, situating the brain in a more ''noise like" state and away from brain dynamics that can lead to seizures.

A plethora of recent experimental literature implicates the abrupt, synchronous activation of GABAergic interneurons in driving the sudden change in brain activity that heralds seizure initiation. However, the mechanisms predisposing an inhibitory network toward sudden coherence specifically during ictogenesis remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyper-excitable interneurons modeled to mimic treatment with 4-Aminopyridine (4-AP), an agent commonly used to model seizures in vivo and in vitro. Our in silico study demonstrates that model inhibitory networks with 4-AP interneurons are more prone than their control counterparts to exist in a bistable state in which asynchronously firing networks can abruptly transition into synchrony due to a brief perturbation. We further show that perturbations driving this transition could reasonably arise in vivo based on models of background excitatory synaptic activity in the cortex. Thus, these results propose a mechanism by which an inhibitory network can transition from incoherent to coherent dynamics in a fashion that may precipitate seizure as a downstream effect. Moreover, this mechanism specifically April 11, 2019 1/36Recently, some studies of seizure initiation have shifted focus to over-activity of 25 inhibitory interneurons. This literature has yielded convincing evidence that 26 interneurons serve a causal role in seizure initiation [1,[8][9][10][11][12][13], laying the groundwork for 27 a novel hypothesis for seizure initiation (a "GABAergic initiation hypothesis") in which 28 synchronous activation of inhibitory interneurons precipitates the onset of a seizure, as 29 diagrammed in Fig 1 [12]. Given the contemporaneous nature of this hypothesis it is an 30ideal target for rigorous computational study; here, such research aims to unearth a 31 mechanism explaining the predisposition of inhibitory interneurons in a hyper-excitable 32April 11, 2019 2/36 environment to suddenly transition into synchrony, the necessary initial step in this 33 hypothesis. We thus focus on the earliest time in the transition to seizure and not 34 aspects of propagation and termination. 35The study of inhibitory network synchrony is decades old, dating back to the work of 36 Wang and Rinzel [14]. Various mechanisms have been proposed to explain the 37 generation of oscillations in purely inhibitory networks, the most prominent of which 38 may be the Interneuron Network Gamma (ING) mechanism [15-20]. Previous work has 39 shown that inhibitory networks built to examine population activity in an in vitro 40 hippocampal preparation manifest "sharp transitions" into coherent population activity 41 caused by a small, permanent increase to the external drive to the network [21]. 42 Additional studies have explored the effect of connection probabilities and cell 43 characteristics manifested by classifications of cell excitability on inhibitory network 44 synchrony [22, 23], and have noted that bist...

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