IL304342B2 - System and method for treating involuntary convulsions in a patient - Google Patents

Description

ICH-RMT-P-028-IL 1 SYSTEM AND METHOD OF TREATING TICS IN A SUBJECT FIELD OF THE INVENTION[001] The present invention relates generally to computer assisted diagnosis and treatment. More specifically, the present invention relates to methods of monitoring, and/or treating tics in a subject.

BACKGROUND OF THE INVENTION[002] Tics, encompassing motoric and vocal tics, are involuntary, repetitive movements or sounds that often occur in individuals with tic disorders. These tics can significantly impact the quality of life for affected individuals, causing discomfort and interfering with daily activities. Various approaches have been employed to address tics, including behavioral therapies and medication. However, there remains a need for more effective and personalized methods for managing tics. [003] Children in developed countries spend a significant portion of their waking hours consuming commercial audiovisual content and playing video games. The impact of media consumption on children's health and well-being has been widely studied, including its effects on tic disorders and Tourette syndrome. Studies have reported that tic frequency is enhanced during gaming and television watching. However, the latter activity was also found to decrease tics, leading to mixed findings.

SUMMARY OF THE INVENTION[004] To gain a better understanding of the ways in which tics are affected by audiovisual media consumption, given its centrality in contemporary child's life, the inventors conducted a fine-grained analysis of the impact of movie and game elements on tic manifestation. Based on moment-to-moment tic annotation, the inventors found that temporal patterns of different individuals are significantly synchronized during film viewing despite substantial diversity in their tic profiles. Furthermore, employing a video game developed for the inventors’ study, the inventors found that tic frequency increases during anticipation for a pending reward. This finding was replicated in a second experiment with an independent cohort. [005] The impact of media consumption on the severity of Tic Disorders (TDs) has recently gained increasing attention with the peculiar case of "Tic Tok Tics". Rapid-onset complex motor and vocal tic-like behaviors, which were rarely reported before 2020, have ICH-RMT-P-028-IL 2 been recently diagnosed in several countries in unprecedented numbers. Interestingly, these functional tic-like behaviors (FTLB) appeared mostly in individuals who reported on consumption of popular TikTok and YouTube videos depicting persons allegedly having Tourette's syndrome. It has been suggested that exposure to this specific video content via social media triggered this unexpected FTLB surge among susceptible individuals with anxiety and depressive symptoms. [006] Previous evidence suggested that media consumption may affect not only FTLB, but also tic manifestation in primary TD, which is significantly more common and have distinctive phenomenology and risk factors. Television content and video games have been mentioned among the most common tic antecedents that increase tic likelihood. At least four studies that examined television watching among other antecedents reported that it was among the most common tic triggers. One of these studies reported that video games are also leading tic antecedents. Thus, while the long-term impact of television and video games on TDs has yet to be scrutinized, accumulating evidence suggests that these media exacerbate tics in the short-term. [007] However, the evidence is not unanimous. A pilot study which continuously measured tics during the viewing of a commercial movie, reported that tic severity was highest not in the emotional moments, but rather during the less or non-cinematic periods including the baseline and opening and closing credits. Furthermore, while an aforementioned daily diary study found that 38% of individuals with TDs reported that passive attendance - including watching television - was a high-risk activity in terms of tic severity, even a higher rate of 45% of the sample categorized it as a low-risk activity. [008] This mixed finding has been interpreted as reflecting variability in the ways in which individuals with TDs react to tic antecedents such as movies and video games, indicating that while media exacerbate tics for some individuals, they alleviate them for others. However, an additional source of variance may account for the indecisive findings about the impact of media content on tic manifestation. Apart from the variability between individual's reaction to media, there is an extreme heterogeneity in movies and games in terms of the intensity of the tic triggers they introduce. For example, thrillers, comedies, and National Geographic documentaries may considerably vary in the prevalence of tic triggers such as stressful events, anticipation cues, and frustrating elements. This heterogeneity calls for a fine-grained investigation of media elements that may either trigger or attenuate tics. The ICH-RMT-P-028-IL 3 inventors have refined the understanding of how media can function as a tic antecedent, by examining the impact of specific possible antecedents in movies and games on tic manifestation in children. [009] In investigating potential tic triggers, the inventors draw on accounts of the psychophysiological processes in TDs that may be activated by such triggers. Current models distinguish between two aspects of TDs: (i) The premonitory urge, which is experienced as a mounting sense of uneasiness and increased tension, or anxiety accompanied with the impulse to act. Tic expression commonly provides a temporary relief of this urge. This sensation implicates limbic brain structures (e.g., anterior cingulated cortex (ACC), nucleus accumbens), as well as insulary and somatosensory cortices. (ii) Stereotypical motor/ vocal hyperactivity – i.e., the behavioral manifestation of the tic. This aspect of TD is hypothesized to result from abnormalities in cortico-striatal-thalamo-cortical pathways. [0010] In terms of neuromodulatory abnormalities, accumulating evidence has pointed to a major role for GABAergic and dopaminergic processes. Deficiencies in GABAergic inhibition have been associated with dysregulated behaviors in TDs, affecting both sensory and motor aspects. At the sensory level, reduced GABAergic inhibition in cortical regions that are implicated in premonitory urges may explain the over-activation of these regions in TDs as reduced GABA concentrations were found in the ACC and somatosensory cortices. At the motor level, evidence suggests that GABA deficiencies might also affect action selection and the inhibition of motor alternatives via a circuit encompassing the basal ganglia, thalamic and sub-thalamic structures, and certain cortical areas. Dopaminergic abnormalities have also been pointed out as a causal agent in TDs in light of evidence from nuclear imaging and postmortem studies and the considerable efficacy of FDA-approved drugs, which act on dopamine receptors. The hyperinnervation hypothesis accounts for the ways in which these limbic and motor processes combine in TDs. It posits that as both tonic and phasic striatal dopamine are enhanced, the balance between the direct and indirect pathways in the basal ganglia changes in favor of the former so that the inhibition is substantially decreased. Based on a computational model of the role of phasic and tonic dopamine in action learning demonstrate how elevated levels of this neurotransmitter can facilitate prompt acquisition of tics via enhanced habit learning. In this process, the tic generates a sense of relief from the uneasiness of the premonitory urge. The relief is ICH-RMT-P-028-IL 4 experienced as a reward, which is particularly powerful in the context of enhanced tonic and phasic dopamine levels that strengthen the direct relative to the indirect pathway. [0011] Which movie and game elements may trigger these limbic and motor processes, which are implicated in TDs? The inventors have examined the impact of the following elements on tic frequency: [0012] Interoceptive audiovisual cues, e.g., moving images of bodily distress or pleasure. Interoception - the sense of the internal body state - has been associated with the etiology of TD and premonitory urges in specific. Importantly, evidence suggests that interoception is involved not only in self-referential processing but also in social cognition where somatic cues communicate the internal state of others. Individuals with TDs respond to images of emotional faces with altered functional connectivity patterns of the insula, which is considered as an "interoceptive hub" and a key site of dysfunction in TDs. The inventors expected that interoceptive video cues would increase tic manifestation. [0013] Animal and human studies have established the notion that expectation for reward involves dopaminergic signaling in the midbrain and the nucleus accumbens. Movies and video games are often rich in moments of anticipation of reward for a character’s or gamer’s actions. The inventors examined whether tic frequency increases during such anticipatory moments. [0014] Instantaneous state value, defined as the "expected future reward discounted by the expected time needed to receive it" is a well-documented factor affecting mesolimbic dopamine release. As the accumulation of phasic dopamine is larger during prolonged anticipation, the inventors expect tic frequency to increase with the duration of anticipatory epoch. The inventors examined the link between these parameters in gamified anticipation periods. [0015] To test their hypotheses, the inventors utilized media content of three types: (i) an excerpt from an animation film (Up (2009), including the film’s dramatic climax); (ii) short clips featuring affective bodily cues with positive and negative valence; and (iii) an in-house designed game (Figs. 1A-1C) with three types of anticipatory events: dice-roll, battle, and card regain. [0016] In this game, which may be an adaptation of the games Ladders and Snakes and War as described below, the participant may compete with alleged bots and/or a human opponent as they move their tokens along a numbered grid, aiming to be the first to reach the end of ICH-RMT-P-028-IL the route. The players may engage in card-battles where they play and later regain cards. The strength of the bot opponents and the expectancy of the card regained from an animated chest were represented by the colors of the token and chest (Gold > Silver > Wood). [0017] In addition, data acquired during free-viewing of the excerpt from the movie (Up) was examined through inter-subject correlation (ISC) analysis. As known in the art, ISC is a method of investigating reactions to complex and naturalistic stimuli, which was originally employed to analyze similarities in the dynamics of neural patterns of reaction of different individuals to the same movie. [0018] This method facilitates a media-effect analysis, which does not rely on hypotheses about the impact of specific elements in the movie, and instead indicates whether the dynamics of a dependent variable are orchestrated - and therefore influenced - by the stimulus. In this case, this method allowed the inventors to test the general prediction that a movie affects tic manifestation, without restricting the analysis to a-priori hypotheses regarding the specific movie elements or moments that elicit this effect. [0019] The inventors tested the following specific hypotheses: [0020] Hypothesis H1: The temporal pattern of tic manifestation during movie viewing (in terms of the number of tics per time unit) may correlate across participants. Using the short clips series, the inventors further tested predictions regarding specific movie elements as postulated. [0021] Hypothesis H2: The valence and presence of bodily cues in a movie may affect tic frequency. The inventors subsequently tested the following hypotheses about the impact of specific video game elements on tic frequency. [0022] Hypothesis H3: Tic frequency may be higher in the anticipatory moments of dice-roll (H3a), battle phase (H3b), and card regain (H3c) than during the viewing of emotionally neutral movie. [0023] Hypothesis H4: Tic frequency may be higher in the anticipatory moments of dice-roll (H4a), battle phase (H4b), and card regain (H4c) than during non-event game progress. [0024] Hypothesis H5: During the anticipation epochs, there may be a time effect on tic frequency and time × expected value interaction. The inventors have been interested in whether tic frequency differed between two modes of anticipation: (i) anticipation where the pending reward is marked by a cue that invokes expectations regarding its value; (ii) anticipation with no such cue. Therefore, during the card-regain epoch where the player ICH-RMT-P-028-IL 6 anticipates the card to be drawn from one out of three chests, the upcoming card regain event may or may not be indicated by the shaking of the target chest. The inventors therefore postulated: [0025] Hypothesis H6: Tic frequency may differ between anticipation epochs in which no specific chest is shaking and epochs in which a specific chest is shaking. [0026] Hypothesis H7: Tic frequency may positively correlate with the expected value of a card as indicated by the chest or opponent type (Gold>Silver>Wood). [0027] Hypothesis H8: Tic frequency may be higher during battles with allegedly human opponent relative to a computer bot. [0028] Hypothesis H9: During dice-roll epochs, the distance between the player's tile and the leading opponent's tile may negatively correlate with tic frequency. [0029] Hypothesis H10: During dice-roll epochs, the distance between the player's tile and the leading opponent's tile weighted by the number of steps left may negatively correlate with tic frequency. [0030] The present invention provides a method and system for monitoring, and/or treating tics in a subject by employing audiovisual stimuli and real-time adjustment based on tic-related characteristics. The term "subject" may be used in this context to refer to a human subjects, e.g., a patient, or a non-human subject, such as an animal under examination. By displaying an audiovisual stimulus designed to induce tics and employing a camera to record the subject's behavior, the onset of tic sequences can be determined. Such tic sequences may be defined as occurrence of a single tic, e.g., a single expression, or movement, or a sequence of basic, vocal or motor tics that comprise a complex, uncontrolled behavioral expression, as known in the art. These tic sequences may then be analyzed in real-time to calculate tic property values that represent respective characteristics of the detected tic sequences. The audiovisual stimulus is adjusted in real time based on these tic property values. [0031] In some embodiments of the invention, the method may include providing a computerized gaming platform as the audiovisual stimulus, allowing the subject to engage in a computer game. The adjustment of the audiovisual stimulus involves calculating a level of reward based on the tic property values and changing parameters of the computer game to reward or penalize the subject accordingly. [0032] To personalize the treatment regimen, a personalized training regimen for controlling tics can be produced based on the calculated levels of reward specifically tailored ICH-RMT-P-028-IL 7 for the subject. This personalized training regimen can be applied in subsequent engagements of the subject with the computer game, further enhancing the effectiveness of the treatment. [0033] Additionally, the method allows for real-time adjustment of the audiovisual stimulus based on other factors. By obtaining an urge severity indication from the subject, representing the severity of the urge to tic, the audiovisual stimulus can be further adjusted. Furthermore, a user engagement indication, reflecting the level of engagement of the subject in the audiovisual stimulus, can also influence the real-time adjustment of the audiovisual stimulus. [0034] These and other features and advantages of the present invention will become apparent from the following detailed description of the invention, accompanying drawings, and appended claims. [0035] Embodiments of the invention may use a closed-loop gamified platform, which triggers tics, records them in real-time, and rewards participants who manage to increase the interval between successive tics or tic sequences, in line with logic of exposure and response prevention (ERP) therapy for tic disorders. [0036] Embodiments may thus offer a practical application in the technological field of computer-assisted therapy, to potently enhance behavioral treatments of tic disorders. [0037] According to some embodiments, the game may be based on a closed-loop logic so it can receive real-time feedback on tic behavior in real time either provided via a user interface or detected automatically by an artificial intelligence system, which may analyze the captured video. [0038] The game may incorporate an algorithm which sets the rate of rewards based on the record of incoming input about the user's tics. This algorithm may allow, for example, individually-tailored and adaptive training. [0039] Additionally, or alternatively, embodiments may include a tutorial of the principles of tic suppression using an audiovisual neurofeedback interface. After an initial guidance on the principles of the behavioral practice, the subject can be trained to alleviate the urge-to-tic where they may be instructed to down-regulate the levels of an electroencephalographic (EEG) fingerprint of amygdala activity (e.g., as measured via fMRI) while receiving a continuous audiovisual (e.g., visual and/or audible) feedback.

ICH-RMT-P-028-IL 8 id="p-40" id="p-40" id="p-40" id="p-40" id="p-40" id="p-40"

[0040] Additionally, or alternatively, embodiments may include a Brain-Computer Interface (BCI) in which the activity of the dorsal striatum and/or the supplementary motor area may be measured in real-time while the subject (e.g., patient) plays the video game. The game may change according to the level of activity of these regions so that the patient may be penalized or rewarded. This can be done without the patient's awareness of the nature of the feedback, or while the patient is explicitly asked to control their brain signal. The level of activity may be measured, e.g., via fMRI or an electrical fingerprint of these regions as manifested in EEG. [0041] Embodiments of the invention may offer an individually-tailored "closed-loop" tic therapy, in which the audiovisual stimulation delivered to the patient is automatically controlled by their behavior in real-time. Embodiments of the invention may further offer an engaging gaming interface, which may target the mechanisms of tic disorder by employing theory-based and empirically-validated reinforcement schemes. [0042] The gaming characteristics of the present invention may increase efficiency of tic treatment by motivating young patients, improving their compliance with the treatment, and minimizing their dependence on clinicians. Additionally, embodiments of the invention may integrate computer sensing technologies to facilitate automatic tic detection and characterization, as well as the monitoring of the treatment course. [0043] Embodiments of the invention may include a method of monitoring, and/or treating tics by utilizing audiovisual stimuli and real-time adjustment based on tic-related characteristics. [0044] An audiovisual stimulus may be displayed to the subject, such as a human subject or a patient, as referred to herein, with the intention of inducing tics. This audiovisual stimulus can be presented using a variety of media, such as videos or interactive computer games. [0045] Simultaneously, a camera may capture or record the subject's behavior, allowing subsequent analysis of the captured or recorded data, in real time, or near real time. [0046] Upon recording the subject's behavior, the onset of one or more tic sequences may be determined based on the obtained recording. These tic sequences may represent the periods during which tics occur and may subsequently be analyzed to optimize characteristics of the treatment. [0047] The method may involve calculating one or more tic property values that represent respective characteristics of the detected tic sequences. These tic property values may ICH-RMT-P-028-IL 9 include, but are not limited to, a duration of at least one tic sequence, a number of tics within a tic sequence, a frequency of tics in a tic sequence, a complexity of tics, an intensity of tics, and an interference, or a level of interference caused by the tics in the sequence. [0048] Using the calculated tic property values, embodiments of the invention may adjust the audiovisual stimulus in real time, or near real time, to optimize treatment. This adjustment can be accomplished by modifying parameters of the audiovisual stimulus, such as the content, pace, or difficulty level. Embodiments may thus dynamically adapt the audiovisual stimulus based on the tic-related characteristics to optimize the therapeutic effect. The term "dynamic" may be used in this context to indicate changing of one or more properties of the audiovisual stimulus over time, in response to tic manifestation. [0049] In some embodiments, the audiovisual stimulus may be provided through a computerized gaming platform. By calculating a level of reward based on the tic property values, the method may enable the adjustment of one or more parameters of the computer game to reward or penalize the subject accordingly. This gamification aspect may enhance engagement and motivation, thereby facilitating the treatment process, and improving the motor learning process on which the therapeutic process is based by providing an immediate and potent feedback about the patient’s performance. [0050] Additionally, or alternatively, a personalized training regimen for controlling tics can be produced based on the calculated levels of reward specifically tailored for the subject. This personalized training regimen can, for example, be utilized in subsequent engagements of the subject with the computer game, contributing to long-term therapeutic benefits. [0051] Additionally, embodiments of the invention may allow real-time adjustment of the audiovisual stimulus based on other factors. For example, by obtaining an urge severity indication from the subject, representing the severity of the urge to tic, embodiments of the invention may further adjust the audiovisual stimulus, to accommodate individual variations and needs. Similarly, a user engagement indication, reflecting the subject's level of engagement in the audiovisual stimulus, can be considered when adjusting the stimulus, to ensure optimal treatment effectiveness. [0052] Embodiments of the invention may include a system for monitoring, and/or treating tics in a subject. Embodiments of the system may include an audiovisual sensor (e.g., a camera), a non-transitory memory device, wherein modules of instruction code are stored, and at least one processor associated with the memory device, and configured to execute the ICH-RMT-P-028-IL modules of instruction code. Upon execution of said modules of instruction code, the at least one processor may display an audiovisual stimulus to the subject, wherein said audiovisual stimulus is designed to induce tics. The at least one processor may employ the camera to record a behavior of the subject, and analyze the recorded behavior to determining onset of one or more tic sequences in the subject. The at least one processor may subsequently calculate one or more tic property values, representing one or more respective characteristics of the detected tic sequences, and adjust the audiovisual stimulus in real time, or near real time based on the one or more tic property values, to improve the subject’s ability to withhold tics. [0053] The present invention may thus provide an innovative method and system for monitoring, and/or treating tics by utilizing audiovisual stimuli and real-time adjustment based on tic-related characteristics. By dynamically adapting the audiovisual stimulus and incorporating personalized training regimens, the method may offer an effective and tailored approach for managing tics in subjects (e.g., human patients). [0054] Embodiments of the invention may include a method of monitoring, and/or treating tics in a subject by at least one processor. Embodiments of the method may include displaying an audiovisual stimulus to the subject, and obtaining indication of onset of one or more tic sequences in the subject, subsequent to said display. Embodiments may further include calculating one or more tic property values, representing one or more respective characteristics of said tic sequences, and adjusting the audiovisual stimulus in real time, or near-real time based on the one or more tic property values. [0055] Embodiments of the invention may include a system for treating tics in a subject. Embodiments of the system may include a non-transitory memory device, wherein modules of instruction code are stored and at least one processor associated with the memory device, and configured to execute the modules of instruction code. Upon execution of said modules of instruction code, the at least one processor may be configured to display an audiovisual stimulus to the subject, and obtain indication of onset of one or more tic sequences in the subject, subsequent to said display. The at least one processor may calculate one or more tic property values, representing one or more respective characteristics of said tic sequences, and adjust the audiovisual stimulus in real time, based on the one or more tic property values.

ICH-RMT-P-028-IL 11 BRIEF DESCRIPTION OF THE DRAWINGS[0056] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which: [0057] Figs. 1A-1C are snapshot images from a video game ("ZenithX") that may be presented to a subject by a system for treating tics, according to some embodiments of the invention. Fig. 1A depicts the main screen of the video game, where a race for the castle is depicted, and where a participant represented by a figure marked by a frame is competing with opponents. When two opponents occupy the same slot, a card battle commences (Fig. 1B). Once the battle's outcome is determined, the participant retrieves a card from the chest (1C). [0058] Fig. 1D includes an upper panel and a lower panel. The upper panel is a graph showing user engagement scores, each relating to a specific aspect of engagement, where each dot represents a specific subject. The lower panel is a graph showing an average of the abovementioned engagement scores, where each dot represents a specific subject. [0059] Fig. 2 is a graph depicting tic rate time course during the viewing of an excerpt from a movie ("Up"). The black curve indicates the average z-scored tic frequency while the gray surface indicates a standard error. Events of peak tic frequency, corresponding to prominent moments in an audiovisual stimulus (e.g., the movie "UP"), are numbered by their magnitude. [0060] Figs. 3A-3C represent effect of gamified anticipation events on tic frequency. Fig. 3A depicts average tic frequencies during the game events of chest anticipation, battle, and dice-roll in Experiment 1, relative to two control conditions: gameplay excluding special events and animation with neutral valence and no bodily cues. The average tic frequencies are represented by three dots connected with lines for each of the participants (N=20). Fig. 3B depicts differences in average tic rates between game events and gameplay excluding special events in Experiment 2 (N=35). Fig. 3C depicts tic frequency increases during anticipation for chest opening when a target chest in marked (shake) relative to general anticipation (no-shake). * QFDR<.05, ** QFDR <.01.

ICH-RMT-P-028-IL 12 id="p-61" id="p-61" id="p-61" id="p-61" id="p-61" id="p-61"

[0061] Fig. 4 is a block diagram, depicting a computing device which may be included in a system for treating tics in a subject according to some embodiments of the invention; [0062] Fig. 5 is a block diagram, depicting a system for treating tics in a subject according to some embodiments of the invention; [0063] Figs. 6A and 6B are graphs depicting results of treatment by a system for treating tics in a subject, according to some embodiments of the invention; [0064] Fig. 7 is a graph depicting results of treatment by a system for treating tics in a subject, according to some embodiments of the invention; and [0065] Fig. 8 is a flow diagram, depicting a method of treating tics in a subject according to some embodiments of the invention. [0066] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION[0067] One skilled in the art will realize the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the invention described herein. Scope of the invention is thus indicated by the appended claims, rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. [0068] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention. Some features or elements described with respect to one embodiment may be combined with features or elements described with respect to other embodiments. For the sake of clarity, discussion of same or similar features or elements may not be repeated.

ICH-RMT-P-028-IL 13 id="p-69" id="p-69" id="p-69" id="p-69" id="p-69" id="p-69"

[0069] Although embodiments of the invention are not limited in this regard, discussions utilizing terms such as, for example, "processing," "computing," "calculating," "determining," "establishing", "analyzing", "checking", or the like, may refer to operation(s) and/or process(es) of a computer, a computing platform, a computing system, or other electronic computing device, that manipulates and/or transforms data represented as physical (e.g., electronic) quantities within the computer’s registers and/or memories into other data similarly represented as physical quantities within the computer’s registers and/or memories or other information non-transitory storage medium that may store instructions to perform operations and/or processes. [0070] Although embodiments of the invention are not limited in this regard, the terms "plurality" and "a plurality" as used herein may include, for example, "multiple" or "two or more". The terms "plurality" or "a plurality" may be used throughout the specification to describe two or more components, devices, elements, units, parameters, or the like. The term "set" when used herein may include one or more items. [0071] Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed simultaneously, at the same point in time, or concurrently. [0072] In a first experiment, Experiment 1, twenty-three children and adolescents with a primary diagnosis of Tic disorder or Tourette syndrome were recruited. [0073] The inventors examined the replicability of findings from the game data analysis in an independent cohort of 36 patients (15 girls; age: 10.56 ± 2.44, range: 7-15 years). This group participated in a clinical study, denoted herein as Experiment 2, utilizing the game developed in the first study. [0074] Experiment 1: Each participant attended a 3-hour session at the Immersive lab, which was conducted by a trained research assistant. The participants were video, and audio recorded by two webcams. One of the webcams was placed in front of the participant for video recording, while the other was placed on a small stool next to them for sound recording. The participants were facing a projector screen, and were instructed to tic as much or as little as they needed throughout the entire session without suppressing tics. [0075] A semi-structured interview was conducted with each participant to gather information regarding their treatment history and any comorbid conditions. After the ICH-RMT-P-028-IL 14 interview, a Yale Global Tic Severity Scale (YGTSS) test was administered to assess symptoms demonstrated within the past three weeks. The session was divided into four parts, which were presented in a counterbalanced order across subjects: (1) two 2.5-minute real-time assessment sessions of urge intensity, (2) viewing six short clips (divided into two blocks separated by the "Up" segment), (3) viewing a segment from the film Up, and (4) playing four rounds of the X-Tics game. [0076] Experiment 2: The inventors examined the replicability of findings from the game data analysis in a different group where the game was used as a behavioral treatment enhancer (paper in preparation). Participants underwent two online sessions of psychoeducation and individual training on tic suppression techniques, followed by two weeks of training consisting of three 60-minute sessions per week, with one week off between the session series. At the beginning of each training week, a baseline game was played on desktop computers with standard LCD 24-inch monitors. The participants were instructed not to suppress their tics. Data from the two baseline games are analyzed herein. [0077] Movie clip: After a brief summary of the general storyline of the film, participants were shown an 11-minute suspenseful segment from the computer-animated film Up (2009) by Pixar. This segment portrays the mission of the 78-year-old protagonists Carl Fredricksen and a boy named Russell to rescue their friend, Kevin the bird, from the clutches of the film’s main antagonist, Charles Muntz, who captures her. The excerpt was selected since it is rich in goal-oriented actions, which are hypothesized to engage the cortico-striatal-thalamo-cortical loop involved in tic manifestation. [0078] Short clips: Participants watched six short clips, each lasting three minutes, from the following categories: (i) positively-valenced clips portraying humans in a pleasurable bodily states (e.g., a boy savoring a cake), (ii) similarly positively-valenced clips that do not feature human bodies (e.g., an enticing piece of cake on a plate), (iii) negatively-valenced clips depicting humans in unpleasant bodily states (e.g., experiencing pain), (iv) similarly negatively-valenced clips that do not feature human bodies (e.g., a spider), (v) emotionally-neutral clips featuring a human body, (vi) emotionally-neutral clips that do not depict human bodies. The clips were divided into two blocks and presented in a random order across participants. Each clip was accompanied by a correspondingly valenced soundtrack adopted from a previous study.

ICH-RMT-P-028-IL id="p-79" id="p-79" id="p-79" id="p-79" id="p-79" id="p-79"

[0079] To assess whether the clips effectively elicit negative and positive emotions, the inventors presented them to another group of children during an intake session to evaluate their tic disorder. After the exclusion of 6 participants due to technical issues with sound playback, the group included 34 children (age: 10.35 ± 2.40 years, 9 girls). Each child viewed up to three clips, randomly selected from the set of six animations and presented in random order. The children rated the clips using the Self-Assessment Manikin (SAM) as known in the art, after viewing, a pictorial assessment technique in which the participant rates the valence and emotion of target stimuli on a 9-point scale. The inventors obtained a total of 15, 13, 17, 16, 15, 13, 15, and 18 ratings for the negative-body, negative no-body, neutral no-body, positive body, and positive no-body clips, respectively. [0080] The inventors designed a video game, also referred to herein as the "ZenithX" game, as a combination of the card game "War" and the board game "Ladders and Snakes" (Fig. 1A). In each game round, participants compete in a race to the top with three opponents (out of four potential opponents including one allegedly human played by the experimenter, and three bots). The first opponent arriving at the top is granted the highest score, while the rest lose points according to their distance from the top. The opponents differ in color, indicating their strength (their success rates in battles). A virtual dice-roll determines the number of forward steps for each player in each round. When two players occupy the same slot, a combat is initiated. The combat may include the following phases: (i) Card selection (Fig. 1B): the participant selects one out of three cards from their hand. The cards are numbered from 1 to 9, where 9 is the strongest card. (ii) Battle: The selected card competes with the opponent's card. The winner advances, and the loser retreats a number of steps equal to the difference between the competing cards' numbers. (iii) Card retrieval (Fig. 1C): An animation of three chests appears on the screen. The chests differ in color, indicating the strength of the cards they contain (i.e., the chests differ in card number probabilities). During the anticipation phase, three chests were presented, and one of them started shaking, indicating that the retrieved card would be drawn from it. The duration of the chest presentation and shaking animation was randomly set to 0.5, 4.5, 9, or 13.5 seconds, with a total duration of 14 seconds for the entire phase. Finally, the chest opened, and the participant retrieved and exposed a card. In Experiment 2, the motionless chest appeared on the screen for 3 seconds, followed by shaking for 3-4 seconds.

ICH-RMT-P-028-IL 16 id="p-81" id="p-81" id="p-81" id="p-81" id="p-81" id="p-81"

[0081] Participant subjects were familiarized with the rules of the game via a short presentation delivered by the research assistant, followed by a short trial game. They were told that they will play four successive game rounds, while the score of each round will be accumulated between rounds for each player. The highest accumulated score presented on the scoreboard at the end of the last round will grant the player the win, and he will receive a gift card. The total duration of this task was approximately 60 minutes. [0082] In Experiment 1, the inventors scripted the course of the game, including the series of cards regained from the chests in each step. The only unexpected parameter was the participant's card selection during the battle, which was addressed by forcing repeating draws until the pre-scripted outcome was possible. The inventors have pre-scripted four alternative game rounds. The participant won two of them, as well as the overall session. [0083] In the replication study, the participants played against bots only (no human opponent was involved). The inventors randomized the game parameters. [0084] The User Engagement Scale (UES): After playing four rounds of the computer game, participants were administered a short version of the User Engagement Scale (UES) questionnaire, as known in the art. In this 12-item questionnaire, four different aspects of the user’s experience may be estimated using a five-point rating scale: (i) Focused attention, estimating the extent to which the user felt absorbed in the interaction and lost track of time; (ii) Perceived usability, indicating negative affect experienced as a result of the interaction and the degree of control and effort expended; (iii) Aesthetic appeal, e.g., the attractiveness and visual appeal of the interface; (iv) Reward factor, e.g., the extent to which the user felt that the experience was satisfying and interesting. [0085] Tic annotation: Previous related research scored visual data using a standard procedure involving exact frequency counts and/or partial-interval coding. Given the considerable variability in the duration and complexity of tics and the inventors’ interest in tic dynamics, the inventors utilized a sensitive, machine-learning (ML) based coding tool. In some embodiments, the inventors employed the currently available Behavioral Observation Research Interactive Software (BORIS) as the ML based coding tool. BORIS may allow for user-specific coding environments to achieve a more complex level of coding. Each coding 'event' was defined as either a 'state' or 'point' event based on its temporal characteristics. The inventors designated an 'event' for each type of tic and defined it as either a vocal or motor tic, a simple or complex tic.

ICH-RMT-P-028-IL 17 id="p-86" id="p-86" id="p-86" id="p-86" id="p-86" id="p-86"

[0086] After identifying each subject's unique array of tics, the inventors co-coded 20% of each subject's video data to assess inter-rater reliability for each coded dataset. The full video data may be coded, dedicating a separate coding session for each tic-event to capture each tic type in high resolution and with a high level of accuracy. All coding was done with coders blind to the condition. [0087] To assess inter-rater reliability, the inventors generated two tic time-series (one per coder) by averaging tics of all types within 3-second bins. Tics annotated as 'state' events were regarded as if their frequency was one tic per second. For each couple of time-series, the inventors computed Krippendorff's alpha, which measures the extent of agreement among coders and is regularly used in content analysis. For this analysis, the inventors used the MATLAB function kriAlpha. According to the recommended guidelines for interpreting the coefficient, α ≥ 0.8 should be considered reliable. The Krippendorff α values obtained in the inventors’ analysis points to the reliability of the inventors’ tic annotation method with an average of 0.85 ± 0.05, ranging between 0.797 and 0.967. [0088] In addition to tic-events, missing data or subject distractions were coded on three categories: (1) epochs where the participant was not looking at the stimuli, (2) significant distractions (e.g., the participant was talking with the research assistant), and (3) epochs in which certain body parts were completely hidden. These epochs were excluded from analysis. [0089] In Experiment 2, the tics were coded in real-time either manually (e.g., by pressing a key whenever a tic was detected) or automatically, e.g., by software adapted to analyze recorded video. [0090] Movie clip(Hypothesis H1): To investigate whether the movie elicits synchronized tic patterns across subjects, the inventors have computed individual tic time courses (sampled in 1, 2, or 3-second time bins) as follows: for each participant, the inventors have calculated the Pearson correlation between their tic time-series and the corresponding average group time course, excluding time points in which the recording was interrupted. The resulting series of Pearson coefficients were then subjected to a t-test after Fisher r-to-z transformation. [0091] To determine the significance of the inventors’ results, the inventors have compared the t-statistic to a null distribution of t-statistics generated by bootstrapping via phase-randomization. This procedure controls for the power spectrum (and thus temporal ICH-RMT-P-028-IL 18 autocorrelation) of the input time-series. The inventors have generated symmetric phase-scrambled Fourier components for the original time-series and used the inverse fast Fourier transform of these components, as described in Regev et al., 2013. Next, the inventors have compared the time-series of each individual participant with the average shuffled time-series of all other participants. The resulting Fisher-z transformed Pearson coefficients were subjected to a t-test across participants. The inventors have repeated this procedure 10,0times. The p-value is reported as the proportion of t-statistics in the resulting null distribution with an absolute value equal to or higher than the t-statistic obtained in the original test. [0092] As an additional control method, the inventors similarly compared the t-statistic of the original test with a null distribution of statistics generated by correlating the tic time-series obtained during the movie with an average of time-series recorded while the participants were watching animations. For each participant, the inventors concatenated tic time-series for six animations while randomizing the order of the animations. The inventors then selected from the randomized time-series an epoch whose length was identical to the movie clip duration (700 sec), starting from a random time-point. These randomly selected time-series were averaged over participants, and the resulting average was correlated to the original time-series. The significance level was assessed in relation to a null distribution of 10,000 values as described in the previous paragraph. [0093] Short clips(Hypothesis H2): The inventors examined the impact specific movie elements on tic manifestation via a two-way repeated measures ANOVA with two within-subject factors: VALENCE (positive, neutral, negative) and BODY (animated bodily gestures, animation with no bodily cues). To determine the significance level of the main effects, the inventors compared the observed F values to a null distribution obtained by randomly shuffling either the VALENCE or the BODY labels. The inventors also tested the significance of the VALENCE × BODY interaction by comparing the observed F value to a null distribution of interaction F values obtained by shuffling the labels 100,000 times. [0094] Game events (Hypotheses H3, H4): The inventors tested whether each of the hypothesized tic-triggering event types, namely, dice-roll (DICE), battle (BATTLE), and anticipation for chest opening (CHEST), enhances tic frequency relative to baseline. The average tic frequency across all DICE, BATTLE, and CHEST events were computed separately per participant, and compared with control conditions of two types: (1) Gameplay time that included none of the three events of interest (DICE, BATTLE, CHEST). Tic ICH-RMT-P-028-IL 19 frequency was computed for the entire game, excluding DICE, BATTLE, and CHEST epochs, and the additional successive three seconds including the participant's tile movement. (2) Passive watching time of emotionally-neutral animation clips. The inventors used a paired Student's t-test to compare the test with each of the control conditions. [0095] As the distribution of tic frequencies is bounded by zero and does not satisfy normality, the inventors assessed the significance of the test by comparing the resulting t-statistics with corresponding null-distributions generated by random label shuffling per subject and test (100,000 shuffles). The p-value was defined as the proportion of items from the null-distribution whose absolute value was equal to or higher than the t-statistic obtained in the original test. To control the six hypotheses tested (three test conditions compared with two control conditions), the inventors have applied FDR correction. [0096] Hypothesis H5: In each CHEST and BATTLE epoch, the inventors have summed up the tic count in 2-second time bins. The inventors have excluded 20.3% and 10.6% of the CHEST and BATTLE epochs, respectively, for which valid data was available for less than bins. To test for a monotonic trend, the inventors have computed Spearman correlation coefficients. The inventors assigned time values to each time bin and calculated the Spearman correlation coefficient between tic count and the corresponding time series values. The inventors subsequently averaged the Fisher-Z transformed Spearman coefficients per participant and t-tested the resulting coefficients. Next, the inventors have compared the absolute value of the resulting z-statistic to absolute values of 10,000 t-statistics generated by repeating the procedure with randomly shuffled time series of tic counts. The inventors determined the p-value as the proportion of null distribution values that were equal to or greater than the t-statistics of the original test. To test for the interaction between time and expected value, the inventors computed Spearman correlations between the coefficients indicating tic trends and the ordinal value of the chest or battle opponent (0-wood, 1-silver, 2-gold) for each participant. The inventors conducted a z-test on the resulting Spearman coefficients. [0097] Hypothesis H6: Tic frequency was computed for each participant during CHEST episodes where no specific chest was shaking ('no-shake') and epochs in which a particular chest was shaking ('shake'), indicating that the card would be regained from that chest. The differences between tic frequencies were averaged per participant and then compared using a paired t-test. The significance of the results was determined relative to a null distribution ICH-RMT-P-028-IL of 10,000 t-values generated by epoch-wise shuffling of the 'no-shake' and 'shake' labels. As an additional control for a potential confound related to the fact that the 'shake' always followed the 'no-shake' condition, the inventors have compared the t-statistic of the original test to a null distribution of 10,000 t-values generated by epoch-wise random splitting of the CHEST episodes into two intervals using the original preset durations, where the 'no-shake' condition precedes the 'shake' condition (i.e., the order is maintained, but durations are randomized). [0098] Hypothesis H7: The inventors calculated average tic frequencies for BATTLE and CHEST ('shake') epochs where the opponent or target chest, respectively, were of wood, silver, and gold type. The inventors tested for a difference in average tic frequency between the conditions using one-way repeated measures ANOVA with three levels (wood, silver, gold). To test for any differences in the average tic frequency between the conditions, the inventors performed a one-way repeated measures ANOVA with three levels (wood, silver, and gold). The resulting F value was compared to a null distribution of 10,000 values generated by repeating this procedure with shuffled labels. [0099] Hypothesis H8: To compare the tic frequency during battles against allegedly human and computer opponents, the inventors calculated the average frequencies of these conditions across participants and conducted a t-test. The inventors compared the results to a null distribution of 10,000 values generated by shuffling the opponents' labels. [00100] Hypothesis H9: Pearson correlation were calculated between tic frequencies during 3-second windows of the dice-roll animation and the distance between the player's and leading opponent's tiles (Z-scored distances per individual). After Fisher r-to-z transformation, the resulting Pearson coefficients were subjected to a z-test for statistical significance. [00101] Hypothesis H10: The distance between the player's tile and the leading opponent's tile (D1) was standardized using z-scores relative to the set of all such distances across the entire study. The same standardization procedure was applied to the distance between the player's tile and the ending point (D2). A composite measure of D1/D2 was computed and correlated with tic frequencies within a 3-second window of the dice roll animation. The resulting Pearson correlation coefficients were subjected to a z-test for statistical significance after Fisher r-to-z transformation.

ICH-RMT-P-028-IL 21 id="p-102" id="p-102" id="p-102" id="p-102" id="p-102" id="p-102"

[00102] Inter-subject synchronization of tic patterns by the movie: In line with the inventors’ hypothesis (H1), the temporal patterns of tic manifestation were significantly correlated across participants. Correlation coefficients for tic time-series measured during film viewing were significantly higher than coefficients computed both for these time-series after random shuffling (Movie-Shuffled) and for randomly selected non-aligned time series with identical size obtained during the viewing of various animations (Movie-Animations). These results were robust in the selection of the tic-sampling time bin with t(19)= 4.13, 4.25, and 4.37, pMovie-Shuffled = .0007, .0005, and .0004, and pMovie-Animations = .0002, .0001, and .0001, for 1-,2-, and 3-second bins, respectively. The average standardized tic frequency time course is visualized in FIG. 2. [00103] Reference is now made to Fig. 4, which is a block diagram depicting a computing device, which may be included within an embodiment of a system for treating tics in a subject, according to some embodiments. [00104] Computing device 1 may include a processor or controller 2 that may be, for example, a central processing unit (CPU) processor, a chip or any suitable computing or computational device, an operating system 3, a memory 4, executable code 5, a storage system 6, input devices 7 and output devices 8. Processor 2 (or one or more controllers or processors, possibly across multiple units or devices) may be configured to carry out methods described herein, and/or to execute or act as the various modules, units, etc. More than one computing device 1 may be included in, and one or more computing devices 1 may act as the components of, a system according to embodiments of the invention. [00105] Operating system 3 may be or may include any code segment (e.g., one similar to executable code 5 described herein) designed and/or configured to perform tasks involving coordination, scheduling, arbitration, supervising, controlling or otherwise managing operation of computing device 1, for example, scheduling execution of software programs or tasks or enabling software programs or other modules or units to communicate. Operating system 3 may be a commercial operating system. It will be noted that an operating system may be an optional component, e.g., in some embodiments, a system may include a computing device that does not require or include an operating system 3. [00106] Memory 4 may be or may include, for example, a Random-Access Memory (RAM), a read only memory (ROM), a Dynamic RAM (DRAM), a Synchronous DRAM (SD-RAM), a double data rate (DDR) memory chip, a Flash memory, a volatile memory, a ICH-RMT-P-028-IL 22 non-volatile memory, a cache memory, a buffer, a short term memory unit, a long term memory unit, or other suitable memory units or storage units. Memory 4 may be or may include a plurality of possibly different memory units. Memory 4 may be a computer or processor non-transitory readable medium, or a computer non-transitory storage medium, e.g., a RAM. In one embodiment, a non-transitory storage medium such as memory 4, a hard disk drive, another storage device, etc. may store instructions or code which when executed by a processor may cause the processor to carry out methods as described herein. [00107] Executable code 5 may be any executable code, e.g., an application, a program, a process, task, or script. Processor or controller 2 may execute executable code 5 possibly under control of operating system 3. For example, executable code 5 may be an application that may treat tics in a subject as further described herein. Although, for the sake of clarity, a single item of executable code 5 is shown in Fig. 4, a system according to some embodiments of the invention may include a plurality of executable code segments similar to executable code 5 that may be loaded into memory 4 and cause processor 2 to carry out methods described herein. [00108] Storage system 6 may be or may include, for example, a flash memory as known in the art, a memory that is internal to, or embedded in, a micro controller or chip as known in the art, a hard disk drive, a CD-Recordable (CD-R) drive, a Blu-ray disk (BD), a universal serial bus (USB) device or other suitable removable and/or fixed storage unit. Data representing occurrence of tics in a subject may be stored in storage system 6 and may be loaded from storage system 6 into memory 4 where it may be processed by processor or controller 2. In some embodiments, some of the components shown in Fig. 4 may be omitted. For example, memory 4 may be a non-volatile memory having the storage capacity of storage system 6. Accordingly, although shown as a separate component, storage system may be embedded or included in memory 4. [00109] Input devices 7 may be or may include any suitable input devices, components, or systems, e.g., a detachable keyboard or keypad, a mouse and the like. Output devices may include one or more optionally detachable displays or monitors, speakers and/or any other suitable output devices. Any applicable input/output (I/O) devices may be connected to Computing device 1 as shown by blocks 7 and 8. For example, a wired or wireless network interface card (NIC), a universal serial bus (USB) device or external hard drive may be included in input devices 7 and/or output devices 8. It will be recognized that any suitable ICH-RMT-P-028-IL 23 number of input devices 7 and output device 8 may be operatively connected to Computing device 1 as shown by blocks 7 and 8. [00110] A system according to some embodiments of the invention may include components such as, but not limited to, a plurality of central processing units (CPU) or any other suitable multi-purpose or specific processors or controllers (e.g., similar to element 2), a plurality of input units, a plurality of output units, a plurality of memory units, and a plurality of storage units. [00111] The term neural network (NN) or artificial neural network (ANN), e.g., a neural network implementing a machine learning (ML) or artificial intelligence (AI) function, may be used herein to refer to an information processing paradigm that may include nodes, referred to as neurons, organized into layers, with links between the neurons. The links may transfer signals between neurons and may be associated with weights. A NN may be configured or trained for a specific task, e.g., pattern recognition or classification. Training a NN for the specific task may involve adjusting these weights based on examples. Each neuron of an intermediate or last layer may receive an input signal, e.g., a weighted sum of output signals from other neurons, and may process the input signal using a linear or nonlinear function (e.g., an activation function). The results of the input and intermediate layers may be transferred to other neurons and the results of the output layer may be provided as the output of the NN. Typically, the neurons and links within a NN are represented by mathematical constructs, such as activation functions and matrices of data elements and weights. At least one processor (e.g., processor 2 of Fig. 4) such as one or more CPUs or graphics processing units (GPUs), or a dedicated hardware device may perform the relevant calculations. [00112] Reference is now made to Fig. 5, which depicts a system 100 for treating tics in a subject, according to some embodiments. [00113] According to some embodiments of the invention, system 100 may be implemented as a software module, a hardware module, or any combination thereof. For example, system may be, or may include a computing device such as element 1 of Fig. 4, and may be adapted to execute one or more modules of executable code (e.g., element 5 of Fig. 4) to treat tics in a subject, as further described herein.

ICH-RMT-P-028-IL 24 id="p-114" id="p-114" id="p-114" id="p-114" id="p-114" id="p-114"

[00114] As shown in Fig. 5, arrows may represent flow of one or more data elements to and from system 100 and/or among modules or elements of system 100. Some arrows have been omitted in Fig. 5 for the purpose of clarity. [00115] According to some embodiments, system 100 may facilitate treatment of tics in a subject or patient by at least one processor (e.g., processor 2 of Fig. 4). [00116] As shown in Fig. 5, system 100 may include, or be communicatively connected to a stimulus module 30. For example, stimulus module 30 may be a computing device (e.g., computing device 1 of Fig. 4), adapted to display (e.g., via a screen) an audiovisual stimulus 30S to the subject. [00117] For example, system 100 may provide an audiovisual stimulus 30S such as computerized gaming platform, also referred to herein as computer game 30GAM, configured to allow the subject to engage in a computer game. Additionally, or alternatively, system 100 may provide an audiovisual stimulus 30S such as an audiovisual or video stimulus 30VID (e.g., a video segment from a movie). The audiovisual stimulus 30S (e.g., 30GAM, 30VID) may be designed to induce tics in a human subject, as elaborated herein. [00118] As shown in Fig. 5, system 100 may include a tic analysis module 10, adapted to identify and analyze occurrence of tics. Tic analysis module 10 may include a plurality of sub-modules, as elaborated herein. One such sub module may be a tic indication module 120. Tic indication module 120 may be configured to obtain, or identify (or "code", as also referred to herein) an indication of onset of one or more tic sequences in the subject, subsequent to the display of audiovisual stimulus 30S (e.g., 30GAM, 30VID). [00119] For example, system 100 may include, or may provide a user interface (UI) module 70 (e.g., input device 7 of Fig. 4). According to some embodiments, UI 70 may prompt a user (e.g., a therapist) to observe a behavior of the human subject, and indicate occurrence of a tic e.g., by pressing a button. [00120] Additionally, or alternatively, system 100 may include, or may be communicatively connected to an audiovisual (AV) input module 20 such as a camera 20. AV input module 20 may be configured to record or capture AV data 20D, such as an audio and/or video data element, such as a file or stream. Captured AV data 20D may depict, or represent behavior of the subject during presentation of audiovisual stimulus 30S. Tic indication module 120 may receive, e.g., via UI 70 manual input which codes, or identifies locations in AV data 20D that represent occurrence of tics in the subject.

ICH-RMT-P-028-IL id="p-121" id="p-121" id="p-121" id="p-121" id="p-121" id="p-121"

[00121] Additionally, or alternatively, tic indication module 120 may include a behavioral feature extraction (FE) module 120FE (or FE 120FE for short). FE module 120FE may be configured to extract one or more behavioral features 120BF based on AV data 20D. For example, FE 120FE may analyze AV data 20D to extract one or more vocal behavioral features 120BF (e.g., voice pitch or uttered syllables) that may indicate occurrence of a vocal tic. In another example, FE 120FE may analyze AV data 20D to extract one or more corporal, or motoric behavioral features 120BF (e.g., representing a posture or movement) that may indicate occurrence of a motor tic. [00122] Tic indication module 120 may subsequently analyze behavioral features 120BF to automatically determine onset of a tic sequence in the subject, based on audiovisual data. [00123] For example, tic indication module 120 may include a machine learning (ML) based algorithm or model 120ML. During a training phase, ML model 120ML may be pretrained, e.g., via a supervised training scheme, and based on an annotated data set of behavioral features 120BF obtained from a plurality of subjects, to ascertain occurrence of tics or tic sequences. During a subsequent inference phase, tic indication module 120 may employ ML model 120ML, and may apply ML model 120ML on the one or more extracted behavioral features 120BF of the subject of interest, to ascertain occurrence of tics or tic sequences in the subject. [00124] Additionally, or alternatively, tic indication module 120 may include, or may employ other analysis tools that may be configured to identify behavioral properties of the depicted subject in audiovisual data 20D, and/or facilitate manual annotation of occurrence of tics and/or tic sequences in AV data 20D. Tic indication module 120 may thus mark specific intervals or locations in AV data 20D where tics appear. [00125] Additionally, or alternatively, system 100 may include, or may be associated with a Brain-Computer Interface (BCI) 50 in which a biosignal 50BS representing brain activity (e.g., activity of the dorsal striatum and/or the supplementary motor area) may be measured in real-time during display of stimulus 30S (e.g., while the subject plays video game 30GAM). Tic indication module 120 may receive biosignal 50BS from BCI 50, and analyze said at least one biosignal to automatically determine onset of one or more tics or tic sequences in the subject. According to some embodiments, video game 30GAM may be changed according to biosignal 50BS so that the patient may be penalized or rewarded, to encourage them to extend or prolong gaps or intervals between tic sequences.

ICH-RMT-P-028-IL 26 id="p-126" id="p-126" id="p-126" id="p-126" id="p-126" id="p-126"

[00126] As shown in Fig. 5, tic analysis module 10 may include a tic properties module 130, configured to calculate one or more tic property values 130P. Each tic property values 130P may represent one or more respective characteristics of the indicated tic sequences 120IND. [00127] Additionally, or alternatively, tic analysis module 10 may include a feedback module 140, configured to calculate a required adjustment 140AD of stimulus 30S. In some embodiments, adjusting the audiovisual stimulus may include calculating a level of reward 140RW, based on the one or more tic property values 130P, so as to encourage the subject to prolong time gaps between subsequent tic sequences. Subsequently, feedback module 1may provide adjustment value 140AD to stimulus module 30 in real time or near real time, e.g., to be experienced by a user of system 100 as substantially concurrent with stimulus 30S. Stimulus module 30 may subsequently adjust audiovisual stimulus 30S (e.g., 30GAM) in real time or near real time, based on the one or more tic property values 130P. [00128] For example, and as elaborated herein, stimulus module 30 may include a computerized gaming platform, which allows the subject to engage in a computer game. In such embodiments, audiovisual stimulus 30S may be gaming audiovisual data 30GAM received from the interactive computer game. Feedback module 140 may calculate an adjustment 140AD or a change in one or more parameters of the computer game, based on the calculated level of reward. [00129] As described herein, the identified tics 120IND may include motor tics and/or vocal tics. The respective tic property values 130P of tic sequences may include, for example: duration of at least one tic sequence, a number of tics in the tic sequence, a frequency of tics within the tic sequence, a complexity of tics within the tic sequence, an intensity of tics within the tic sequence, an interference of the tics within the tic sequence, a gap or interval between successive tic sequences, an average of gaps or intervals between successive tic sequences, and the like. [00130] According to some embodiments, during a session, a participant or subject may be encouraged to avoid tics over increasing periods of time. In a preliminary phase, tic properties module 130 may calculate a tic property value 130P representing baseline Average Tic-to-Tic Interval (ATTI 130P), e.g., an average of gaps or intervals between successive tics or tic sequences. Tic properties module 130 may subsequently calculate a tic property value 130P representing an Average Gap (AG 130P) between successive Tic-to- ICH-RMT-P-028-IL 27 Tic Intervals (TTI 130P, e.g., intervals between successive tics or tic sequences) whose lengths are equal to, or higher than ATTI 130P. [00131] During a subsequent phase, the participant may be presented with a gamified AV stimulus 30S, e.g., prompted to play game 30GAM. In the example provided herein (e.g., in relation to Figs. 1A-1C), the participant’s tic manifestation cause feedback module 140 to calculate a reward 140RW and/or subsequent adjustment 140AD in at least one core game event. [00132] For example, adjustment 140AD may manifest a level of reward or penalty 140RW (e.g., increase or decrease of credit points in the game), to reward or penalize the subject according to their ability to withhold manifestation of tics. Additionally, or alternatively, adjustment 140AD may include modification of other aspects in the game, such as extension or shortening of suspension periods, to optimally train the subject to withhold tics. [00133] For example, feedback module 140 may calculate a numeric positive reward 140RW representing improvement (e.g., prolonging) of TTIs 130P, or a negative reward 140RW representing deteriorated (e.g., shortened) TTIs 130P. Feedback module 140 may subsequently calculate adjustment 140AD to apply changes to core events of game 30GAM characteristics. [00134] For example adjustment 140AD may determine dice outcomes, where high scores are attributed to longer TTIs 130P. In another example, adjustment 140AD may determine an opponent’s card, where weaker cards are attributed to longer TTIs 130P. In another example, adjustment 140AD may determine a chest type (e.g., wood, silver, or gold chests), where favorable chests are selected, or provided with longer TTIs 130P. In another example, adjustment 140AD may determine a value of a retrieved card, where stronger cards are provided for longer TTIs 130P. [00135] Depending on the participant’s TTIs 130P in the current game and on the baseline ATTI 130P and AG 130P, feedback module 140 may calculate a preset so that the chance to obtain a desired outcome improves with longer TTIs 130P. [00136] In each core game event, a composite performance score is calculated. A vector of the participant’s TTIs 130P up to the core game event is generated. Only TTIs 130P equal to, or larger than the ATTI 130P may be counted. The timing differences between the core game event and the TTIs 130P endings may be calculated, and weighted by an inverse ICH-RMT-P-028-IL 28 sigmoid function f. The composite measure ?? for a certain core game event, corresponding to the jth TTI 130P in the game, is then computed according to equation Eq. 1, below: Eq. 1 ? ? = ∑ ? ? ? (? ? − ? ? )? ? =1 where ? ? is the duration of an TTI 130P, ? ? is the timing of the TTI 130P ending. The inflection point of sigmoid function f is dependent on the baseline ATTI 130P so that in steeper sigmoid for shorter ATTIs 130P, TTIs 130P that ended long before the current core game event may only have negligible effect on the composite score and vice versa. The inflection point's maximal value was set to 25 seconds. [00137] Feedback module 140 may subsequently divide the composite measure ?? by the simulated ?? , which is computed using the same formula, but with a synthetic vector of TTIs 130P identical to ATTI 130P, separated by AG 130P. Thus, the event score ? ? = ? ? ? ? represents the participant's improvement relative to the baseline at the specific point in the game. According to predefined ? ? ranges, a preset is selected so that high ? ? values yield distributions with higher chance for favorable outcomes. [00138] According to some embodiments, computer game 30GAM may include, or may be characterized by a plurality of probability presets 30PP. Probability presets 30PP may dictate a chance to produce a desired outcome in game 30GAM. In the example of the game described herein (e.g., in relation to Figs. 1A-1C) probability presets 30PP may dictate a chance to get certain outcomes in core events such as dice throws, battles, or chest outcomes. Probability presets 30PP may range from an almost-certain chance of winning, to an almost-certain chance of losing in a specific core event. [00139] According to some embodiments, probability presets 30PP may be calculated as a function of a composite TTIs 130P (e.g., baseline TTI, gap between successive TTIs, etc.) sigmoid score. The sigmoid may become "more difficult" with the improvement of parameters 130P, e.g., as the subject improves suppression of tics. [00140] Additionally, or alternatively, tic analysis module 10 may include a regimen module 150, configured to produce a personalized training scheme or regimen 150R for controlling tics. For example, regimen module 150 may collaborate with feedback module 140 and/or tic properties module 130, calculate the participant’s improvement ? ? , and ICH-RMT-P-028-IL 29 subsequently to calculate a personalized training regimen 150R. In other words, training regimen 150R may include adjustments 140AD or characteristics of gaming stimulus 30GAM, specifically tailored for the subject. Regimen module 150R may subsequently provide regimen 150R (e.g., via feedback module 140) to stimulus module 30, to apply the personalized training regimen 150R in a subsequent engagement of the subject with the computer game. [00141] Additionally, or alternatively, regimen 150R may include a prescription of therapy or training, such as duration, frequency, timing, etc. of games (e.g., three weekly training sessions with 3 games per session, for three weeks). Such prescription may be based on the subject's performance or improvement, e.g., where more sessions may be prescribed if improvement is mild or unsatisfactory. In another example, the prescription may be based on the subject's Level of engagement (e.g., providing more sessions as the engagement level increases. ) In another example, the prescription may be based on the subject's age (providing more sessions for older subjects) for optimal results. [00142] Additionally, or alternatively, tic analysis module 10 may obtain, via UI 40 (e.g., input device 7 of Fig. 4), an urge severity indication 40URG from the subject. Urge severity indication 40URG may include, for example, a numerical value representing a level of severity in which the subject experiences an urge to tic. [00143] According to some embodiments, feedback module 140 may calculate an adjustment value 140AD, and adjust the audiovisual stimulus 30S in real time, further based on the urge severity indication 40URG. [00144] For example, feedback module 140 may incur a low level of positive adjustment 140AD (e.g., corresponding to a weak positive reward 140RW) when the subject withholds tics under a weak urge to tic 40URG, and incur a higher level of positive adjustment 140AD (e.g., corresponding to a strong positive reward 140RW) when the subject withholds tics under a strong urge to tic 40URG. [00145] In a complementary manner, feedback module 140 may incur a low level of negative adjustment 140AD (e.g., corresponding to a weak negative reward or penalty 140RW) when the subject manifests tics under a strong urge to tic 40URG, and incur a higher level of negative adjustment 140AD (e.g., corresponding to a strong negative reward or penalty 140RW) when the subject manifests tics under a weak urge to tic 40URG.

ICH-RMT-P-028-IL id="p-146" id="p-146" id="p-146" id="p-146" id="p-146" id="p-146"

[00146] Additionally, or alternatively, tic analysis module 10 may obtain, a user engagement indication 40ENG, represents a level of engagement of the subject in the audiovisual stimulus. For example, and as depicted in the example of Fig. 5, tic analysis module 10 may, for example obtain engagement indication 40ENG by a questionnaire that may be prompted or input via UI 40. In another example tic analysis module 10 may calculate engagement indication 40ENG by monitoring the subject’s actions throughout the game. [00147] Feedback module 140 may subsequently calculate an adjustment value 140AD, and adjust the audiovisual stimulus 30S in real time, further based on engagement indication 40ENG. For example, feedback module 140 may change characteristics of the game, e.g., shorten an anticipation or suspense period when engagement indication 40ENG is low, and increase an anticipation or suspense period when engagement indication 40ENG is high. [00148] Additionally, or alternatively, tic analysis module 10 may produce one or more recommendations 60 that may correspond to the training regimen 150R. For example, recommendations 60 may include estimation of drug therapy impact on a specific subject, and/or recommendation of a most effective drug or prescription for the specific subject, e.g., as a function of their progress, or improvement of parameters 130P. [00149] Reference is now made to Figs. 6A and 6B, which are graphs depicting results of treatment by a system for treating tics in a subject, according to some embodiments. [00150] After two weeks of training, which included 14 training games in total, the inventors have observed a significant decrease in tic as measured by the Yale Global Tic Severity Scale (YGTSS) (Fig. 6A) and the Parent Tic Questionnaire (PTQ) (Fig. 6B). In the case of PTQ, this decrease was maintained for three additional months. Average individual change in YGTSS and PTQ scores relative to baseline is indicated for each of the measurement time points. N=35. [00151] Reference is now made to Fig. 7, which is a graph depicting results of treatment by a system for treating tics in a subject, according to some embodiments. As shown in Fig. an improvement is clearly evident in TTI 130P when adjustment value 140AD is applied on audiovisual stimulus 30S (e.g., 30GAM) in real time, or near real time (black line). A less explicit improvement is obtained when the adjustment of audiovisual stimulus 30S is delayed (gray line).

ICH-RMT-P-028-IL 31 id="p-152" id="p-152" id="p-152" id="p-152" id="p-152" id="p-152"

[00152] Reference is now made to Fig. 8, which is a flow diagram depicting a method of treating tics in a subject (e.g., a human patient), by at least one processor (e.g., processor of Fig. 4), according to some embodiments of the invention. [00153] As shown in step S1005, the at least one processor 2 may display (e.g., via output device 8 of Fig. 4, such as a screen) an audiovisual stimulus (e.g., 30S of Fig. 5), such as a computer game (e.g., 30GAM of Fig. 5) to the subject. [00154] As shown in step S1010, the at least one processor 2 may obtain or calculate an indication (e.g., indication 120IND of Fig. 5) of onset of one or more tic sequences in the subject, subsequent to said display 30S (e.g., 30GAM). [00155] As shown in step S1015, the at least one processor 2 may calculate one or more tic property values (e.g., 130P of Fig. 5) that may represent one or more respective characteristics of said tic sequences, as elaborated herein. [00156] As shown in step S1020, the at least one processor 2 may calculate a level of reward (e.g., 140RW of Fig. 5) based on the one or more tic property values, so as to encourage the subject to prolong time gaps between subsequent tic sequences. [00157] As shown in step S1025, the at least one processor 2 may subsequently adjust the audiovisual stimulus 30S (30GAM) in real time, or near-real time, based on the one or more tic property values 130P, e.g., by adjusting (e.g., 140AD of Fig. 5) one or more parameters of the audiovisual stimulus 30S (e.g., computer game 30GAM) based on the calculated level of reward 140RW. [00158] Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Furthermore, all formulas described herein are intended as examples only and other or different formulas may be used. Additionally, some of the described method embodiments or elements thereof may occur or be performed at the same point in time. [00159] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents may occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. [00160] Various embodiments have been presented. Each of these embodiments may of course include features from other embodiments presented, and embodiments not specifically described may include various features described herein.

Claims (20)

1. ICH-RMT-P-028-IL 32

2. CLAIMS 1. A system comprising: a non-transitory memory device, wherein modules of instruction code are stored; and at least one processor associated with the memory device, and configured to execute the modules of instruction code, whereupon execution of said modules of instruction code, the at least one processor is configured to: display an audiovisual stimulus to the subject; obtain indication of onset of one or more tic sequences in the subject, said sequences comprising one or more tics, subsequent to said display; calculate one or more tic property values, representing one or more respective characteristics of said tic sequences; and adjust the audiovisual stimulus in real time, based on the one or more tic property values. 2. The system of claim 1, further comprising a camera, wherein the at least one processor is configured to obtain indication of onset of a tic sequence by: receiving, from the camera, audiovisual data depicting behavior of the subject; extracting one or more behavioral features based on said audiovisual data; and applying a machine learning (ML) based algorithm on the one or more behavioral features to automatically determine onset of the tic sequence in the subject, based on said audiovisual data. 3. The system according to any one of claims 1-2, wherein the at least one processor is configured to obtain indication of onset of a tic sequence by: receiving, from a brain-computer interface (BCI) at least one biosignal representing brain activity in at least one of a dorsal striatum and a supplementary motor area of the subject; and analyzing said at least one biosignal to automatically determine onset of the tic sequence in the subject.

3. ICH-RMT-P-028-IL 33

4. The system according to any one of claims 1-3, wherein the at least one processor is configured to display the audiovisual stimulus by providing a computerized gaming platform, configured to allow the subject to engage in a computer game.

5. The system according to any one of claims 1-4, wherein the at least one processor is configured to adjust the audiovisual stimulus by: calculating a level of reward based on the one or more tic property values, so as to encourage the subject to prolong time gaps between subsequent tic sequences; and changing one or more parameters of the computer game based on the calculated level of reward.

6. The system according to any one of claims 1-5, wherein the at least one processor is further configured to: produce a personalized training regimen for controlling tics, wherein the training regimen comprises calculated levels of reward specifically tailored for the subject; and apply the personalized training regimen in a subsequent engagement of the subject with the computer game.

7. The system according to any one of claims 1-6, wherein the at least one processor is configured to categorize according to at least one of motoric tics and vocal tics.

8. The system according to any one of claims 1-7 wherein the property values are selected from a list consisting of: a duration of at least one tic sequence, a number of tics in the tic sequence, a frequency of tics within the tic sequence, a complexity of tics within the tic sequence, an intensity of tics within the tic sequence, an interference of the tics within the tic sequence, an interval between successive tic sequences, and an average of intervals between successive tic sequences.

9. The system according to any one of claims 1-8, wherein the at least one processor is configured to provide a user interface (UI) allowing the subject to indicate, in real time, a severity of an urge to tic. ICH-RMT-P-028-IL 34

10. The system according to any one of claims 1-9 wherein the at least one processor is further configured to: obtain an urge severity indication from the subject, via the UI; and adjust the audiovisual stimulus in real time, further based on the tic urge severity indication.

11. The system according to any one of claims 1-10, wherein the at least one processor is further configured to: obtain, via the UI, a user engagement indication, representing a level of engagement of the subject in the audiovisual stimulus; and adjusting the audiovisual stimulus in real time, further based on the user engagement indication.

12. A method of treating tics in a subject by at least one processor, the method comprising: displaying an audiovisual stimulus to the subject; obtaining indication of onset of one or more tic sequences in the subject, said tic sequences comprising one or more tics, subsequent to said display; calculating one or more tic property values, representing one or more respective characteristics of said tic sequences; and adjusting the audiovisual stimulus in real time, based on the one or more tic property values.

13. The method of claim 12, wherein obtaining indication of onset of a tic sequence comprises: receiving, from a camera, audiovisual data depicting behaviour of the subject; extracting one or more behavioural features based on said audiovisual data; and applying a machine learning (ML) based algorithm on the one or more behavioural features to automatically determine onset of the tic sequence in the subject, based on said audiovisual data.

14. The method according to any one of claims 12-13, wherein obtaining indication of onset of a tic sequence comprises: ICH-RMT-P-028-IL 35 receiving, from a brain-computer interface (BCI) at least one biosignal representing brain activity in at least one of a dorsal striatum and a supplementary motor area of the subject; and analyzing said at least one biosignal to automatically determine onset of the tic sequence in the subject.

15. The method according to any one of claims 12-14, wherein displaying an audiovisual stimulus comprises providing a computerized gaming platform, configured to allow the subject to engage in a computer game.

16. The method according to any one of claims 12-15, wherein adjusting the audiovisual stimulus comprises: calculating a level of reward based on the one or more tic property values, so as to encourage the subject to prolong time gaps between subsequent tic sequences; and changing one or more parameters of the computer game based on the calculated level of reward.

17. The method according to any one of claims 12-16, further comprising: producing a personalized training regimen for controlling tics, wherein the training regimen comprises calculated levels of reward specifically tailored for the subject; and applying the personalized training regimen in a subsequent engagement of the subject with the computer game.

18. The method according to any one of claims 12-17, wherein the tics are selected from motoric tics and vocal tics, and wherein the property values are selected from a list consisting of: a duration of at least one tic sequence, a number of tics in the tic sequence, a frequency of tics within the tic sequence, a complexity of tics within the tic sequence, an intensity of tics within the tic sequence, an interference of the tics within the tic sequence, an interval between successive tic sequences, and an average of intervals between successive tic sequences.

19. The method according to any one of claims 12-18, further comprising: ICH-RMT-P-028-IL 36 obtaining an urge severity indication from the subject, via a user interface (UI), wherein said urge severity indication represents severity of an urge to tic; and adjusting the audiovisual stimulus in real time, further based on the urge severity indication.

20. The method according to any one of claims 12-19, further comprising: obtaining a user engagement indication, wherein said user engagement indication represents a level of engagement of the subject in the audiovisual stimulus; and adjusting the audiovisual stimulus in real time, further based on the user engagement indication.