Barriers and facilitators to implementing a Canadian shared-care ADHD program in pediatric settings in Shanghai: a consolidated framework for implementation research approach.

OBJECTIVES: The vast majority of children with Attention-Deficit Hyperactivity Disorder (ADHD) do not have access to proper diagnosis and treatment in China. The goal of this project is to identify the challenges and facilitators in implementing a Canadian ADHD Shared Care Pathways program in pediatric settings in Shanghai region. METHODS: Purposive semi-structured focus groups were conducted on a total of 13 healthcare practitioners from the Shanghai Xinuha, Ninghai and Chongming hospitals. Two independent researchers conducted a thematic analysis of the data with themes emerging based on the Consolidated Framework for Implementation Research (CFIR). RESULTS: Notable barriers identified by participants included: (1) lack of knowledge in the management of ADHD, primarily among general practitioners; (2) lack of resources such as lack of staff, time, and medication for ADHD; (3) challenges in implementing an international multicentre intervention (such as communication difficulties between teams and integration of resources available in different hospitals); and (4) mental health stigma, difficulties in identifying ADHD patients, and logistical problems related to medication procurement rules put in place by provincial governments. Notable facilitators included: (1) the strong motivation of stakeholders and their confidence in their ability to learn and subsequently execute action plans to achieve the implementation goal; (2) the compatibility between the values and goals of the stakeholders and those of the program despite some cultural tension, a positive learning climate, strong tensions for change, and the high interest of organization leaders in engaging in the program (3) the perceived benefits of the program, such as standardization of the diagnostic and treatment process, and engaging primary care providers in ADHD management; and (4) the strong relationship between participating institutions and schools as well as provincial health initiatives available to support collaborative models of care. Mixed factors to implementation were also explored. CONCLUSIONS: Appropriate training of health care providers, cultural adaptation of the program, increase public awareness about ADHD to decrease stigma, as well as strong project management and guidelines that clearly describe the role and expectations of each team member appeared essential to successful implementation.

Cumulative Dosage of Intrathecal Chemotherapy Agents Predicts White Matter Integrity in Long-Term Survivors of Acute Lymphoblastic Leukemia: A PETALE Study.

Acute lymphoblastic leukemia (ALL) stands as the most prevalent form of pediatric cancer in North America, with a current five-year survival rate of 85%. While more children achieved ALL remission and transition into adulthood, the prevalence of long-term treatment-related effects, especially neurocognitive sequelae, remains significant. This study pursues two objectives. Firstly, it investigates if Magnetization Transfer Ratio (MTR), a method assessing myelin integrity, is sensitive to white matter (WM) microstructural changes in long-term ALL survivors and whether these relate to cognitive impairments. Secondly, it examines the dose-related effects of chemotherapy agents on the MTR and its relationship to other risk factors such as female sex, early age diagnosis, and cranial radiotherapy. Magnetization transfer imaging was utilized to assess WM integrity in 35 survivors at a mean of 18.9 years after the onset of ALL (range since diagnosis: 6.9-26.8). Additionally, 21 controls matched for age, sex, and education level, with no history of cancer, were included. MTR was extracted from both the entire brain's WM and the corpus callosum through semi-automated procedures. The results indicated lower MTR means in survivors, which is linked to cognitive function. Negative associations between MTR means and intrathecal agents' (MTX, cytarabine, and hydrocortisone) cumulative doses received were highlighted. This study offers valuable insights into the connections between myelin deterioration, cognitive impairment, and the implications of IT chemotherapy, enhancing our understanding of ALL survivorship dynamics. It underscores MTR's relevance in monitoring neurotoxicity during oncological drug follow-up examinations.

Contributing factors to well-being in a sample of long-term survivors of childhood acute lymphoblastic leukemia: the role of social support in emotional regulation.

Objectives: To understand why some long-term childhood cancer survivors experience positive adjustment in the long run,[Q1] this study aimed to (1) explore associations between well-being, health status, social support, and emotion regulation (ER) strategies in a cohort of long-term childhood lymphoblastic leukemia (cALL) survivors, (2) identify the individual contribution of each ER strategy to well-being (3) and their interaction with social support. Methods: We used data from 92 participants from the PETALE cohort (51% female, aged 24 ± 7 years). Measures included well-being (WHO-5), health status (15D), social support (SSQ-6), cognitive reappraisal and expressive suppression (ERQ), and emotional processing and expression (EAC). We modeled the odds of high well-being adjusting for health status in logistic regressions and explored the moderating role of social support with bootstrap techniques. Independent of clinical history, high well-being was associated with better health status, higher social support, more frequent use of cognitive reappraisal and emotional processing. Results: We found a main contribution of emotional processing to well-being (OR = 2.12, 95% CI = 1.09-5.37). The interaction between low suppression and high social support was significant (OR = .40, 95% CI = .13-.79). Probabilities for high well-being were 96% when expressive suppression was low and social support was high. Results suggest approaching one's own emotions may contribute to well-being in long-term childhood cancer survivors. Clinical implications: Combining curbing emotional suppression with promoting supportive social environment could be a promising target for future supportive care interventions in survivors.

Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.

BACKGROUND: An increased risk of neurocognitive deficits, anxiety, and depression has been reported in childhood cancer survivors. METHODS: We analyzed associations of neurocognitive deficits, as well as anxiety and depression, with common and rare genetic variants derived from whole-exome sequencing data of acute lymphoblastic leukemia (ALL) survivors from the PETALE cohort. In addition, significant associations were assessed using stratified and multivariable analyses. Next, top-ranking common associations were analyzed in an independent SJLIFE replication cohort of ALL survivors. RESULTS: Significant associations were identified in the entire discovery cohort (N = 229) between the AK8 gene and changes in neurocognitive function, whereas PTPRZ1, MUC16, TNRC6C-AS1 were associated with anxiety. Following stratification according to sex, the ZNF382 gene was linked to a neurocognitive deficit in males, whereas APOL2 and C6orf165 were associated with anxiety and EXO5 with depression. Following stratification according to prognostic risk groups, the modulatory effect of rare variants on depression was additionally found in the CYP2W1 and PCMTD1 genes. In the replication SJLIFE cohort (N = 688), the male-specific association in the ZNF382 gene was not significant; however, a P value<0.05 was observed when the entire SJLIFE cohort was analyzed. ZNF382 was significant in males in the combined cohorts as shown by meta-analyses as well as the depression-associated gene EXO5. CONCLUSIONS: Further research is needed to confirm whether the current findings, along with other known risk factors, may be valuable in identifying patients at increased risk of these long-term complications. IMPACT: Our results suggest that specific genes may be related to increased neuropsychological consequences.

Mediators and moderators of the effects of the COVID-19 crisis on parent-child conflict in children in tertiary mental health care.

This study focused on children treated for mental health problems during the pandemic. The present study examined how parent's difficulties in managing COVID-19 restrictions increased children's behavioral problems (internalizing and externalizing) and parent-child conflict through parental mental health and parental stress. Family functioning, particularly problem-solving ability, was tested as a resilience factor. were collected using online surveys from 337 parents with a child between the ages of 4 and 18 years who was receiving active outpatient mental health treatment at a pediatric tertiary care center. Parents who reported a greater impact of COVID-19 reported more behavioral difficulties in their children. This relationship was significantly mediated by parental mental health (general stress, anxiety, and depression) and parental stress. Similar indirect pathways were observed when examining internalizing and externalizing problems in children, where the most significant pathway had parental stress as the sole mediator. Furthermore, the effect of COVID-19 impact on parent-child conflict through parental stress was significantly moderated by problem-solving skills within the family. Parenting stress mediates the impact of COVID-19 on parent-child conflict. Interventions improving within family problem solving-skills may decrease the effect of parental stress on parent-child conflict.

Safety and Tolerability of tDCS across Different Ages, Sexes, Diagnoses, and Amperages: A Randomized Double-Blind Controlled Study.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with substantial evidence for its safety and tolerability in adults. However, less than 5% of published tDCS research is in pediatrics. Our primary objective was to investigate tDCS safety, tolerability, and acceptability in a sample of children and adults. We hypothesized that children and adults would be equal with regard to tDCS safety, tolerability, and acceptability. We tested this hypothesis using a Bayesian approach. Sixty participants aged 6-45 (balanced for sex) participated in a randomized double-blind controlled trial. They were randomly assigned to two ten-minute tDCS sessions with varying amperages and electrode locations. The primary outcome measure of this study was the intensity of 13 potential side effects evaluated at six different time points spanning two weeks. Independent sample Bayes factor tests were conducted between children/adults, males/females, clinical/healthy, and low/high amperage groups. As predicted, there was moderate support for the null hypothesis in all between-group analyses. There were no serious adverse events or dropouts, and the number needed to treat for an additional harmful outcome was 23. This study provided evidence supporting the overall short-term safety, tolerability, and acceptability of tDCS including amperages up to 2 mA and different electrode placements.

Contribution of Fatigue to Cognitive Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors.

Late effects such as neurocognitive issues and fatigue have been reported in childhood acute lymphoblastic leukemia (cALL) survivors. Yet, their association is often poorly understood. In this study, we wished to (1) describe neurocognitive difficulties and fatigue in a well-characterized cohort of long-term cALL survivors and (2) explore the risk of having neurocognitive deficits as a function of fatigue. Childhood ALL survivors (N = 285) from three Canadian treatment centers completed the DIVERGT battery of cognitive tests and the PedsQL Multidimensional Fatigue Scale. We performed logistic regressions to assess the risk of a survivor to show cognitive deficits (<2.0 SD) depending on their fatigue levels. At least one cognitive deficit on the DIVERGT was present in 31% of participants. Domains primarily affected were working memory, fine motor skills, and verbal fluency. Sleep/rest fatigue in youths was higher than norms (d = 0.35). The risk for cognitive deficits increased independently with levels of fatigue in the domains of cognitive speed and flexibility, working memory, and verbal fluency. For every 10-point increase on general or sleep/rest fatigue on the 0-100 scale, there was a median +23-35% risk of showing a deficit among the 7 tasks significantly associated with fatigue. Fatigue may constitute a complementary target when searching to mitigate cognitive issues in this population.

An exploratory analysis of the performance of methylphenidate regimens based on a PKPD model of dopamine and norepinephrine transporter occupancy.

Methylphenidate (MPH) is a psychostimulant which inhibits the uptake of dopamine and norepinephrine transporters, DAT and NET, and is mostly used to treat Attention Deficit/Hyperactivity Disorder. The current dose optimization is done through titration, a cumbersome approach for patients. To assess the therapeutic performance of MPH regimens, we introduce an in silico framework composed of (i) a population pharmacokinetic model of MPH, (ii) a pharmacodynamic (PD) model of DAT and NET occupancy, (iii) a therapeutic box delimited by time and DAT occupancy, and (iv) a performance score computation. DAT occupancy data was digitized (n = 152) and described with Emax models. NET occupancy was described with a KPD model. We used this integrative framework to simulate the performance of extended-release (18-99 mg) and tid MPH regimens (25-40 mg). Early blood samples of MPH seem to lead to higher DAT occupancy, consistent with an acute tolerance observed in clinical rating scales. An Emax model with a time-dependent tolerance was fitted to available data to assess the observed clockwise hysteresis. Peak performance is observed at 63 mg. While our analysis does not deny the existence of an acute tolerance, data precision in terms of formulation and sampling times does not allow a definite confirmation of this phenomenon. This work justifies the need for a more systematic collection of DAT and NET occupancy data to further investigate the presence of acute tolerance and assess the impact of low MPH doses on its efficacy.

A mechanistic model of ADHD as resulting from dopamine phasic/tonic imbalance during reinforcement learning.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Although the involvement of dopamine in this disorder seems to be established, the nature of dopaminergic dysfunction remains controversial. The purpose of this study was to test whether the key response characteristics of ADHD could be simulated by a mechanistic model that combines a decrease in tonic dopaminergic activity with an increase in phasic responses in cortical-striatal loops during learning reinforcement. To this end, we combined a dynamic model of dopamine with a neurocomputational model of the basal ganglia with multiple action channels. We also included a dynamic model of tonic and phasic dopamine release and control, and a learning procedure driven by tonic and phasic dopamine levels. In the model, the dopamine imbalance is the result of impaired presynaptic regulation of dopamine at the terminal level. Using this model, virtual individuals from a dopamine imbalance group and a control group were trained to associate four stimuli with four actions with fully informative reinforcement feedback. In a second phase, they were tested without feedback. Subjects in the dopamine imbalance group showed poorer performance with more variable reaction times due to the presence of fast and very slow responses, difficulty in choosing between stimuli even when they were of high intensity, and greater sensitivity to noise. Learning history was also significantly more variable in the dopamine imbalance group, explaining 75% of the variability in reaction time using quadratic regression. The response profile of the virtual subjects varied as a function of the learning history variability index to produce increasingly severe impairment, beginning with an increase in response variability alone, then accumulating a decrease in performance and finally a learning deficit. Although ADHD is certainly a heterogeneous disorder, these results suggest that typical features of ADHD can be explained by a phasic/tonic imbalance in dopaminergic activity alone.

Implementing a Canadian shared-care ADHD program in Beijing: Barriers and facilitators to consider prior to start-up.

BACKGROUND: The shared care pathway for ADHD is a program developed in Canada with two main strategies: (a) implement a shared care pathway between general practitioners (GPs) and specialists, and (b) step up or down care so that the patient is treated at the most appropriate level of care, depending on the complexity or outcome of their illness. The current study aims to identify the challenges and facilitators of implementing this program in a Chinese mental health service setting. METHODS: Two focus groups were conducted using semi-structured interviews with a total of 7 health care providers in Beijing. An adapted grounded theory methodology using open-ended, axial and selective coding was used for data analysis. RESULTS: We identified three main levels related to barriers and facilitators: (1) a sociocultural level of patients' and health care providers' perspectives; (2) a structural level related to internal and external organizational environments; (3) and the level of the intervention itself with its characteristics. The project is generally aligned with the mandates and goals of the health system, but two of the main obstacles are the varying qualifications of physicians in hospitals of different levels, implying different needs and flexible and adapted training programs, and the lack of appropriate patient referral systems between the different hospital levels. CONCLUSION: Our study highlights the importance of consultation to obtain a "lay of the land" for deciding on the implementation steps of an a priori well accepted model of care.

Magnetoencephalography resting-state correlates of executive and language components of verbal fluency.

Verbal fluency (VF) is a heterogeneous cognitive function that requires executive as well as language abilities. The purpose of this study was to elucidate the specificity of the resting state MEG correlates of the executive and language components. To this end, we administered a VF test, another verbal test (Vocabulary), and another executive test (Trail Making Test), and we recorded 5-min eyes-open resting-state MEG data in 28 healthy participants. We used source-reconstructed spectral power estimates to compute correlation/anticorrelation MEG clusters with the performance at each test, as well as with the advantage in performance between tests, across individuals using cluster-level statistics in the standard frequency bands. By obtaining conjunction clusters between verbal fluency scores and factor loading obtained for verbal fluency and each of the two other tests, we showed a core of slow clusters (delta to beta) localized in the right hemisphere, in adjacent parts of the premotor, pre-central and post-central cortex in the mid-lateral regions related to executive monitoring. We also found slow parietal clusters bilaterally and a cluster in the gamma 2 and 3 bands in the left inferior frontal gyrus likely associated with phonological processing involved in verbal fluency.

Acceptability of transcranial direct current stimulation in children and adolescents with ADHD: The point of view of parents.

Transcranial direct current stimulation (tDCS) is a novel treatment option for attention deficit hyperactivity disorder. To facilitate translation into clinical practice, we interviewed parents of children who have experienced experimental tDCS. A grounded theory approach using open, axial, and selective coding provided seven emergent themes for acceptability: tDCS provides hope for parents, safety tolerability and side effects of tDCS versus medication, burden of treatment, education and trust with care providers, cost and coverage, unestablished tDCS efficacy versus established medication effectiveness, perceived compliance of tDCS versus medication. Results suggest tDCS is acceptable but depends on evidence of effectiveness and regular availability.

Screening for distress in pediatric cancer survivors: A systematic comparison of one-step and two-step strategies to minimize detection errors.

BACKGROUND: Childhood cancer survivors should be routinely screened for psychological distress. However, existing screening tools promoted by cancer care institutions, such as the Distress Thermometer (DT) generate high rates of errors. The aim of this study is to help refining strategies of screening psychological distress in this population by exploring two-step methods combining the DT on step #1 with one question on step #2. PROCEDURE: Data from 255 survivors of childhood acute lymphoblastic leukemia aged 13-40 years were analyzed (38% 13-18 years, 62% 19+ years, 53% females). We used the DT on step #1 and the individual emotion items from the Pediatric Quality of Life Questionnaire (PedsQL) on step #2, to detect distress, depression and anxiety as measured by standard instruments. We compared sensitivity, specificity, negative and positive predictive values, Youden index, and clinical utility indices, in newly developed two-step strategies. RESULTS: The best two-step strategies to screen anxious-depressive distress were DT ≥ 2 on step #1, with the item of Sadness on step #2, and DT ≥ 2 combined with the item of Concerns. Two-step strategies outperformed the DT alone on the correct identification of distressed survivors. However, two-step strategies did not outperform the DT used alone on the correct detection of no distressed survivors. Results were similar when predicting depression or anxiety alone. CONCLUSION: Completing the DT with one single question on emotions from the PedsQL may minimize the number of participants falsely identified as distressed, which could be particularly pertinent in resource-limited clinics.

Two-month administration of methylphenidate improves olfactory sensitivity and suppresses appetite in individuals with obesity.

Olfaction contributes to feeding behaviour and is modulated by changes in dopamine levels. Methylphenidate (MPH) increases brain dopamine levels and has been shown to reduce appetite and promote weight loss in patients with attention deficit hyperactivity disorder. The objectives of this study were to test the effect of MPH on olfaction, appetite, energy intake, and body weight (BW) on individuals with obesity. In a randomized, double-blind study, 12 participants (age 28.9 ± 6.7 years) with a body mass index (BMI) of 36.1 ± 4.5 kg/m2 were assigned to MPH (0.5 mg/kg) (n = 5) or placebo (n = 7) twice daily for 2 months. Appetite (visual analog scale), odour threshold (Sniffin' Sticks®), energy intake (food menu), and BW (DEXA scan) were measured at day 1 and day 60. MPH intake significantly increased odour threshold scores (6.3 ± 1.4 vs. 9.4 ± 2.1 and 7.9 ± 2.3 vs. 7.8 ± 1.9, respectively; p = 0.029) versus placebo. There was a significantly greater suppression of appetite sensations (desire to eat (p = 0.001), hunger (p = 0.008), prospective food consumption (p = 0.003)) and an increase in fullness (p = 0.028) over time in the MPH versus placebo. MPH suppressed appetite and improved olfactory sensitivity in individuals with obesity. These data provide novel findings on the favourable effects of MPH on appetite and weight regulation in individuals living with obesity.

Systematic Review on the Safety and Tolerability of Transcranial Direct Current Stimulation in Children and Adolescents.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a safe, tolerable, and acceptable technique in adults. However, there is limited evidence for its safety in youth. Although limited, there are a handful of important empirical articles that have evaluated safety and tolerability outcomes in youth. However, a synthesis of pediatric safety studies is not currently available. OBJECTIVE: To synthesize objective evidence regarding the safety and tolerability of pediatric tDCS based on the current state of the literature. METHODS: Our search and report used PRISMA guidelines. Our method systematically examined investigations purposefully designed to evaluate the safety, tolerability, and acceptability of tDCS in healthy and atypical youth that were submitted to three databases, from the beginning of the database to November 2019. Safety considerations were evaluated by studies utilizing neuroimaging, physiological changes, performance on tasks, and by analyzing reported and objective side effects; tolerability via rate of adverse events; and acceptability via rate of dropouts. RESULTS: We report on 203 sham sessions, 864 active sessions up to 2 mA, and 303 active hours of stimulation in 156 children. A total of 4.4% of the active sessions were in neurotypical controls, with the other 95.6% in clinical subjects. CONCLUSION: In spite of the fact that the current evidence is sporadic and scarce, the presently reviewed literature provides support for the safety, tolerability, and acceptability, of tDCS in youth for 1-20 sessions of 20 min up to 2 mA. Future pediatric tDCS research is encouraged.

Differential stress response to psychological and physical stressors in children using spatial versus response-dependent navigation strategies.

Previous work from our lab has shown that basal cortisol levels are different between healthy young adults who spontaneously use caudate nucleus-dependent response strategies compared to young adults who use hippocampus-dependent spatial navigation strategies. Young adults who use caudate nucleus dependent strategies display lower basal cortisol levels compared to those who use hippocampus-dependent strategies. In the current study, we assessed navigation strategies in children using a virtual navigation task and measured cortisol at baseline as well as cortisol reactivity to both a psychological and to a physical stressor. Replicating what is observed in adults, we found that children who used caudate nucleus-dependent navigation strategies displayed lower cortisol levels at baseline compared to those who used hippocampus-dependent strategies. The psychological stressor, knowledge that a blood draw would be performed by a nurse, caused a significant increase in cortisol uniquely in response learners. The physical stressor, the actual blood draw, produced a significant increase in cortisol amongst spatial learners that was then comparable to levels observed in response learners. Lower baseline cortisol and higher cortisol psychological stress response observed amongst children who used response strategies may therefore reflect early biological changes during development which may have an impact later in life when considering risk for neuropsychiatric disorders.

Contributing Factors of Unmet Needs Among Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia with Comorbidities.

Purpose: This study aimed to: (1) describe the domains and levels of unmet needs of young adult survivors of childhood acute lymphoblastic leukemia (cALL) with comorbidities, and (2) to explore the factors associated with higher levels of unmet needs. Unmet need was considered as supportive care needs not met. Methods: The most vulnerable cALL survivors from the PETALE study cohort completed the Short-Form Survivor Unmet Needs Survey, the Brief Pain Inventory and the 15D instrument of health-related quality of life. Demographic and clinical information, including comorbidities, were obtained from medical records or self-reporting. The participants' needs and contributing factors to their needs were evaluated using nonparametric tests. Results: Of the 72 participants, 9 (13%) reported moderate/high levels of overall unmet needs. "Worry about earning money" (56%) and "Dealing with feeling tired" (51%) were the most frequent unmet needs (all levels combined). The factors associated significantly with any domain of unmet needs were: having a comorbidity, reporting altered functional health status, high ALL risk status, pain, age (<26 years), and having previously received psychological support. Conclusion: A minority of young adult survivors of cALL with comorbidities interviewed reported moderate/high levels of unmet needs. However, financial concerns and emotional health and relationship are the two domains of greatest need. Survivors with altered health condition are most at risk of experiencing moderate/high levels of unmet needs. If confirmed in larger samples, interventions should target modifiable contributors of unmet needs such as physical health and comfort, fatigue, and emotional health.

An integrative model of Parkinson's disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression.

Levodopa is considered the gold standard treatment of Parkinson's disease. Although very effective in alleviating symptoms at their onset, its chronic use with the progressive neuronal denervation in the basal ganglia leads to a decrease in levodopa's effect duration and to the appearance of motor complications. This evolution challenges the establishment of optimal regimens to manage the symptoms as the disease progresses. Based on up-to-date pathophysiological and pharmacological knowledge, we developed an integrative model for Parkinson's disease to evaluate motor function in response to levodopa treatment as the disease progresses. We combined a pharmacokinetic model of levodopa to a model of dopamine's kinetics and a neurocomputational model of basal ganglia. The parameter values were either measured directly or estimated from human and animal data. The concentrations and behaviors predicted by our model were compared to available information and data. Using this model, we were able to predict levodopa plasma concentration, its related dopamine concentration in the brain and the response performance of a motor task for different stages of disease.

Nonlinear pharmacodynamics of levodopa through Parkinson's disease progression.

The effect of levodopa in alleviating the symptoms of Parkinson's disease is altered in a highly nonlinear manner as the disease progresses. This can be attributed to different compensation mechanisms taking place in the basal ganglia where the dopaminergic neurons are progressively lost. This alteration in the effect of levodopa complicates the optimization of a drug regimen. The present work aims at investigating the nonlinear dynamics of Parkinson's disease and its therapy through mechanistic mathematical modeling. Using a holistic approach, a pharmacokinetic model of levodopa was combined to a dopamine dynamics and a neurocomputational model of basal ganglia. The influence of neuronal death on these different mechanisms was also integrated. Using this model, we were able to investigate the nonlinear relationships between the levodopa plasma concentration, the dopamine brain concentration, and a response to a motor task. Variations in dopamine concentrations in the brain for different levodopa doses were also studied. Finally, we investigated the narrowing of a levodopa therapeutic index with the progression of the disease as a result of these nonlinearities. In conclusion, various consequences of nonlinear dynamics in Parkinson's disease treatment were studied by developing an integrative model. This model paves the way toward individualization of a dosing regimen. Using sensor based information, the parameters of the model could be fitted to individual data to propose optimal individual regimens.