Lessons learned from a pediatric powered mobility lending program.

PURPOSE: To evaluate children's characteristics and impact of a powered wheelchair lending program including comparisons of diagnostic sub-groups, and validation of a predictive model of powered mobility proficiency. METHODS AND MATERIALS: This retrospective study included 172 children who participated in the ALYN powered mobility lending program from 3/2009-7/2022. Demographics and functional levels were measured via questionnaires; driving proficiency was evaluated when the wheelchair was returned, and parents and children were interviewed following their participation in the program. RESULTS: Two diagnostic groups were identified: cerebral palsy (CP) (n = 136, median = 9.75 yrs) and other neuromuscular diseases (NMD) (n = 30, median = 5.83 yrs). They differed significantly in the age they commenced PM training, the male/female ratio, walking ability and access mode. Fifty-seven percent of the participants with CP achieved powered mobility proficiency, a rate that was significantly lower than the 73% proficiency found for the NMD group. Four significant predictors were identified: communication, manual wheelchair operation, access mode and go-stop upon request. They predicted proficiency in approximately 80% of cases. Overall feedback from the parents and children indicated that their personal and family's quality of life improved as a result of their child's ability to use a powered wheelchair. CONCLUSIONS: A lending program provides children with opportunities to improve mobility skills in an appropriate powered wheelchair. Children who can communicate verbally, propel a manual wheelchair, use a joystick and go-stop upon request are significantly more likely to become proficient drivers; however, many who were unable to complete these tasks also improved and even became proficient drivers.

Children who are able to engage in verbal communication, propel a manual wheelchair for short distances, use a joystick and go-stop upon request are significantly likely to become a proficient powered wheelchair drivers.Children with cerebral palsy who have greater physical challenges (e.g., cannot walk at all or propel a manual wheelchair) can reach powered mobility proficiency following practice with a powered wheelchair borrowed from a lending program, although at a lower rate than those with other neuromuscular diseases; additional training strategies should be developed to increase the percent success for children with cerebral palsy.A multivariate logistic regression was able to correctly predict whether a child will become proficient driver in 80% of case.Training with a powered wheelchair from the lending program enabled parents to observe their children's independent mobility in their home environment; they reported improvement in the family's quality of life.

Pediatric powered mobility training: powered wheelchair versus simulator-based practice.

METHOD: Participants included 30 children and adolescents (23 males, 13 females) with cerebral palsy and other neuromuscular diseases, aged 6-18. Data were collected and compared at baseline and after 12 weeks of home-based practice via a powered wheelchair or a simulator. Powered mobility ability was determined by the Powered Mobility Program (PMP), the Israel Ministry of Health's Powered Mobility Proficiency Test (PM-PT) and the Assessment of Learning Powered Mobility (ALP). RESULTS: All participants practiced for the required amount of time and both groups reported a similar user experience. Both groups achieved significant improvement following the practice period as assessed by the PMP and PM-PT assessments, with no significant differences between them. A significant improvement was found in the ALP assessment outcomes for the powered wheelchair group only. CONCLUSIONS: This is the first study, to our knowledge, that compares two different wheelchair training methods. Simulator-based practice is an effective training option for powered mobility for children with physical disabilities aged 6-18 years old, demonstrating that it is possible to provide driving skill practice opportunities safe, controlled environments.

Reliability and validity of pediatric powered mobility outcome measures.

PURPOSE: To determine the intra-rater and inter-rater reliability of the Powered Mobility Program (PMP) and the Israel Ministry of Health Powered Mobility Proficiency Test (PM-PT); to test inter-rater reliability of the Assessment of Learning Powered Mobility (ALP) tool; to determine the convergent validity of these measures for children with physical disabilities. MATERIALS AND METHODS: Participants included 30 children (mean 10 years, 6 months [SD 3 years, 7 months]; range: 6-18 years) with cerebral palsy and other neuromuscular disorders. Participants were non-proficient powered wheelchair drivers. Two blinded raters assessed the driving ability by viewing videos of the participants twice as they drove a pre-designed route at ALYN Hospital, Israel. They were assessed via the PMP, ALP and PM-PT outcome measures. Intra-class correlation coefficients (ICC2,1) were used to test intra-rater and inter-rater reliability and Spearman correlation coefficients were used to assess convergent validity. RESULTS: The PMP intra-rater reliability revealed ICCs2,1 of coefficients were 0.97/0.98 for both raters. For the PM-PT the ICC2,1 was 0.89/0.96 for both raters. The PMP inter-rater reliability ICC2,1 was 0.94/0.87 for the two tests, for the PM-PT the ICC2,1 was 0.91/0.87 for the two tests and for the ALP the ICC2,1 was 0.83. The convergent validity between the PMP and the PM-PT was rs=0.96, between the PMP and ALP was rs=0.89 and between the PM-PT and ALP was rs=0.87. CONCLUSIONS: The PMP and PM-PT intra and interrater reliability were good to excellent, the ALP inter-rater reliability was good and the convergent validity between all three measures was good to excellent.Implications for rehabilitationThere is evidence of validity and reliability for three tests of powered wheelchair proficiency (PMP, PM-PT and ALP).Children using powered mobility, aged 6-18 years, now have outcome measures with empirical evidence that was previously lacking.When time for assessment is limited, the shorter PM-PT can be used instead of the more comprehensive PMP.

Comparing children's driving abilities in physical and virtual environments.

PURPOSE: To compare children's driving abilities in a physical and virtual environment and to validate the McGill Immersive Wheelchair Simulator (MiWe-C) for the use of children with disabilities. MATERIALS AND METHODS: Participants included 30 children (17 males, 13 females; mean age 14 y 1 mo, [SD 3 y 6 mo]; range: 5-18 y) with cerebral palsy, neuromuscular disease and spinal cord injury. All children were proficient drivers with more than 3 months' experience, who had their own powered wheelchairs. Participants drove a 15-minute physical route and high-fidelity simulation of that route in a counterbalanced order. Performance of the two routes was compared using the 32 item Powered Mobility Programme (PMP). Differences between the driving modes were analyzed with the non-parametric Wilcoxon signed-rank test. Significance was set at α = 0.05. RESULTS: The scores for the total PMP score as rated during both simulator wheelchair driving and during physical driving were very high (M = 4.90, SD = 0.20; M = 4.96, SD = 0.12, respectively) with no significant difference between them (z= -1.69, p = .09). Five out of the 32 PMP tasks showed significant differences between driving modes (narrow corridors, crowded corridors, doorway, sidewalks), with higher scores for the physical driving mode. CONCLUSIONS: Having a validated powered mobility simulator for children provides a viable option for an additional practice mode. The MiWe-C simulator is affordable and a user-friendly simulator that can be used anywhere including at home and in school. Children can be independent when practicing even if they are not yet proficient drivers since continual adult assistance is not needed.Implications for rehabilitationHaving a validated powered mobility simulator for children provides a viable option for an additional practice mode.The MiWe-C is now validated to be used with children 5-18 years with physical disabilities.The MiWe-C is one of the few options for children to practice outside of a research environment.

Age at Onset of Parkinson's Disease Among Ashkenazi Jewish Patients: Contribution of Environmental Factors, LRRK2 p.G2019S and GBA p.N370S Mutations.

BACKGROUND: Both genetic and environmental factors contribute to Parkinson's disease (PD) risk. OBJECTIVE: We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations. METHODS: Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included LRRK2 p.G2019S and GBA p.N370S mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables. RESULTS: 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of these mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (p = 0.033-0.082). Smoking was associated with older AAO (p = 0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (p = 0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analyses, increased coffee and tea consumption levels were associated with older AAO (p = 0.001 and p = 0.002, respectively). CONCLUSIONS: Our results suggest that genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required.

Evaluation of Diagnostic Yield in Fetal Whole-Exome Sequencing: A Report on 45 Consecutive Families.

Prenatal ultrasound (US) abnormalities often pose a clinical dilemma and necessitate facilitated investigations in the search of diagnosis. The strategy of pursuing fetal whole-exome sequencing (WES) for pregnancies complicated by abnormal US findings is gaining attention, but the reported diagnostic yield is variable. In this study, we describe a tertiary center's experience with fetal WES from both terminated and ongoing pregnancies, and examine the clinical factors affecting the diagnostic rate. A total of 45 consecutive families of Jewish descent were included in the analysis, for which clinical fetal WES was performed under either single (fetus only), trio (fetus and parents) or quatro (two fetuses and parents) design. Except one, all families were non-consanguineous. In 41 of the 45 families, WES was sought following abnormal fetal US findings, and 18 of them had positive relevant family history (two or more fetuses with US abnormalities, or single fetus with US abnormalities and an affected parent). The overall diagnostic yield was 28.9% (13/45 families), and 31.7% among families with fetal US abnormalities (13/41). It was significantly higher in families with prenatal US abnormalities and relevant family history (10/18, 55.6%), compared to families with prenatal US abnormal findings and lack of such history (3/23, 13%) (p = 0.004). WES yield was relatively high (42.9-60%) among families with involvement of brain, renal or musculoskeletal US findings. Taken together, our results in a real-world setting of genetic counseling demonstrates that fetal WES is especially indicated in families with positive family history, as well as in fetuses with specific types of congenital malformation.

Predictive model of proficiency in powered mobility of children and young adults with motor impairments.

AIM: To identify variables that can predict proficiency in powered mobility use for children in young adults. METHOD: Participants included 80 children and young adults (42 males, 38 females; mean age 10y 2mo, [SD 5y 1mo]; range: 2-22y) with cerebral palsy, neuromuscular disease, and spinal cord injury who participated in the ALYN Hospital Powered Mobility Lending Program from 2009 to 2016. Data were collected and compared before and after participation in the program and powered mobility levels were determined by the Israeli Ministry of Health (MOH) Powered Mobility Proficiency Test. Multivariate logistic regression analysis followed by a bootstrapping procedure that was based on 1000 samples were used to determine if the variables were predictive of success on the Israeli MOH Powered Mobility Proficiency Test. RESULTS: Significant variables for predicting success were identified: manual wheelchair propulsion, go-stop voluntarily upon request, and using a joystick. The model was able to correctly identify 80% of the children. INTERPRETATION: Children and young adults with the ability to go-stop upon request, propel a manual wheelchair short distances, and use a joystick to activate the powered wheelchair had a higher chance of becoming proficient. In countries where wheelchair proficiency is a requirement for powered wheelchair procurement, these findings may support policy changes, as they did in Israel. WHAT THIS PAPER ADDS: Using powered wheelchairs offers children earlier and more natural practice to determine driving proficiency. Manual wheelchair propulsion, go-stop voluntarily upon request, and using a joystick were predictors of powered mobility proficiency. More than 80% of children use a joystick with their hand to activate a powered wheelchair.

MODELO PREDICTIVO DE LA COMPETENCIA EN MOVILIDAD MOTORIZADA DE NIÑOS Y ADULTOS JÓVENES CON DEFICIENCIAS MOTORAS: OBJETIVO: Identificar variables que puedan predecir la capacidad de uso de la movilidad motorizada para niños en adultos jóvenes. MÉTODO: Fueron incluidos 80 niños y adultos jóvenes (42 varones, 38 mujeres; edad media 10a 2m, [SD 5a 1m]; rango: 2-22a) con parálisis cerebral, enfermedad neuromuscular y lesión de la médula espinal que participaron en el Programa de Movilidad Motorizada del ALYN Hospital del 2009 a 2016. Los datos se recopilaron y compararon antes y después de la participación en el programa y los niveles de movilidad impulsados ​​se determinaron mediante la Prueba de competencia de movilidad impulsada por el Ministerio de Salud de Israel. Se utilizó el análisis de regresión logística multivariable seguido de un procedimiento de arranque que se basó en 1000 muestras para determinar si las variables eran predictivas de éxito en la Prueba de Competencia de Movilidad Movida por MOH de Israel. RESULTADOS: Se identificaron variables significativas para predecir el éxito: propulsión manual en silla de ruedas, posibilidad de arranque y freno a la orden, y uso de un joystick. El modelo fue capaz de identificar correctamente al 80% de los niños. INTERPRETACIÓN: Los niños y adultos jóvenes que tienen la capacidad de detenerse cuando se lo requiere, que pueden impulsar una silla de ruedas manual a corta distancia y que pueden usar un joystick para activar la silla de ruedas motorizada tienen una mayor probabilidad de convertirse en expertos. En los países donde el dominio de las sillas de ruedas es un requisito para la adquisición de sillas de ruedas motorizadas, estos hallazgos pueden respaldar cambios en las políticas, como lo hicieron en Israel.

MODELO PREDITIVO DE PROFICIÊNCIA NA MOBILIDADE MOTORIZADA DE CRIANÇAS E ADULTOS COM DEFICIÊNCIAS MOTORAS: OBJETIVO: Identificar variáveis que podem predizer proficiência no uso da mobilidade motorizada para crianças e adultos jovens. MÉTODO: Os participantes incluíram 80 crianças e jovens adultos (42 do sexo masculino, 38 do sexo feminino; média de idade 10a 2m, [DP 5a 1m]; variação: 2-22a) com paralisia cerebral, doença neuromuscular, e lesão da medula espinhal que participaram do Programa de Mobilidade Motorizada do Hospital ALYN de 2009 a 2016. Os dados foram coletados e comparados antes e após a participação no programa, e os níveis de mobilidade motorizada foram determinados pelo Teste de Proficiência em Mobilidade Motorizada do Ministério da Saúde (MS) Israelense. Análise de regressão logística multivariada seguida por procedimento e bootstrapping baseado em 1.000 amostras foi usada para determiner se as variáveis eram preditivas do sucesso no Teste de Proficiência em Mobilidade Motorizada do MS Israelense. RESULTADOS: Variáveis significativas na predição de sucesso foram identificadas: propulsão da cadeira manual, capacidade de iniciar e parar voluntariamente quando solicitado, e uso de controle do tipo joystick. O modelo foi capaz de identificar corretamente 80% das crianças. INTERPRETAÇÃO: Crianças e adultos jovens com a capacidade de iniciar e parar quando solicitados, de impulsionar uma cadeira de rodas manual por distâncias curtas, e usar um joystick para ativar a cadeira de rodas tiveram maior chance de se tornar proficientes. Em países em que a proficiência na cadeira é um requisite para solicitar a cadeira de rodas motorizada, estes achados podem dar suporte a mudanças nas políticas empregadas, como ocorreu em Israel.

An exploratory study of parent-child association in sensory modulation disorder involving ADHD-related symptoms.

BACKGROUND: Sensory modulation disorder (SMD) and attention deficit hyperactivity disorder (ADHD) can co-occur and have overlapping symptoms, thus challenging practitioners. This study aimed to phenotypically explore parent-child associations in SMD, and the interplay between SMD- and ADHD-related symptoms in children with SMD and their parents. METHODS: A cross-sectional study examined 70 parents (n = 35 mothers; n = 35 fathers) and their 35 children with and without SMD, aged 4-6 years. Parents completed care-giver reports: The Short Sensory Profile (SSP) and the ADHD Rating Scale, and self-reports: The Sensory Responsiveness Questionnaire (SRQ) and the ADHD Self-Report Scale (ASRS). RESULTS: In the entire sample, we found a mother-offspring correlation between SSP and SRQ-Aversive scores (rs = -0.68; p < 0.001), but no such father-offspring correlation. However, when testing the ADHD Rating Scale and ASRS scores, we found correlations between mothers and offspring (rs = 0.54, p = 0.0008), and between fathers and offspring (rs = 0.34, p = 0.0494). In the entire sample a high correlation was found between SSP and ADHD Rating Scale scores (rs = -0.837, p < 0.001). We further found a high correlation in mothers (rs = 0.70, p < 0.001), and a moderate correlation in fathers (rs = 0.40, p = 0.019) between SRQ-Aversive and ASRS scores. CONCLUSIONS: Novel findings reveal that parents-offspring heritability patterns differ in both these related conditions. These may contribute to familial practice and research.

White matter lesions, cerebral inflammation and cognitive function in a mouse model of cerebral hypoperfusion.

Development of specific treatments for vascular dementia requires appropriate animal models. Bilateral carotid artery stenosis (BCAS) employs metal coils wrapped around both common carotid arteries to induce cerebral hypoperfusion, white matter lesions and memory impairment in mice. We focused on the relationship of memory impairment induced by BCAS to white matter lesions demonstrated by ex vivo magnetic resonance imaging (MRI). We found a significant effect of BCAS on perceptual learning in the novel object recognition test and on number of errors and latency to platform in the radial arm water maze. MRI analysis revealed a significant effect of BCAS on diffusion tensor imaging (DTI) parameters in white matter areas. After correction for multiple testing, significantly lower fractional anisotropy (FA) values were found in the corpus callosum and anterior commissure and significantly higher mean diffusivity values in the internal capsule. Focusing on the corpus callosum, we found that correlations between FA and number of errors on the RAWM test were significant after controlling for treatment. We further found that the effects of BCAS on cognition were partly mediated by its effects on white matter integrity. Immunofluorescence studies demonstrated significantly higher microglia cell density and soma size in the corpus callosum of BCAS mice compared to controls, and these parameters were correlated with the imaging data. The results of this study indicate that cognitive deficits induced by cerebral hypoperfusion due to BCAS result in part from microglia activation and disruption of white matter integrity, supporting the face and construct validity of this unique model of vascular dementia.

The role of exposure to pesticides in the etiology of Parkinson's disease: a 18F-DOPA positron emission tomography study.

Susceptibility to Parkinson's disease (PD) is believed to involve an interaction between genetic and environmental factors. The role of pesticides as a risk factor of PD and neurodegeneration remains controversial. An asymmetric decrease in ligand uptake on 18F-DOPA positron emission tomography (PET), especially in the dorsal putamen, is a sensitive marker of PD. The aim of this study was to examine the pattern of ligand uptake on 18F-DOPA PET in patients with PD exposed or not exposed to pesticides. The main sample included 26 Israeli patients with PD, 13 who were exposed to pesticides and 13 who were not, matched for age and disease duration. All underwent 18F-DOPA PET imaging, and an asymmetry index of ligand uptake between the ipsilateral and contralateral caudate, putamen, and whole striatum was calculated. No significant between-group differences were found in demographic variables, clinical asymmetry index (P = 0.15), or asymmetry index of ligand uptake in the putamen (P = 0.84), caudate (P = 0.78) and striatum (P = 0.45). Comparison of the 18F-DOPA results of the Israeli cohort with those of 17 non-pesticide-exposed patients with PD from Austria yielded no significant differences, further validating our findings. Our observations suggest that although exposure to pesticides might be a risk factor for PD, it does not have an effect on the asymmetry pattern in the nigrostriatal system over non-exposure. We assume that once the disease process is initiated in pesticide-exposed patients, the pathogenic mechanism does not differ from that of idiopathic PD.

Brain Lesions as a Predictor of Therapeutic Outcomes of Hand Function in Infants With Unilateral Cerebral Palsy.

AIM: The present study aimed to investigate whether the response variability of infants to modified constraint-induced movement therapy and bimanual therapy are associated with different types of brain lesions. METHOD: Infants with unilateral cerebral palsy (N = 22) ages 8-15 months (mean = 10.95, standard deviation = 2.15 months) were grouped according to having either a periventricular brain lesion or a middle cerebral artery infarct lesion. Improvement in hand function was analyzed based on the mini-Assistive Hand Assessment results. RESULTS: Infants with periventricular brain lesion displayed greater positive response to upper limb treatment compared to those with middle cerebral artery infarct ( P = .02). A significant difference in improvement according to type of treatment was found in the middle cerebral artery infarct group but not in the periventricular brain lesion. CONCLUSION: The present study showed an association between the type of brain lesion and the efficacy of upper limb treatment in infants. Infants with periventricular brain lesions displayed greater positive responses than those with middle cerebral artery infarct.

Can early dopamine transporter imaging serve as a predictor of Parkinson's disease progression and late motor complications?

BACKGROUND: The role of nuclear imaging in predicting Parkinson's disease (PD) progression is unclear. This study investigated whether the degree of reduced striatal dopamine transporter binding at diagnosis of PD predicts later motor complications and time to disease progression. METHODS: We retrospectively studied 41 patients with early PD who underwent 123I-FP-CIT SPECT and were followed thereafter with a mean disease duration of 9.51 ±â€¯3.18 years. The association of quantitatively analyzed 123I-FP-CIT binding in striatal subregions with the development of motor fluctuations, dyskinesias, freezing of gait (FOG) and falls as well as the time to Hoehn and Yahr (H&Y) stage 3 was evaluated. RESULTS: Logistic regression models controlling for age at diagnosis, sex, disease duration, and L-dopa dose revealed that 123I-FP-CIT binding in the putamen and striatum significantly predicted FOG (OR = 0.02, p = 0.03; OR = 0.01, p = 0.04; respectively) but not falls. Cox proportional hazard analysis did not reveal significant relationship between 123I-FP-CIT binding and motor fluctuations, dyskinesias, or H&Y stage 3. CONCLUSIONS: Our results suggest that a more severe depletion of presynaptic dopamine in early PD is a bad prognostic sign in terms of FOG development. These findings, if replicated, may point to dopaminergic transmission as part of the mechanism underlying FOG in PD.

Repetitive Deep TMS for Parkinson Disease: A 3-Month Double-Blind, Randomized Sham-Controlled Study.

PURPOSE: To study the effects of a repetitive deep transcranial magnetic stimulation (rDTMS) in patients with Parkinson disease using the H5 coil for the low-frequency stimulation of the primary motor cortex, followed by the high-frequency rDTMS of the prefrontal cortex. METHODS: The main outcome measures were the total and motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). Secondary measures included rating of depression and quantitative motor tasks. RESULTS: Forty-eight patients were randomized 1:1 into real or sham rDTMS treatment arms. Analyses (n = 42) of both UPDRS scores revealed a significant main effect for time between baseline and day 90 (end of treatment), indicating that there was an improvement of both scores over time in the whole sample. Although effects of treatment and time-by-treatment were insignificant, simple effects analysis of both measures was significant in the rDTMS group and reached a P-value of 0.06 in the sham group. The response rate was higher in patients with longer disease duration and higher motor UPDRS scores. Side effects were more common in the rDTMS group but were transient and tolerable. CONCLUSIONS: Although rDTMS treatment exhibited some motor improvements, we could not demonstrate an advantage for real treatment over sham. Further research is required to establish stimulation parameters that may induce potentially more beneficial outcomes, probably in patients with longer and more sever disease.

Effectiveness of Modified Constraint-Induced Movement Therapy Compared With Bimanual Therapy Home Programs for Infants With Hemiplegia: A Randomized Controlled Trial.

OBJECTIVE: We examined the effectiveness of modified constraint-induced movement therapy (mCIMT) in treating infants with hemiplegic cerebral palsy and compared therapy outcomes with a nonconstraining bimanual therapy (BIM) of equal intensity. METHOD: In a single-blinded randomized controlled trial, 33 infants with hemiplegia (mean corrected age = 11.1 mo, standard deviation = 2.2) received either mCIMT (n = 17) or BIM (n = 16). Both interventions included home programs encouraging the use of the affected hand during daily 1-hr play sessions for 8 wk. Outcome measures were administered pre- and posttreatment and included the Mini-Assisting Hand Assessment for babies and the Functional Inventory. At baseline, parents also filled out the Dimensions of Mastery Questionnaire. RESULTS: Both groups demonstrated a significantly large and equal improvement in hand and gross motor function posttreatment (p < .001) and high treatment compliance. CONCLUSION: mCIMT and BIM are equally effective methods for treating infants with hemiplegia.

Repetitive deep transcranial magnetic stimulation for motor symptoms in Parkinson's disease: A feasibility study.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinson's disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial. To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation. PATIENTS AND METHODS: An open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n=9) or combined with HF PFC rDTMS (M1-PFC, n=10). Outcome measures included the total and motor Unified Parkinson's Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60. RESULTS: For the M1+PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p=0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p=0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant. CONCLUSION: rDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies.

Ultra-Low-Dose Buprenorphine as a Time-Limited Treatment for Severe Suicidal Ideation: A Randomized Controlled Trial.

OBJECTIVE: Suicidal ideation and behavior currently have no quick-acting pharmacological treatments that are suitable for independent outpatient use. Suicidality is linked to mental pain, which is modulated by the separation distress system through endogenous opioids. The authors tested the efficacy and safety of very low dosages of sublingual buprenorphine as a time-limited treatment for severe suicidal ideation. METHOD: This was a multisite randomized double-blind placebo-controlled trial of ultra-low-dose sublingual buprenorphine as an adjunctive treatment. Severely suicidal patients without substance abuse were randomly assigned to receive either buprenorphine or placebo (in a 2:1 ratio), in addition to their ongoing individual treatments. The primary outcome measure was change in suicidal ideation, as assessed by the Beck Suicide Ideation Scale at the end of each of 4 weeks of treatment. RESULTS: Patients who received ultra-low-dose buprenorphine (initial dosage, 0.1 mg once or twice daily; mean final dosage=0.44 mg/day; N=40) had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo (N=22), both after 2 weeks (mean difference -4.3, 95% CI=-8.5, -0.2) and after 4 weeks (mean difference=-7.1, 95% CI=-12.0, -2.3). Concurrent use of antidepressants and a diagnosis of borderline personality disorder did not affect the response to buprenorphine. No withdrawal symptoms were reported after treatment discontinuation at the end of the trial. CONCLUSIONS: The time-limited, short-term use of very low dosages of sublingual buprenorphine was associated with decreased suicidal ideation in severely suicidal patients without substance abuse. Further research is needed to establish the efficacy, safety, dosing, and appropriate patient populations for this experimental treatment.

Decoding emotion of the other differs among schizophrenia patients and schizoaffective patients: A pilot study.

The deficit in ability to attribute mental states such as thoughts, beliefs, and intentions of another person is a key component in the functional impairment of social cognition in schizophrenia. In the current study, we compared the ability of persons with first episode schizophrenia (FE-SZ) and individuals with schizophrenia displaying symptomatic remission (SZ-CR) to decode the mental state of others with healthy individuals and schizoaffective patients. In addition, we analyzed the effect of dopamine-related genes polymorphism on the ability to decode the mental state of another, and searched for different genetic signatures. Our results show that overall, individuals with schizophrenia performed worse in the "Reading the Mind in the Eyes" (eyes) test, a simple well-defined task to infer the mental state of others than healthy individuals. Within the schizophrenia group, schizoaffective scored significantly higher than FE-SZ, SZ-CR, and healthy individuals. No difference was observed in performance between FE-SZ and SZ-CR subjects. Interestingly, FE-SZ and SZ-CR, but not schizoaffective individuals, performed worse in decoding negative and neutral emotional valance than the healthy control group. At the genetic level, we observed a significant effect of the DAT genotype, but not D4R genotype, on the eyes test performance. Our data suggest that understanding the mental state of another person is a trait marker of the illness, and might serve as an intermediate phenotype in the diagnostic process of schizophrenia disorders, and raise the possibility that DA-related DAT gene might have a role in decoding the mental state of another person.

Perspective: Identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson's disease.

Parkinson's disease (PD) is slowly progressive, and heterogeneity of its severity among individuals may be due to endogenous mechanisms that counterbalance the striatal dopamine loss. In this perspective paper, we introduce a neuroimaging-genetic approach to identify genetic variants, which may contribute to this compensation. First, we briefly review current known potential compensatory mechanisms for premotor and early disease PD, located in the striatum and other brain regions. Then, we claim that a mismatch between mild symptomatic disease, manifested by low motor score on the Unified PD Rating Scale (UPDRS), and extensive Nigro-Striatal (NS) degeneration, manifested by reduced uptake of [(123)I]FP-CIT, is indicative of compensatory processes. If genetic variants are associated with the severity of motor symptoms, while the level of striatal terminals degeneration measured by ligand uptake is taken into account and controlled in the analysis, then these variants may be involved in functional compensatory mechanisms for striatal dopamine deficit. To demonstrate feasibility of this approach, we performed a small "proof of concept" study (candidate gene design) in a sample of 28 Jewish PD patients, and preliminary results are presented.

Association of nicotine dependence susceptibility gene, CHRNA5, with Parkinson's disease age at onset: gene and smoking status interaction.

BACKGROUND: Smoking is a well documented environmental factor that reduces susceptibility to Parkinson's disease (PD). Several genetic variants within the nicotinic cholinergic receptor gene cluster, CHRNA5-CHRNA3-CHRNB4 have been reported to be associated with nicotine dependence (ND), and this association has been validated in multiple studies. OBJECTIVES: Due to the inverse correlation between smoking and PD susceptibility, we investigated whether ND-related genetic variants are associated with age at onset (AAO) of PD among smokers. METHODS: We performed a genetic association study in a sample of 677 Italian PD patients, ages 34-76. 438 had never smoked (NS), and 239 were current or past smokers (ever-smokers, ES). Three independent SNPs within the CHRNA5-CHRNA3-CHRNB4 gene cluster (rs588765, rs16969968, rs578776) were analyzed for association with AAO. RESULTS: We demonstrated an interaction between the rs588765 SNP and smoking status (NS vs. ES) that was nominally significant in its effect on PD AAO (p = 0.04). The rs588765 ND risk allele 'C' was associated with delayed AAO among ES (even when smoking intensity variables are accounted for), but had no significant effect among NS. In the ES group, a dominant model of inheritance was observed: carriers of the 'CC' genotype presented delayed AAO compared to carriers of the 'CT' or 'TT' genotypes. CONCLUSION: Our preliminary results suggest that the ND risk variant, rs588765, has a protective effect in PD, and is associated with later AAO, but only when the individual was previously exposed to nicotine. This may be explained by modulating the neuroprotective effect of chronic nicotine exposure against striatal dopaminergic damage. Further validation studies in additional populations are required.

Involvement of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase, in schizophrenia and cognition.

OBJECTIVE: Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific member of the protein tyrosine phosphatase (PTP) family that has been implicated in learning and memory. In this study, we examined the association of the protein tyrosine phosphatase non-receptor 5 (PTPN5) gene, which encodes for STEP, with both schizophrenia and cognitive functioning in the Israeli Jewish population. METHODS: A schizophrenia (SZ) case-control study of 868 participants was carried out (286 patients and 582 controls). Eleven PTPN5 tagging single-nucleotide polymorphisms (SNPs) were selected and single markers and haplotype association analyses were carried out. A cognitive variability study included 437 healthy women who completed a computerized cognitive battery. We performed univariate associations between the SNPs and cognitive performance. The possible functional role of these variants was examined by studying their association with gene expression levels in the brain. RESULTS: In the SZ study, we found a nominal association in the whole sample between rs4075664 and SZ. Male patients with SZ showed a more significant association for three SNPs (rs4075664, rs2278732, and rs4757710). Haplotypes of the studied SNPs were associated with SZ both in the overall sample and within the male subsample. Expression analysis provided some support for the effects of the associated SNPs on PTPN5 expression level. The cognitive variability study showed positive associations between PTPN5 SNPs and different cognitive subtests. Principal component analysis showed an 'attention index' neurocognitive component that was associated with two SNP pairs (rs10832983 × rs10766504 and rs7932938 × rs4757718). CONCLUSION: The results imply a model in which PTPN5 may play a role in normal cognitive functioning and contribute to aspects of the neuropathology of SZ.