Developing better digital health measures of Parkinson's disease using free living data and a crowdsourced data analysis challenge.

One of the promising opportunities of digital health is its potential to lead to more holistic understandings of diseases by interacting with the daily life of patients and through the collection of large amounts of real-world data. Validating and benchmarking indicators of disease severity in the home setting is difficult, however, given the large number of confounders present in the real world and the challenges in collecting ground truth data in the home. Here we leverage two datasets collected from patients with Parkinson's disease, which couples continuous wrist-worn accelerometer data with frequent symptom reports in the home setting, to develop digital biomarkers of symptom severity. Using these data, we performed a public benchmarking challenge in which participants were asked to build measures of severity across 3 symptoms (on/off medication, dyskinesia, and tremor). 42 teams participated and performance was improved over baseline models for each subchallenge. Additional ensemble modeling across submissions further improved performance, and the top models validated in a subset of patients whose symptoms were observed and rated by trained clinicians.

Generating Acute and Chronic Experimental Models of Motor Tic Expression in Rats.

Motor tics are sudden, rapid, recurrent movements that are the key symptoms of Tourette syndrome and other tic disorders. The pathophysiology of tic generation is associated with abnormal inhibition of the basal ganglia, particularly its primary input structure, the striatum. In animal models of both rodents and non-human primates, local application of GABAA antagonists, such as bicuculline and picrotoxin, into the motor parts of the striatum induces local disinhibition resulting in the expression of motor tics. Here, we present acute and chronic models of motor tics in rats. In the acute model, bicuculline microinjections through a cannula implanted in the dorsal striatum elicit the expression of tics lasting for short time periods of up to an hour. The chronic model is an alternative enabling the extension of tic expression to periods of several days or even weeks, utilizing continuous infusion of bicuculline via a sub-cutaneous mini-osmotic pump. The models enable the study of the behavioral and neural mechanisms of tic generation throughout the cortico-basal ganglia pathway. The models support the implantation of additional recording and stimulation devices in addition to the injection cannulas, thus allowing for a wide variety of usages such as electrical and optical stimulation and electrophysiological recordings. Each method has different advantages and shortcomings: the acute model enables the comparison of the kinematic properties of movement and the corresponding electrophysiological changes before, during and after tic expression and the effects of short-term modulators on tic expression. This acute model is simple to establish; however, it is limited to a short period of time. The chronic model, while more complex, makes feasible the study of tic dynamics and behavioral effects on tic expression over prolonged periods. Thus, the type of empirical query drives the choice between these two complementary models of tic expression.

Dissociation of tic generation from tic expression during the sleep-wake cycle.

Motor tics, the hallmark of Tourette syndrome (TS), are modulated by different behavioral and environmental factors. A major modulating factor is the sleep-wake cycle in which tics are attenuated to a large extent during sleep. This study demonstrates a similar reduction in tic expression during sleep in an animal model of chronic tic disorders and investigates the underlying neural mechanism. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABAA antagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a state-dependent dissociation between motor tic expression and their macro-level neural correlates ("LFP spikes") during the sleep-wake cycle. Local field potential (LFP) spikes, which are highly correlated with tic expression during wakefulness, persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was time-locked to the LFP spikes during wakefulness, but this locking decreased significantly during sleep. These results suggest that whereas LFP spikes encode motor tic generation and feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in patients with TS during sleep and potentially during other behavioral states.

Endocannabinoids and Dopamine Balance Basal Ganglia Output.

The entopeduncular nucleus is one of the basal ganglia's output nuclei, thereby controlling basal ganglia information processing. Entopeduncular nucleus neurons integrate GABAergic inputs from the Striatum and the globus pallidus, together with glutamatergic inputs from the subthalamic nucleus. We show that endocannabinoids and dopamine interact to modulate the long-term plasticity of all these primary afferents to the entopeduncular nucleus. Our results suggest that the interplay between dopamine and endocannabinoids determines the balance between direct pathway (striatum) and indirect pathway (globus pallidus) in entopeduncular nucleus output. Furthermore, we demonstrate that, despite the lack of axon collaterals, information is transferred between neighboring neurons in the entopeduncular nucleus via endocannabinoid diffusion. These results transform the prevailing view of the entopeduncular nucleus as a feedforward "relay" nucleus to an intricate control unit, which may play a vital role in the process of action selection.

Common neuronal mechanisms underlying tics and hyperactivity.

Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) are two neurodevelopmental hyper-behavioral disorders that are highly comorbid. The source of this comorbidity and the neuronal mechanisms underlying these disorders are still unclear. We examined the neuronal activity of freely behaving rats before and after striatal disinhibition, to reveal the similar and distinct neuronal components underlying the mechanisms of TS-like and ADHD-like symptom expression. Focal disinhibition induced motor tics, locomotor hyperactivity or a comorbid effect depending on the location of the injection within the different functional domains of the striatum. While injections within the motor domain induced motor tics, injections into the limbic domain induced mainly locomotor hyperactivity. Disinhibition, regardless of its striatal location, led to qualitatively similar macro-scale and micro-scale neuronal changes. These changes were localized to the domain of the manipulation and remained partly segregated, indicating that hyperactivity is induced as a result of changes in the limbic domain without directly activating the motor domain. Despite the general similarity of induced neuronal changes, these changes were associated with different behavioral effects and were more stereotypic and pronounced following motor-domain disinhibition in comparison to limbic-domain disinhibition. Our recordings revealed a disparity in the neuronal input-output transformation of the two models of the disorders. The results suggest that tic expression and hyperactivity states share similar local neuronal activity changes which manifest in different neuronal and behavioral outcomes. These results expose an intriguing link between tics and their comorbid symptoms and hint at striatal disinhibition, resulting from GABAergic alterations, as a potential common mechanism underlying distinct symptoms expressed by hyper-behavioral patients.

Dynamic input-dependent encoding of individual basal ganglia neurons.

Computational models are crucial to studying the encoding of individual neurons. Static models are composed of a fixed set of parameters, thus resulting in static encoding properties that do not change under different inputs. Here, we challenge this basic concept which underlies these models. Using generalized linear models, we quantify the encoding and information processing properties of basal ganglia neurons recorded in-vitro. These properties are highly sensitive to the internal state of the neuron due to factors such as dependency on the baseline firing rate. Verification of these experimental results with simulations provides insights into the mechanisms underlying this input-dependent encoding. Thus, static models, which are not context dependent, represent only part of the neuronal encoding capabilities, and are not sufficient to represent the dynamics of a neuron over varying inputs. Input-dependent encoding is crucial for expanding our understanding of neuronal behavior in health and disease and underscores the need for a new generation of dynamic neuronal models.

Disinhibition of the Nucleus Accumbens Leads to Macro-Scale Hyperactivity Consisting of Micro-Scale Behavioral Segments Encoded by Striatal Activity.

The striatum comprises of multiple functional territories involved with multilevel control of behavior. Disinhibition of different functional territories leads to territory-specific hyperkinetic and hyperbehavioral symptoms. The ventromedial striatum, including the nucleus accumbens (NAc) core, is typically associated with limbic input but was historically linked to high-level motor control. In this study, performed in female Long-Evans rats, we show that the NAc core directly controls motor behavior on multiple timescales. On the macro-scale, following NAc disinhibition, the animals manifested prolonged hyperactivity, expressed as excessive normal behavior, whereas on the micro-scale multiple behavior transitions occurred, generating short movement segments. The underlying striatal network displayed population-based local field potential transient deflections (LFP spikes) whose rate determined the magnitude of the hyperactivity and whose timing corresponded to unitary behavioral transition events. Individual striatal neurons preserved normal baseline activity and network interactions following the disinhibition, maintaining the normal encoding of behavioral primitives and forming a sparse link between the LFP spikes and single neuron activity. Disinhibition of this classically limbic territory leads to profound motor changes resembling hyperactivity and attention deficit. These behavioral and neuronal results highlight the direct interplay on multiple timescales between different striatal territories during normal and pathological conditions.SIGNIFICANCE STATEMENT The nucleus accumbens (NAc) is a key part of the striatal limbic territory. In the current study we show that this classically limbic area directly controls motor behavior on multiple timescales. Focal disinhibition of the NAc core in freely behaving rats led to macro-scale hyperactivity and micro-scale behavioral transitions, symptoms typically associated with attention deficit hyperactivity disorder. The behavioral changes were encoded by the striatal LFP signal and single-unit spiking activity in line with the neuronal changes observed during tic expression following disinhibition of the striatal motor territory. These results point to the need to extend the existing parallel functional pathway concept of basal ganglia function to include the study of limbic-motor cross-territory interactions in both health and disease.

Filter-Based Phase Shifts Distort Neuronal Timing Information.

Filters are widely used for the modulation, typically attenuation, of amplitudes of different frequencies within neurophysiological signals. Filters, however, also induce changes in the phases of different frequencies whose amplitude is unmodulated. These phase shifts cause time lags in the filtered signals, leading to a disruption of the timing information between different frequencies within the same signal and between different signals. The emerging time lags can be either constant in the case of linear phase (LP) filters or vary as a function of the frequency in the more common case of non-LP (NLP) filters. Since filters are used ubiquitously online in the early stages of data acquisition, the vast majority of neurophysiological signals thus suffer from distortion of the timing information even prior to their sampling. This distortion is often exacerbated by further multiple offline filtering stages of the sampled signal. The distortion of timing information may cause misinterpretation of the results and lead to erroneous conclusions. Here we present a variety of typical examples of filter-induced phase distortions and discuss the evaluation and restoration of the timing information underlying the original signal.

Aripiprazole Selectively Reduces Motor Tics in a Young Animal Model for Tourette's Syndrome and Comorbid Attention Deficit and Hyperactivity Disorder.

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized primarily by motor and vocal tics. Comorbidities such as attention deficit and hyperactivity disorder (ADHD) are observed in over 50% of TS patients. We applied aripiprazole in a juvenile rat model that displays motor tics and hyperactivity. We additionally assessed the amount of ultrasonic vocalizations (USVs) as an indicator for the presence of vocal tics and evaluated the changes in the striatal neurometabolism using in vivo proton magnetic resonance spectroscopy (1H-MRS) at 11.7T. Thirty-one juvenile spontaneously hypertensive rats (SHRs) underwent bicuculline striatal microinjection and treatment with either aripiprazole or vehicle. Control groups were sham operated and sham injected. Behavior, USVs, and striatal neurochemical profile were analyzed at early, middle, and late adolescence (postnatal days 35 to 50). Bicuculline microinjections in the dorsolateral striatum induced motor tics in SHR juvenile rats. Acute aripiprazole administration selectively reduced both tic frequency and latency, whereas stereotypies, USVs, and hyperactivity remained unaltered. The striatal neurochemical profile was only moderately altered after tic-induction and was not affected by systemic drug treatment. When applied to a young rat model that provides high degrees of construct, face, and predictive validity for TS and comorbid ADHD, aripiprazole selectively reduces motor tics, revealing that tics and stereotypies are distinct phenomena in line with clinical treatment of patients. Finally, our 1H-MRS results suggest a critical revision of the striatal role in the hypothesized cortico-striatal dysregulation in TS pathophysiology.

Dopamine receptors in the rat entopeduncular nucleus.

Dopamine is critical for the normal functioning of the basal ganglia, modulating both input and output nuclei of this system. The distribution and function of each of the five dopamine receptor subtypes have been studied extensively in the striatum. However, the role of extrastriatal dopamine receptors in basal ganglia information processing is less clear. Here, we studied the anatomical distribution of dopamine receptors in one of the output nuclei of the rodent basal ganglia, the entopeduncular nucleus (EP). The presence of all dopamine receptor subtypes was verified in the EP using immunostaining. We detected co-localization of dopamine receptors with VGAT, which suggests presynaptic expression on GABAergic terminals. D1R and D2R were strongly colocalized with VGAT, whereas DR3-5 showed only sparse co-localization. We further labeled striatal or pallidal neurons with GFP and showed that only D1 receptors were co-localized with striatal terminals, while only D2R and D3R were co-localized with pallidal terminals. Dopamine receptors were also strongly co-localized with MAP2, indicating postsynaptic expression. Overall, these findings suggest that the dopaminergic system modulates activity in the EP both directly via postsynaptic receptors, and indirectly via GABAergic synapses stemming from the direct and indirect pathways.

Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor.

Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders.SIGNIFICANCE STATEMENT Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these neurons. The injections led to the appearance of episodic rest tremor, accompanied by coherent oscillations in neuronal activity, which was reversed following corticostriatal inhibition. These results suggest that the balance between corticostriatal excitation and feedforward FSI inhibition is crucial for maintaining the striatal decorrelation process, and that its breakdown leads to the formation of oscillations resulting in rest tremor typical of multiple basal ganglia disorders.

Dopaminergic Modulation of Synaptic Integration and Firing Patterns in the Rat Entopeduncular Nucleus.

Dopamine is known to differentially modulate the impact of cortical input to the striatum between the direct and indirect pathways of the basal ganglia (BG). However, the role of extrastriatal dopamine receptors (DRs) in BG information processing is less clear. To investigate the role of extrastriatal DRs, we studied their distribution and function in one of the output nuclei of the BG of the rodent, the entopeduncular nucleus (EP). qRT-PCR indicated that all DR subtypes were expressed by EP neurons, suggesting that both D1-like receptors (D1LRs) and D2-like receptors (D2LRs) were likely to affect information processing in the EP. Whole-cell recordings revealed that striatal inputs to the EP were potentiated by D1LRs whereas pallidal inputs to the EP were depressed by D2LRs. Changes to the paired-pulse ratio of inputs to the EP suggested that dopaminergic modulation of striatal inputs is mediated by postsynaptic receptors, and that of globus pallidus-evoked inputs is mediated by presynaptic receptors. We show that these changes in synaptic efficacy changed the information content of EP neuron firing. Overall, the findings suggest that the dopaminergic system affects the passage of feedforward information through the BG by modulating input divergence in the striatum and output convergence in the EP.SIGNIFICANCE STATEMENT The entopeduncular nucleus (EP), one of the basal ganglia (BG) output nuclei, is an important station in information processing in BG. However, it remains unclear how EP neurons encode information and how dopamine affects this process. This contrasts with the well established role of dopamine in the striatum, which is known to redistribute cortical input between the direct and indirect pathways. Here we show that, in symmetry with the striatum, dopamine controls the rebalancing of information flow between the two pathways in the EP. Specifically, we demonstrate that dopamine regulates EP activity by differentially modulating striatal and pallidal GABAergic inputs. These results call for a reassessment of current perspectives on BG information processing by highlighting the functional role of extrastriatal dopamine receptors.

Tonic and phasic changes in anteromedial globus pallidus activity in Tourette syndrome.

BACKGROUND: Tourette syndrome is a hyperkinetic neurodevelopmental disorder characterized by tics. OBJECTIVE: Assess the neuronal changes in the associative/limbic GP associated with Tourette syndrome. METHODS: Neurophysiological recordings were performed from the anterior (associative/limbic) GPe and GPi of 8 awake patients during DBS electrode implantation surgeries. RESULTS: The baseline firing rate of the neurons was low in a state-dependent manner in both segments of the GP. Tic-dependent transient rate changes were found in the activity of individual neurons of both segments around the time of the tic. Neither oscillatory activity of individual neurons nor correlations in their interactions were observed. CONCLUSIONS: The results demonstrate the involvement of the associative/limbic pathway in the underlying pathophysiology of Tourette syndrome and point to tonic and phasic modulations of basal ganglia output as a key mechanisms underlying the abnormal state of the disorder and the expression of individual tics, respectively. © 2017 International Parkinson and Movement Disorder Society.

Temporal dynamics of saccades explained by a self-paced process.

Sensory organs are thought to sample the environment rhythmically thereby providing periodic perceptual input. Whisking and sniffing are governed by oscillators which impose rhythms on the motor-control of sensory acquisition and consequently on sensory input. Saccadic eye movements are the main visual sampling mechanism in primates, and were suggested to constitute part of such a rhythmic exploration system. In this study we characterized saccadic rhythmicity, and examined whether it is consistent with autonomous oscillatory generator or with self-paced generation. Eye movements were tracked while observers were either free-viewing a movie or fixating a static stimulus. We inspected the temporal dynamics of exploratory and fixational saccades and quantified their first-order and high-order dependencies. Data were analyzed using methods derived from spike-train analysis, and tested against mathematical models and simulations. The findings show that saccade timings are explained by first-order dependencies, specifically by their refractory period. Saccade-timings are inconsistent with an autonomous pace-maker but are consistent with a "self-paced" generator, where each saccade is a link in a chain of neural processes that depend on the outcome of the saccade itself. We propose a mathematical model parsimoniously capturing various facets of saccade-timings, and suggest a possible neural mechanism producing the observed dynamics.

Prolonged striatal disinhibition as a chronic animal model of tic disorders.

BACKGROUND: Experimental findings and theoretical models have associated Tourette syndrome with abnormal striatal inhibition. The expression of tics, the hallmark symptom of this disorder, has been transiently induced in non-human primates and rodents by the injection of GABAA antagonists into the striatum, leading to temporary disinhibition. NEW METHOD: The novel chronic model of tic expression utilizes mini-osmotic pumps implanted subcutaneously in the rat's back for prolonged infusion of bicuculline into the dorsolateral striatum. RESULTS: Tics were expressed on the contralateral side to the infusion over a period of multiple days. Tic expression was stable, and maintained similar properties throughout the infusion period. Electrophysiological recordings revealed the existence of tic-related local field potential spikes and individual neuron activity changes that remained stable throughout the infusion period. COMPARISON WITH EXISTING METHODS: The striatal disinhibition model provides a unique combination of face validity (tic expression) and construct validity (abnormal striatal inhibition) but is limited to sub-hour periods. The new chronic model extends the period of tic expression to multiple days and thus enables the study of tic dynamics and the effects of behavior and pharmacological agents on tic expression. CONCLUSIONS: The chronic model provides similar behavioral and neuronal correlates of tics as the acute striatal disinhibition model but over prolonged periods of time, thus providing a unique, basal ganglia initiated model of tic expression. Chronic expression of symptoms is the key to studying the time varying properties of Tourette syndrome and the effects of multiple internal and external factors on this disorder.

Filter based phase distortions in extracellular spikes.

Extracellular recordings are the primary tool for extracting neuronal spike trains in-vivo. One of the crucial pre-processing stages of this signal is the high-pass filtration used to isolate neuronal spiking activity. Filters are characterized by changes in the magnitude and phase of different frequencies. While filters are typically chosen for their effect on magnitudes, little attention has been paid to the impact of these filters on the phase of each frequency. In this study we show that in the case of nonlinear phase shifts generated by most online and offline filters, the signal is severely distorted, resulting in an alteration of the spike waveform. This distortion leads to a shape that deviates from the original waveform as a function of its constituent frequencies, and a dramatic reduction in the SNR of the waveform that disrupts spike detectability. Currently, the vast majority of articles utilizing extracellular data are subject to these distortions since most commercial and academic hardware and software utilize nonlinear phase filters. We show that this severe problem can be avoided by recording wide-band signals followed by zero phase filtering, or alternatively corrected by reversed filtering of a narrow-band filtered, and in some cases even segmented signals. Implementation of either zero phase filtering or phase correction of the nonlinear phase filtering reproduces the original spike waveforms and increases the spike detection rates while reducing the number of false negative and positive errors. This process, in turn, helps eliminate subsequent errors in downstream analyses and misinterpretations of the results.

Beta oscillations in the parkinsonian primate: Similar oscillations across different populations.

Parkinson's disease (PD) is characterized by excessive beta band oscillations (BBO) in neuronal spiking activity across basal ganglia (BG) nuclei. High frequency stimulation of the subthalamic nucleus, an effective treatment for PD, suppresses these oscillations. There is still a heated debate on the origin and propagation of BBO and their association to clinical symptoms. The key prerequisite in addressing these issues is to obtain an accurate estimation of the subpopulation of oscillatory neurons and the magnitude of their oscillations. Studies have shown that neurons in different BG nuclei vary dramatically in the magnitude of their oscillations. However, the stochastic nature of neuronal activity subsamples the oscillatory neuronal rate functions, thus causing standard spectral analysis methods to be dramatically biased by biological and experimental factors such as variations in the neuronal firing rate across BG nuclei. In order to overcome these biases, and directly analyze the expression of BBO within BG nuclei, we used a novel objective method, the modulation index. This method reveals that unlike previous spectral results, individual neurons in the different nuclei display similar magnitudes of oscillations, whereas only the size of the oscillatory subpopulation varies between nuclei. During stimulation, the magnitude of the BBO does not change but the fraction of oscillatory neurons decreases in the globus pallidus internus, leading to a significant change in BG output. This non-biased oscillation quantification thus enables the reconstruction of oscillations at the single neuron and nuclei population levels, and calls for a reassessment of the role of BBO during PD.

Animal Models of Tourette Syndrome-From Proliferation to Standardization.

Tourette syndrome (TS) is a childhood onset disorder characterized by motor and vocal tics and associated with multiple comorbid symptoms. Over the last decade, the accumulation of findings from TS patients and the emergence of new technologies have led to the development of novel animal models with high construct validity. In addition, animal models which were previously associated with other disorders were recently attributed to TS. The proliferation of TS animal models has accelerated TS research and provided a better understanding of the mechanism underlying the disorder. This newfound success generates novel challenges, since the conclusions that can be drawn from TS animal model studies are constrained by the considerable variation across models. Typically, each animal model examines a specific subset of deficits and centers on one field of research (physiology/genetics/pharmacology/etc.). Moreover, different studies do not use a standard lexicon to characterize different properties of the model. These factors hinder the evaluation of individual model validity as well as the comparison across models, leading to a formation of a fuzzy, segregated landscape of TS pathophysiology. Here, we call for a standardization process in the study of TS animal models as the next logical step. We believe that a generation of standard examination criteria will improve the utility of these models and enable their consolidation into a general framework. This should lead to a better understanding of these models and their relationship to TS, thereby improving the research of the mechanism underlying this disorder and aiding the development of new treatments.

Corticostriatal Divergent Function in Determining the Temporal and Spatial Properties of Motor Tics.

Striatal disinhibition leads to the formation of motor tics resembling those expressed during Tourette syndrome and other tic disorders. The spatial properties of these tics are dependent on the location of the focal disinhibition within the striatum; however, the factors affecting the temporal properties of tic expression are still unknown. Here, we used microstimulation within the motor cortex of freely behaving rats before and after striatal disinhibition to explore the factors underlying the timing of individual tics. Cortical activation determined the timing of individual tics via an accumulation process of inputs that was dependent on the frequency and amplitude of the inputs. The resulting tics and their neuronal representation within the striatum were highly stereotypic and independent of the cortical activity properties. The generation of tics was limited by absolute and relative tic refractory periods that were derived from an internal striatal state. Thus, the precise time of the tic expression depends on the interaction between the summation of incoming excitatory inputs to the striatum and the timing of the previous tic. A data-driven computational model of corticostriatal function closely replicated the temporal properties of tic generation and enabled the prediction of tic timing based on incoming cortical activity and tic history. These converging experimental and computational findings suggest a clear functional dichotomy within the corticostriatal network, pointing to disparate temporal (cortical) versus spatial (striatal) encoding. Thus, the abnormal striatal inhibition typical of Tourette syndrome and other tic disorders results in tics due to cortical activation of the abnormal striatal network. SIGNIFICANCE STATEMENT: The factors underlying the temporal properties of tics expressed in Tourette syndrome and other tic disorders have eluded clinicians and scientists for decades. In this study, we highlight the key role of corticostriatal activity in determining the timing of individual tics. We found that cortical activation determined the timing of tics but did not determine their form. A data-driven computational model of the corticostriatal network closely replicated the temporal properties of tic generation and enabled the prediction of tic timing based on incoming cortical activity and tic history. This study thus shows that, although tics originate in the striatum, their timing depends on the interplay between incoming excitatory corticostriatal inputs and the internal striatal state.