Scott J Sherman
- Professor, Neurology
- Associate Professor, Physiology
- Clinical Instructor
- Associate Professor, Neuroscience - GIDP
- Associate Professor, Physiological Sciences - GIDP
- Associate Professor, Neurosurgery
- Member of the Graduate Faculty
- M.D. Medical Studies
- University of Washington, Seattle, Washington, United States
- Ph.D. Pharmacology
- University of Washington, Seattle, Washington, United States
- The developmental regulation of voltage-gated Na channels in skeletal muscle
- B.A. Biochemistry
- Brandeis University, Waltham, Massachusetts, United States
- School of Mind, Brain & Behavior, College of Science (2013 - Ongoing)
- Carl T. Hayden VA Medical Center (2008 - 2010)
- University of Arizona Medical Center - South Campus (2006 - Ongoing)
- Tucson Medical Center (2001 - Ongoing)
- American Parkinson's Disease Association (1999 - Ongoing)
- Parkinson's Disease Program, HealthSouth Rehabilitation Institute of Tucson (1998 - Ongoing)
- HealthSouth Rehabilitation Institute of Tucson (1998 - Ongoing)
- Movement Disorders Clinic (1997 - Ongoing)
- University Medical Center (1997 - Ongoing)
- Veteran's Administration Medical Center (1997 - Ongoing)
- University of Arizona, Tucson, Arizona (1997 - 2003)
- Emergency Services, Holy Cross Hospital (1991 - 1992)
- Tucson General Hospital (1990 - 1996)
- Holy Cross Hospital (1990 - 1995)
- Phoenix Memorial Hospital (1990 - 1993)
Licensure & Certification
- Board Certification in Neurology, American Board of Psychiatry and Neurology (1997)
- Medical License, Arizona Medical Board (2012)
No activities entered.
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2022)
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2021)
Neuro+Rehab Med ClerkshpNEUR 813C (Spring 2021)
Neurology Clerkship ClinicalNEUR 813C2 (Spring 2021)
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2020)
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2019)
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2018)
Neuro+Rehab Med ClerkshpNEUR 813C (Fall 2017)
Neuro+Rehab Med ClerkshpNEUR 813C (Spring 2017)
Neurology Gen. Inpatient Svc.NEUR 850A (Spring 2017)
- Frank, M. J., Scheres, A., & Sherman, S. J. (2011). Modelling Natural Action Selection: Understanding decision-making deficits in neurological conditions: insights from models of natural action selection. In Philosophical Transactions of The Royal Society. doi:10.1017/CBO9780511731525.019
- Sherman, S. J., Estevez, M., Magill, A. B., & Falk, T. (2021). Case Reports Showing a Long-Term Effect of Subanesthetic Ketamine Infusion in Reducing l-DOPA-Induced Dyskinesias. Case reports in neurology, 8(1), 53-8.More infoKetamine is an FDA-approved drug with a known safety profile. Low-dose subanesthetic intravenous ketamine infusion treatment has led to long-term reduction of treatment-resistant depression and of chronic pain states. We report on low-dose subanesthetic intravenous ketamine infusion treatment in Parkinson's disease (PD) patients by 5 case studies and show a long-lasting therapeutic benefit to reduce l-DOPA-induced dyskinesia (LID), improve on time, and reduce depression. Based on the literature we hypothesize that low-dose ketamine may act as a 'chemical deep brain stimulation', by desynchronizing hypersynchronous oscillatory brain activity, including in the basal ganglia and the motor cortex. The presented PD case reports indicate tolerability, safety and long-term beneficial effects of low-dose ketamine infusion that should be further investigated in a properly controlled prospective clinical trial for treatment of LID, as well as the prevalent nonmotor features pain and depression in PD patients.
- Sherman, S. J., Falk, T., Ye, T., Sherman, S. J., Falk, T., Cowen, S. L., & Bartlett, M. J. (2021). Spectral signatures of L-DOPA-induced dyskinesia depend on L-DOPA dose and are suppressed by ketamine.. Experimental neurology, 340, 113670. doi:10.1016/j.expneurol.2021.113670More infoL-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson's disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 h. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine's therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.
- Sherman, S. J., Pottenger, A. E., Morrison, H. W., Falk, T., & Bartlett, M. J. (2021). Evaluation of microglia in a rodent model of Parkinson's disease primed with L-DOPA after sub-anesthetic ketamine treatment.. Neuroscience letters, 765, 136251. doi:10.1016/j.neulet.2021.136251More infoParkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characterized by motor dysfunction. While PD symptoms are well treated with L-DOPA, continuous use can cause L-DOPA-induced dyskinesia (LID). We have previously demonstrated that sub-anesthetic ketamine attenuated LID development in rodents, measured by abnormal involuntary movements (AIMs), and reduced the density of maladaptive striatal dendritic mushroom spines. Microglia may play a role by phagocytosing maladaptive neuronal spines. In this exploratory study, we hypothesized that ketamine would prevent AIMs and change microglia ramified morphology - an indicator of a microglia response. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats were primed with daily injections of L-DOPA for 14 days, treated on days 0 and 7 for 10-hours with sub-anesthetic ketamine (i.p.), and we replicated that this attenuated LID development. We further extended our prior work by showing that while ketamine treatment did lead to an increase of striatal interleukin-6 in dyskinetic rats, indicating a modulation of an inflammatory response, it did not change microglia number or morphology in the dyskinetic striatum. Yet an increase of CD68 in the SNpc of 6-OHDA-lesioned hemispheres post-ketamine indicates increased microglia phagocytosis suggestive of a lingering microglial response to 6-OHDA injury in the SNpc pointing to possible anti-inflammatory action in the PD model in addition to anti-dyskinetic action. In conclusion, we provide further support for sub-anesthetic ketamine treatment of LID. The mechanisms of action for ketamine, specifically related to inflammation and microglia phagocytic functions, are emerging, and require further examination.
- Bartlett, M. J., Flores, A. J., Ye, T., Smidt, S. I., Dollish, H. K., Stancati, J. A., Farrell, D. C., Parent, K. L., Doyle, K. P., Besselsen, D. G., Heien, M. L., Cowen, S. L., Steece-Collier, K., Sherman, S. J., & Falk, T. (2020). Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia. Experimental neurology, 333, 113413.More infoParkinson's disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.
- Bartlett, M. J., Mabrouk, O. S., Szabo, L., Flores, A. J., Bidlack, J. M., Parent, K. L., Heien, M. L., Kennedy, R. T., Polt, R. L., Sherman, S. J., & Falk, T. (2020). The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia. International Journal of Molecular Sciences.
- Bartlett, M. J., Mabrouk, O. S., Szabò, L., Flores, A. J., Parent, K. L., Bidlack, J. M., Heien, M. L., Kennedy, R. T., Polt, R., Sherman, S. J., & Falk, T. (2020). The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia. International journal of molecular sciences, 22(1).More infoIn previous work we evaluated an opioid glycopeptide with mixed μ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood-brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson's disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus ). We tested BBI-11008 for BBB-penetration after intraperitoneal () injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The -methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.
- Bartlett, M. J., So, L. Y., Szabò, L., Skinner, D. P., Parent, K. L., Heien, M. L., Vanderah, T. W., Polt, R., Sherman, S. J., & Falk, T. (2020). Highly-selective µ-opioid receptor antagonism does not block L-DOPA-induced dyskinesia in a rodent model. BMC research notes, 13(1), 149.More infoDopamine-replacement utilizing L-DOPA is still the mainstay treatment for Parkinson's disease (PD), but often leads to development of L-DOPA-induced dyskinesia (LID), which can be as debilitating as the motor deficits. There is currently no satisfactory pharmacological adjunct therapy. The endogenous opioid peptides enkephalin and dynorphin are important co-transmitters in the direct and indirect striatofugal pathways and have been implicated in genesis and expression of LID. Opioid receptor antagonists and agonists with different selectivity profiles have been investigated for anti-dyskinetic potential in preclinical models. In this study we investigated effects of the highly-selective μ-opioid receptor antagonist CTAP (> 1200-fold selectivity for μ- over δ-opioid receptors) and a novel glycopeptide congener (gCTAP5) that was glycosylated to increase stability, in the standard rat LID model.
- Falk, T., Sherman, S. J., Steece-Collier, K., Cowen, S. L., Heien, M. L., Doyle, K., Besselsen, D. G., Parent, K. L., Farrell, D. C., Stancati, J. A., Dollish, H. K., Smidt, S. I., Ye, T., Flores, A. J., & Bartlett, M. J. (2020). Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.. Experimental Neurology.
- Lundeen, T. F., Covington, M., Krupinski, E. A., Avery, R., Lei, H., Sherman, S. J., & Kuo, P. H. (2020). Accuracy of Dopamine Transporter Imaging with I-Ioflupane in Hispanic and Non-Hispanic Patients. Journal of nuclear medicine technology, 48(2), 154-157.More infoRacial and ethnic disparities in the prevalence of neurodegenerative diseases exist. This study examined the agreement between gold standard diagnosis and visual assessment of dopamine transporter (DaT) imaging in Hispanic and non-Hispanic patients being evaluated for Parkinsonian syndromes (PS). A retrospective review of DaT imaging and demographic data was performed with institutional review board approval. Documented interpretation by visual assessment was used to classify scans as normal or abnormal. The gold standard for the final diagnosis of PS was determined by a neurologist after 2 or more years of clinical follow-up. Data were analyzed with a -test for uncorrelated samples. In 30 Hispanic patients, DaT imaging was abnormal in 17, normal in 12, and nondiagnostic in 1. Of those with abnormal imaging, PS was confirmed in 16 of 17. Of those with normal imaging, no PS was confirmed in any patient. Sensitivity was 100%, and specificity was 92%. The single patient with nondiagnostic imaging was excluded. Of 77 non-Hispanic patients, visual assessment of DaT imaging was abnormal in 51. Of those with abnormal imaging, PS was confirmed in 48 of 51. Of those with normal imaging, no PS was confirmed in 22 of 26. Sensitivity was 92%, and specificity was 88%. There was no statistically significant difference ( = 0.34) in the rates of agreement between the gold standard and DaT imaging in Hispanic versus non-Hispanic patients. The study sample size afforded a power of 0.60. No significant difference was found in the accuracy of DaT imaging between Hispanic and non-Hispanic patients. Accuracy was high for both groups.
- Bhattacharjee, S., Vadiei, N., Goldstone, L., Alrabiah, Z., & Sherman, S. J. (2018). Patterns and Predictors of Depression Treatment among Older Adults with Parkinson's Disease and Depression in Ambulatory Care Settings in the United States. Parkinson's disease, 2018, 3402983.More infoLittle is known regarding depression treatment patterns and predictors among older adults with comorbid Parkinson's disease and depression (dPD) in the United States (US). The objective of this study was to assess the patterns and predictors of depression treatment among older adults with dPD in the US. We adopted a cross-sectional study design by pooling multiple-year data (2005-2011) from the National Ambulatory Medical Care Survey (NAMCS) and the outpatient department of the National Hospital Ambulatory Medical Care Survey (NHAMCS). The final study sample consisted of visits by older adults with dPD. Depression treatment was defined as antidepressant use with or without psychotherapy. To identify predictors of depression treatment, multivariate logistic regression analysis was conducted adjusting for predisposing, enabling, and need factors. Individuals with dPD and polypharmacy were 74% more likely to receive depression treatment (odds ratio = 1.743, 95% CI 1.376-2.209), while dPD subjects with comorbid chronic conditions were 44% less likely (odds ratio = 0.559, 95% CI 0.396-0.790) to receive depression treatment. Approximately six out of ten older adults with PD and depression received depression treatment. Treatment options for dPD are underutilized in routine clinical practice, and further research should explore how overall medical complexity presents a barrier to depression treatment.
- Chen, N. K., Chou, Y. H., Sundman, M., Hickey, P., Kasoff, W. S., Bernstein, A., Trouard, T. P., Lin, T., Rapcsak, S. Z., Sherman, S. J., & Weingarten, C. P. (2018). Alteration of Diffusion-Tensor Magnetic Resonance Imaging Measures in Brain Regions Involved in Early Stages of Parkinson's Disease. Brain connectivity, 8(6), 343-349.More infoMany nonmotor symptoms (e.g., hyposmia) appear years before the cardinal motor features of Parkinson's disease (PD). It is thus desirable to be able to use noninvasive brain imaging methods, such as magnetic resonance imaging (MRI), to detect brain abnormalities in early PD stages. Among the MRI modalities, diffusion-tensor imaging (DTI) is suitable for detecting changes in brain tissue structure due to neurological diseases. The main purpose of this study was to investigate whether DTI signals measured from brain regions involved in early stages of PD differ from those of healthy controls. To answer this question, we analyzed whole-brain DTI data of 30 early-stage PD patients and 30 controls using improved region of interest-based analysis methods. Results showed that (i) the fractional anisotropy (FA) values in the olfactory tract (connected with the olfactory bulb: one of the first structures affected by PD) are lower in PD patients than healthy controls; (ii) FA values are higher in PD patients than healthy controls in the following brain regions: corticospinal tract, cingulum (near hippocampus), and superior longitudinal fasciculus (temporal part). Experimental results suggest that the tissue property, measured by FA, in olfactory regions is structurally modulated by PD with a mechanism that is different from other brain regions.
- Falk, T., Sherman, S. J., Polt, R. L., Porreca, F., Heien, M. L., Parent, K. L., Root, B. K., Bartlett, M. J., & Flores, A. J. (2018). The combination of the opioid glycopeptide MMP-2200 and a NMDA receptor antagonist reduced L-DOPA-induced dyskinesia and MMP-2200 by itself reduced dopamine receptor 2-like agonist-induced dyskinesia. Neuropharmacology, 141, 260-271. doi:doi: 10.1016/j.neuropharm.2018.09.005
- Ye, T., Bartlett, M. J., Schmit, M. B., Sherman, S. J., Falk, T., & Cowen, S. L. (2018). Ten-Hour Exposure to Low-Dose Ketamine Enhances Corticostriatal Cross-Frequency Coupling and Hippocampal Broad-Band Gamma Oscillations. Frontiers in neural circuits, 12, 61.More infoTreatment-resistant depression, post-traumatic stress disorder, chronic pain, and L-DOPA-induced dyskinesia in Parkinson's disease are characterized by hypersynchronous neural oscillations. Sub-anesthetic ketamine is effective at treating these conditions, and this may relate to ketamine's capacity to reorganize oscillatory activity throughout the brain. For example, a single ketamine injection increases gamma (∼40 Hz) and high-frequency oscillations (HFOs, 120-160 Hz) in the cortex, hippocampus, and striatum. While the effects of single injections have been investigated, clinical ketamine treatments can involve 5-h up to 3-day sub-anesthetic infusions. Little is known about the effects of such prolonged exposure on neural synchrony. We hypothesized that hours-long exposure entrains circuits that generate HFOs so that HFOs become sustained after ketamine's direct effects on receptors subside. Local-field recordings were acquired from motor cortex (M1), striatum, and hippocampus of behaving rats ( = 8), and neural responses were measured while rats received 5 ketamine injections (20 mg/kg, i.p., every 2 h, 10-h exposure). In a second experiment, the same animals received injections of D1-receptor antagonist (SCH-23390, 1 mg/kg, i.p.) prior to ketamine injection to determine if D1 receptors were involved in producing HFOs. Although HFOs remained stable throughout extended ketamine exposure, broad-band high-frequency activity (40-140 Hz) in the hippocampus and delta-HFO cross-frequency coupling (CFC) in dorsal striatum increased with the duration of exposure. Furthermore, while ketamine-triggered HFOs were not affected by D1 receptor blockade, ketamine-associated gamma in motor cortex was suppressed, suggesting involvement of D1 receptors in ketamine-mediated gamma activity in motor cortex. Prolonged ketamine exposure does not enhance HFOs in corticostriatal circuits, but, instead, enhances coordination between low and high frequencies in the striatum and reduces synchrony in the hippocampus. Increased striatal CFC may facilitate spike-timing dependent plasticity, resulting in lasting changes in motor activity. In contrast, the observed wide-band high-frequency "noise" in the hippocampus suggests that ketamine disrupts action-potential timing and reorganizes connectivity in this region. Differential restructuring of corticostriatal and limbic circuits may contribute to ketamine's clinical benefits.
- Ye, T., Bartlett, M. J., Schmitt, M. B., Sherman, S. J., Falk, T., & Cowen, S. L. (2018). Ten-Hour Exposure to Ketamine Enhances Corticostriatal Cross-Frequency Coupling and Broad-Band Gamma Oscillations in the Hippocampus.. Frontiers in Neural Circuits, 12:61. doi:doi: 10.3389/fncir.2018.00061.
- Caballero, B., Sherman, S. J., & Falk, T. (2017). Insights into the Mechanisms Involved in Protective Effects of VEGF-B in Dopaminergic Neurons. Parkinson's disease, 2017, 4263795.More infoVascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, vascular endothelial growth factor-A (VEGF-A). Studies demonstrated that VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about the mechanism of action of VEGF-B in pathological processes. We explore its potential as a homeostatic protective factor that improves mitochondrial function in the setting of cardiovascular and neurological disease, with a specific focus on dopaminergic neurons in Parkinson's disease.
- Teves, J. M., Bhargava, V., Kirwan, K. R., Corenblum, M. J., Justiniano, R., Wondrak, G. T., Anandhan, A., Flores, A. J., Schipper, D. A., Khalpey, Z., Sligh, J. E., Curiel-Lewandrowski, C., Sherman, S. J., & Madhavan, L. (2017). Parkinson's Disease Skin Fibroblasts Display Signature Alterations in Growth, Redox Homeostasis, Mitochondrial Function, and Autophagy. Frontiers in neuroscience, 11, 737.More infoThe discovery of biomarkers for Parkinson's disease (PD) is challenging due to the heterogeneous nature of this disorder, and a poor correlation between the underlying pathology and the clinically expressed phenotype. An ideal biomarker would inform on PD-relevant pathological changes via an easily assayed biological characteristic, which reliably tracks clinical symptoms. Human dermal (skin) fibroblasts are accessible peripheral cells that constitute a patient-specific system, which potentially recapitulates the PD chronological and epigenetic aging history. Here, we compared primary skin fibroblasts obtained from individuals diagnosed with late-onset sporadic PD, and healthy age-matched controls. These fibroblasts were studied from fundamental viewpoints of growth and morphology, as well as redox, mitochondrial, and autophagic function. It was observed that fibroblasts from PD subjects had higher growth rates, and appeared distinctly different in terms of morphology and spatial organization in culture, compared to control cells. It was also found that the PD fibroblasts exhibited significantly compromised mitochondrial structure and function when assessed via morphological and oxidative phosphorylation assays. Additionally, a striking increase in baseline macroautophagy levels was seen in cells from PD subjects. Exposure of the skin fibroblasts to physiologically relevant stress, specifically ultraviolet irradiation (UVA), further exaggerated the autophagic dysfunction in the PD cells. Moreover, the PD fibroblasts accumulated higher levels of reactive oxygen species (ROS) coupled with lower cell viability upon UVA treatment. In essence, these studies highlight primary skin fibroblasts as a patient-relevant model that captures fundamental PD molecular mechanisms, and supports their potential utility to develop diagnostic and prognostic biomarkers for the disease.
- Langevin, J. P., Skoch, J. M., & Sherman, S. J. (2016). Deep brain stimulation of a patient with psychogenic movement disorder. Surgical neurology international, 7(Suppl 35), S824-S826.More infoThe long-term safety of deep brain stimulation (DBS) is an important issue because new applications are being investigated for a variety of disorders. Studying instances where DBS was inadvertently implanted in patients without a movement disorder may provide information about the safety of the therapy. We report the case of a patient with a psychogenic movement disorder treated with deep brain stimulation (DBS).
- Covington, M., Lewis, D., Krupinski, E. A., Sherman, S. J., Lei, H., & Kuo, P. H. (2015). Patient Survey on Satisfaction and Impact of 123I-Ioflupane Dopamine Transporter Imaging. PLoS One. doi:10.1371/journal.pone.0134457. eCollection 2015.
- Toosizadeh, N., Lei, H., Schwenk, M., Sherman, S. J., Sternberg, E., Mohler, J., & Najafi, B. (2015). Does integrative medicine enhance balance in aging adults? Proof of concept for the benefit of electroacupuncture therapy in Parkinson's disease. Gerontology, 61(1), 3-14.More infoPostural balance and potentially fall risk increases among older adults living with neurological diseases, especially Parkinson's disease (PD). Since conventional therapies such as levodopa or deep brain stimulation may fail to alleviate or may even worsen balance, interest is growing in evaluating alternative PD therapies.
- Toosizadeh, N., Mohler, J., Lei, H., Parvaneh, S., Sherman, S., & Najafi, B. (2015). Motor Performance Assessment in Parkinson's Disease: Association between Objective In-Clinic, Objective In-Home, and Subjective/Semi-Objective Measures. PloS one, 10(4), e0124763.More infoAdvances in wearable technology allow for the objective assessment of motor performance in both in-home and in-clinic environments and were used to explore motor impairments in Parkinson's disease (PD). The aims of this study were to: 1) assess differences between in-clinic and in-home gait speed, and sit-to-stand and stand-to-sit duration in PD patients (in comparison with healthy controls); and 2) determine the objective physical activity measures, including gait, postural balance, instrumented Timed-up-and-go (iTUG), and in-home spontaneous physical activity (SPA), with the highest correlation with subjective/semi-objective measures, including health survey, fall history (fallers vs. non-fallers), fear of falling, pain, Unified Parkinson's Disease Rating Scale, and PD stage (Hoehn and Yahr). Objective assessments of motor performance were made by measuring physical activities in the same sample of PD patients (n = 15, Age: 71.2±6.3 years) and age-matched healthy controls (n = 35, Age: 71.9±3.8 years). The association between in-clinic and in-home parameters, and between objective parameters and subjective/semi-objective evaluations in the PD group was assessed using linear regression-analysis of variance models and reported as Pearson correlations (R). Both in-home SPA and in-clinic assessments demonstrated strong discriminatory power in detecting impaired motor function in PD. However, mean effect size (0.94±0.37) for in-home measures was smaller compared to in-clinic assessments (1.30±0.34) for parameters that were significantly different between PD and healthy groups. No significant correlation was observed between identical in-clinic and in-home parameters in the PD group (R = 0.10-0.25; p>0.40), while the healthy showed stronger correlation in gait speed, sit-to-stand duration, and stand-to-sit duration (R = 0.36-0.56; p
- Cavanagh, J. F., Sanguinetti, J. L., Allen, J. J., Sherman, S. J., & Frank, M. J. (2014). The subthalamic nucleus contributes to post-error slowing. Journal of cognitive neuroscience, 26(11), 2637-44.More infopFC is proposed to implement cognitive control via directed "top-down" influence over behavior. But how is this feat achieved? The virtue of such a descriptive model is contingent on a mechanistic understanding of how motor execution is altered in specific circumstances. In this report, we provide evidence that the well-known phenomenon of slowed RTs following mistakes (post-error slowing) is directly influenced by the degree of subthalamic nucleus (STN) activity. The STN is proposed to act as a brake on motor execution following conflict or errors, buying time so a more cautious response can be made on the next trial. STN local field potentials from nine Parkinson disease patients undergoing deep brain stimulation surgery were recorded while they performed a response conflict task. In a 2.5- to 5-Hz frequency range previously associated with conflict and error processing, the degree phase consistency preceding the response was associated with increasingly slower RTs specifically following errors. These findings provide compelling evidence that post-error slowing is in part mediated by a corticosubthalamic "hyperdirect" pathway for increased response caution.
- Flores, A. J., Bartlett, M. J., So, L. Y., Laude, N. D., Parent, K. L., Heien, M. L., Sherman, S. J., & Falk, T. (2014). Differential effects of the NMDA receptor antagonist MK-801 on dopamine receptor D1- and D2-induced abnormal involuntary movements in a preclinical model. Neuroscience letters, 564, 48-52.More infoDopamine-replacement therapy with l-DOPA is still the gold standard treatment for Parkinson's disease (PD). One drawback is the common development of l-DOPA-induced dyskinesia (LID) in patients, which can be as disabling as the disease itself. There is no satisfactory adjunct therapy available. Glutamatergic transmission in the basal ganglia circuitry has been shown to be an important player in the development of LID. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has previously been shown to reduce l-DOPA-induced abnormal involuntary movements (AIMs) in a rat preclinical model but only at concentrations that worsen parkinsonism. We investigated the contribution of the direct and indirect striatofugal pathways to these effects. In the direct pathway, dopamine D1 receptors (D1R) are expressed, whereas in the indirect pathway, dopamine D2 receptors (D2R) are expressed. We used the 6-hydroxydopamine-lesioned hemi-parkinsonian rat model initially primed with l-DOPA to induce dyskinesia. When the rats were then primed and probed with the D1R agonist SKF81297, co-injection of MK-801 worsened the D1R-induced limb, axial, and orolingual (LAO) AIMs by 18% (predominantly dystonic axial AIMs) but did not aggravate parkinsonian hypokinesia as reflected by a surrogate measure of ipsiversive rotations in this model. In contrast, when the rats were then primed and probed with the D2R agonist quinpirole, co-injection of MK-801 reduced D2R-induced LAO AIMs by 89% while inducing ipsiversive rotations. The data show that only inhibition of the indirect striatopallidal pathway is sufficient for the full anti-dyskinetic/pro-parkinsonian effects of the NMDA receptor antagonist MK-801, and that MK-801 modestly worsens dyskinesias that are due to activation of the direct striatonigral pathway alone. This differential activation of the glutamatergic systems in D1R- and D2R-mediated responses is relevant to current therapy for PD which generally includes a mixture of dopamine agonists and l-DOPA.
- Kuo, P. H., Avery, R., Sherman, S. J., Zubal, G. I., Sherman, S. J., Seibyl, J., Mcmillan, N., Lei, H. H., Kuo, P. H., Krupinski, E. A., Bauer, A., & Avery, R. (2014). Evaluation of an Objective Striatal Analysis Program for Determining Laterality in Uptake of ¹²³I-Ioflupane SPECT Images: Comparison to Clinical Symptoms and to Visual Reads.. Journal of nuclear medicine technology, 42(2), 105-8. doi:10.2967/jnmt.113.134940More infoAn automated objective striatal analysis (OSA) software program was applied to dopamine transporter (123)I-ioflupane images acquired on subjects with varying severities of parkinsonism. The striatal binding ratios (SBR) of the left and right putamina (relative to the occipital lobe) were computed, and the laterality of that measure was compared with clinical symptoms and visual reads. The objective over-read of OSA was evaluated as an aid in confirming the laterality of disease onset..One hundred one (123)I-ioflupane scans were acquired on clinically referred subjects. SPECT images were analyzed using the OSA software, which locates the slices containing the striatal and background (occipital) structures, positions regions over the left and right caudate nuclei and putamina, and calculates the background-subtracted SBR. Seven images were uninterpretable because of patient motion or lack of visualization of the striatum. The remaining 94 scans were analyzed with OSA. Differences between left and right putaminal SBR ranged from 0% to 36.6%, with a mean of 11.4%. When the difference between the SBR of the left and right putamina was greater than 6%, the lower side was taken as the side of onset. Left-to-right differences less than 6% were considered to be nonlateralizing (symmetric). The 94 scans were reviewed independently by 3 masked expert readers. By majority consensus, abnormal findings were seen on 67 of the 94 scans, of which 46 had available clinical findings..Clinically, 34 subjects presented with lateralized tremors and 12 with symmetric or no tremors. Of the 34 cases of clinically lateralized tremors, 26 (76%) were concordant with the OSA findings, 5 were disparate with OSA (15%), and in 3 the OSA results were symmetric (9%). For the same 34 patients, the visual reads were concurrent with clinical tremor findings in 24 cases (71%), 1 was disparate (3%), and 9 visual reads were symmetric (26%). Of the 9 scans deemed symmetric by readers, 4 were correctly lateralized by OSA, and of the 3 symmetric OSA results, 2 were correctly lateralized visually..The OSA program may be a helpful aid in the interpretation of (123)I-ioflupane SPECT images for determining laterality representing the asymmetric loss of dopamine transporters in the striata. OSA offers an objective, reproducible over-read evaluation for the laterality of onset in Parkinson disease.
- Sherman, S. J., Zhang, S., Yue, X., Wullner, U., Sherman, S. J., Mount, D. W., Kaut, O., Hariri, D. J., Falk, T., Caballero, B., & Bartlett, M. J. (2014). Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.. Neuroscience, 258, 385-400. doi:10.1016/j.neuroscience.2013.11.038More infoVascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.
- Kuo, P. H., Avery, R., Sherman, S. J., Zubal, G., Sherman, S. J., Seibyl, J., Mcmillan, N., Lei, H., Kuo, P. H., Krupinski, E. A., Bauer, A., & Avery, R. (2013). Receiver-operating-characteristic analysis of an automated program for analyzing striatal uptake of 123I-ioflupane SPECT images: calibration using visual reads.. Journal of nuclear medicine technology, 41(1), 26-31. doi:10.2967/jnmt.112.114827More infoA fully automated objective striatal analysis (OSA) program that quantitates dopamine transporter uptake in subjects with suspected Parkinson's disease was applied to images from clinical (123)I-ioflupane studies. The striatal binding ratios or alternatively the specific binding ratio (SBR) of the lowest putamen uptake was computed, and receiver-operating-characteristic (ROC) analysis was applied to 94 subjects to determine the best discriminator using this quantitative method..Ninety-four (123)I-ioflupane SPECT scans were analyzed from patients referred to our clinical imaging department and were reconstructed using the manufacturer-supplied reconstruction and filtering parameters for the radiotracer. Three trained readers conducted independent visual interpretations and reported each case as either normal or showing dopaminergic deficit (abnormal). The same images were analyzed using the OSA software, which locates the striatal and occipital structures and places regions of interest on the caudate and putamen. Additionally, the OSA places a region of interest on the occipital region that is used to calculate the background-subtracted SBR. The lower SBR of the 2 putamen regions was taken as the quantitative report. The 33 normal (bilateral comma-shaped striata) and 61 abnormal (unilateral or bilateral dopaminergic deficit) studies were analyzed to generate ROC curves..Twenty-nine of the scans were interpreted as normal and 59 as abnormal by all 3 readers. For 12 scans, the 3 readers did not unanimously agree in their interpretations (discordant). The ROC analysis, which used the visual-majority-consensus interpretation from the readers as the gold standard, yielded an area under the curve of 0.958 when using 1.08 as the threshold SBR for the lowest putamen. The sensitivity and specificity of the automated quantitative analysis were 95% and 89%, respectively..The OSA program delivers SBR quantitative values that have a high sensitivity and specificity, compared with visual interpretations by trained nuclear medicine readers. Such a program could be a helpful aid for readers not yet experienced with (123)I-ioflupane SPECT images and if further adapted and validated may be useful to assess disease progression during pharmaceutical testing of therapies.
- Falk, T., Congrove, N. R., Zhang, S., McCourt, A. D., Sherman, S. J., & McKay, B. S. (2012). PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers. Journal of biomedicine & biotechnology, 2012, 278932.More infoHuman retinal pigment epithelial (hRPE) cells have been tested as a cell-based therapy for Parkinson's disease but will require additional study before further clinical trials can be planned. We now show that the long-term survival and neurotrophic potential of hRPE cells can be enhanced by the use of FDA-approved plastic-based microcarriers compared to a gelatin-based microcarrier as used in failed clinical trials. The hRPE cells grown on these plastic-based microcarriers display several important characteristics of hRPE found in vivo: (1) characteristic morphological features, (2) accumulation of melanin pigment, and (3) high levels of production of the neurotrophic factors pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A). Growth of hRPE cells on plastic-based microcarriers led to sustained levels (>1 ng/ml) of PEDF and VEGF-A in conditioned media for two months. We also show that the expression of VEGF-A and PEDF is reciprocally regulated by activation of the GPR143 pathway. GPR143 is activated by L-DOPA (1 μM) which decreased VEGF-A secretion as opposed to the previously reported increase in PEDF secretion. The hRPE microcarriers are therefore novel candidate delivery systems for achieving long-term delivery of the neuroprotective factors PEDF and VEGF-A, which could have a value in neurodegenerative conditions such as Parkinson's disease.
- Mabrouk, O. S., Falk, T., Sherman, S. J., Kennedy, R. T., & Polt, R. (2012). CNS penetration of the opioid glycopeptide MMP-2200: a microdialysis study. Neuroscience letters, 531(2), 99-103.More infoEndogenous opioid peptides enkephalin and dynorphin are major co-transmitters of striatofugal pathways of the basal ganglia. They are involved in the genesis of levodopa-induced dyskinesia and in the modulation of direct and indirect striatal output pathways that are disrupted in Parkinson's disease. One pharmacologic approach is to develop synthetic glycopeptides closely resembling endogenous peptides to restore their normal functions. Glycosylation promotes penetration of the blood-brain barrier. We investigated CNS penetration of the opioid glycopeptide MMP-2200, a mixed δ/μ-agonist based on leu-enkephalin, as measured by in vivo microdialysis and subsequent mass spectrometric analysis in awake, freely moving rats. The glycopeptide (10 mg/kg) reaches the dorsolateral striatum (DLS) rapidly after systemic (i.p.) administration and is stably detectable for the duration of the experiment (80 min). The detected level at the end of the experiment (around 250 pM) is about 10-fold higher than the level of the endogenous leu-enkephalin, measured simultaneously. This is one of the first studies to directly prove that glycosylation of an endogenous opioid peptide leads to excellent blood-brain barrier penetration after systemic injection, and explains robust behavioral effects seen in previous studies by measuring how much glycopeptide reaches the target structure, in this case the DLS.
- Cavanagh, J. F., Wiecki, T. V., Cohen, M. X., Figueroa, C. M., Samanta, J., Sherman, S. J., & Frank, M. J. (2011). Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold. Nature neuroscience, 14(11), 1462-7.More infoIt takes effort and time to tame one's impulses. Although medial prefrontal cortex (mPFC) is broadly implicated in effortful control over behavior, the subthalamic nucleus (STN) is specifically thought to contribute by acting as a brake on cortico-striatal function during decision conflict, buying time until the right decision can be made. Using the drift diffusion model of decision making, we found that trial-to-trial increases in mPFC activity (EEG theta power, 4-8 Hz) were related to an increased threshold for evidence accumulation (decision threshold) as a function of conflict. Deep brain stimulation of the STN in individuals with Parkinson's disease reversed this relationship, resulting in impulsive choice. In addition, intracranial recordings of the STN area revealed increased activity (2.5-5 Hz) during these same high-conflict decisions. Activity in these slow frequency bands may reflect a neural substrate for cortico-basal ganglia communication regulating decision processes.
- Falk, T., Yue, X., Zhang, S., McCourt, A. D., Yee, B. J., Gonzalez, R. T., & Sherman, S. J. (2011). Vascular endothelial growth factor-B is neuroprotective in an in vivo rat model of Parkinson's disease. Neuroscience letters, 496(1), 43-7.More infoDeveloping novel neuroprotective strategies for the treatment of Parkinson's disease (PD) is of great importance. We have previously shown that vascular endothelial growth factor-B (VEGF-B) is up-regulated in an in vitro model of PD using the neurotoxin rotenone. Addition of exogenous VEGF-B(167) was neuroprotective in this same model, suggesting that VEGF-B is a natural response to neurodegenerative challenges. Now we have extended this research using in vivo experiments. We tested a single intra-striatal injection of 3 μg VEGF-B(186), the more diffusible VEGF-B isoform, in a mild progressive unilateral 6-hydroxydopamine (6-OHDA) rat in vivo PD model. Treatment with VEGF-B(186) 6h prior to lesioning with 6-OHDA improved amphetamine-induced rotations and forepaw preference at 2, 4 and 6 weeks post-injection, indicating a neuroprotective effect. Immunohistochemical analysis showed that VEGF-B(186) treatment partially protected dopaminergic fibers in the striatum and demonstrated a partial rescue of the dopaminergic neurons in the caudal sub-region of the substantia nigra. Altogether our data suggest that VEGF-B(186) could be a new candidate trophic factor for the treatment of PD.
- Yue, X., Falk, T., Zuniga, L. A., Szabò, L., Porreca, F., Polt, R., & Sherman, S. J. (2011). Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease. Brain research, 1413, 72-83.More infoIn Parkinson's disease (PD), the consequence of dopaminergic denervation is an imbalance in the activity of the direct and indirect striatofugal pathways, which include potentially important changes in opioid peptide expression and/or activity. The systemic administration of a novel glycosylated opioid peptide MMP-2200 (a.k.a. lactomorphin) was shown to have potent effects in two standard models of PD: 1) amphetamine-induced rotations in the hemi-Parkinsonian 6-hydroxydopamine (6-OHDA)-treated rat and 2) locomotion in the reserpine-treated rat. MMP-2200, an opioid mu and delta receptor agonist, reduced amphetamine-induced rotations in severely-lesioned hemi-Parkinsonian rats; this effect was fully blocked by naloxone, an opioid receptor antagonist. The selective δ-opioid receptor antagonist naltrindole only partially blocked the effect of MMP-2200. MMP-2200 alone did not induce rotations. This effect was also observed in a mild progressive rat 6-OHDA-lesion model. In animals treated with reserpine, profound akinesia was induced that was reversed with apomorphine. There was a prominent overshoot in animals that received apomorphine compared to non-reserpine treated animals, reflecting the well described phenomenon of dopamine supersensitivity indicating that apomorphine not only reversed akinesia but also induced hyper-kinesia. The opioid peptide MMP-2200 blocked the apomorphine-induced hyper-kinesia. This effect of MMP-2200 was prevented by pre-administration of naloxone. MMP-2200 had no effect in preventing the reserpine-induced akinesia, nor did it affect locomotion in control animals. Taken together, the results from these two models are consistent with the glycopeptide opioid agonist MMP-2200 having a potent effect on movements related to dopaminergic hyper-stimulation following striatal dopamine depletion that are best explained by a reduction in the downstream effects of dopamine agonists in these models.
- Falk, T., Gonzalez, R. T., & Sherman, S. J. (2010). The yin and yang of VEGF and PEDF: multifaceted neurotrophic factors and their potential in the treatment of Parkinson's Disease. International journal of molecular sciences, 11(8), 2875-900.More infoOver the last few decades, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) have emerged as multifaceted players in not only the pathogenesis, but potential treatment, of numerous diseases. They activate diverse intracellular signaling cascades known to have extensive crosstalk, and have been best studied for their effects in cardiology and cancer biology. Recent work with the two factors indicates that the activity of one growth factor is often directly related to the action of the other. Their respective neuroprotective effects, in particular, raise important questions regarding the treatment of neurodegenerative disorders, including Parkinson's disease.
- Falk, T., Zhang, S., & Sherman, S. J. (2009). Pigment epithelium derived factor (PEDF) is neuroprotective in two in vitro models of Parkinson's disease. Neuroscience letters, 458(2), 49-52.More infoTransplantation of retinal pigment epithelial (RPE) cells in the basal ganglia has been proposed as a novel cell-based therapy for Parkinson's disease (PD), by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We have demonstrated previously that human RPE cells also produce a neurotrophic effect on primary cultures of rat striata mesencephalic (dopaminergic) neurons and showed that pigment epithelium derived factor (PEDF) accounted for a major portion of the neurotrophic effect. We now have also begun studies that demonstrate that the neurotrophic effect of PEDF corresponds to neuroprotection against toxins used to produce experimental PD. This was shown in (1) rotenone and (2) 6-hydroxydopamine (6-OHDA) in vitro models. The toxins were added at day 10 in culture, PEDF was added 1h prior. The cultures were fixed and analyzed after tyrosine hydroxylase (TH) immunocytochemical staining. Cell count of TH+ neurons clearly shows the neuroprotective potential of PEDF in both neurotoxin models. The neurotoxic effect of rotenone (25nM) on dopaminergic neurons is reversed by addition of PEDF. At a concentration of 1ng/ml PEDF the neurotoxic effect of rotenone is completely counteracted. PEDF (1ng/ml) has also a neuroprotective effect in the 6-OHDA midbrain in vitro model. The effect is most pronounced at concentrations of 25microM and 50microM 6-OHDA. We conclude that the neurotrophic factor PEDF, produced from RPE cells, can improve neuronal survival in models of PD, and plan to test if this effect can be observed using in vivo models of PD following RPE transplantation.
- Falk, T., Zhang, S., & Sherman, S. J. (2009). Vascular endothelial growth factor B (VEGF-B) is up-regulated and exogenous VEGF-B is neuroprotective in a culture model of Parkinson's disease. Molecular neurodegeneration, 4, 49.More infoParkinson's disease (PD) results from the degeneration of dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine released in the striatum. Current oral dopamine replacement or surgical therapies do not address the underlying issue of neurodegeneration, they neither slow nor halt disease. Neurotrophic factors have shown preclinical promise, but the choice of an appropriate growth factor as well as the delivery has proven difficult. In this study, we used a rotenone rat midbrain culture model to identify genes that are changed after addition of the neurotoxin. (1) We challenged rat midbrain cultures with rotenone (20 nM), a pesticide that has been shown to be toxic for dopaminergic neurons and that has been a well-characterized model of PD. A gene chip array analysis demonstrated that several genes were up-regulated after the rotenone treatment. Interestingly transcriptional activation of vascular endothelial growth factor B (VEGF-B) was evident, while vascular endothelial growth factor A (VEGF-A) levels remained unaltered. The results from the gene chip array experiment were verified with real time PCR and semi-quantitative western analysis using beta-actin as the internal standard. (2) We have also found evidence that exogenously applied VEGF-B performed as a neuroprotective agent facilitating neuron survival in an even more severe rotenone culture model of PD (40 nM rotenone). VEGF-B has very recently been added to the list of trophic factors that reduce effects of neurodegeneration, as was shown in an in vivo model of motor neuron degeneration, while lacking potential adverse angiogenic activity. The data of an in vivo protective effect on motor neurons taken together with the presented results demonstrate that VEGF-B is a new candidate trophic factor distinct from the GDNF family of trophic factors. VEGF-B is activated by neurodegenerative challenges to the midbrain, and exogenous application of VEGF-B has a neuroprotective effect in a culture model of PD. Strengthening this natural protective response by either adding exogenous VEGF-B or up-regulating the endogenous VEGF-B levels may have the potential to be a disease modifying therapy for PD. We conclude that the growth factor VEGF-B can improve neuronal survival in a culture model of PD.
- Moustafa, A. A., Cohen, M. X., Sherman, S. J., & Frank, M. J. (2008). A role for dopamine in temporal decision making and reward maximization in parkinsonism. The Journal of neuroscience : the official journal of the Society for Neuroscience, 28(47), 12294-304.More infoConverging evidence implicates striatal dopamine (DA) in reinforcement learning, such that DA increases enhance "Go learning" to pursue actions with rewarding outcomes, whereas DA decreases enhance "NoGo learning" to avoid non-rewarding actions. Here we test whether these effects apply to the response time domain. We employ a novel paradigm which requires the adjustment of response times to a single response. Reward probability varies as a function of response time, whereas reward magnitude changes in the opposite direction. In the control condition, these factors exactly cancel, such that the expected value across time is constant (CEV). In two other conditions, expected value increases (IEV) or decreases (DEV), such that reward maximization requires either speeding up (Go learning) or slowing down (NoGo learning) relative to the CEV condition. We tested patients with Parkinson's disease (depleted striatal DA levels) on and off dopaminergic medication, compared with age-matched controls. While medicated, patients were better at speeding up in the DEV relative to CEV conditions. Conversely, nonmedicated patients were better at slowing down to maximize reward in the IEV condition. These effects of DA manipulation on cumulative Go/NoGo response time adaptation were captured with our a priori computational model of the basal ganglia, previously applied only to forced-choice tasks. There were also robust trial-to-trial changes in response time, but these single trial adaptations were not affected by disease or medication and are posited to rely on extrastriatal, possibly prefrontal, structures.
- Sherman, S. J., Ciucci, M. R., & Barkmeier-kraemer, J. M. (2008). Subthalamic nucleus deep brain stimulation improves deglutition in Parkinson's disease.. Movement disorders : official journal of the Movement Disorder Society, 23(5), 676-83. doi:10.1002/mds.21891More infoRelatively little is known about the role of the basal ganglia in human deglutition. Deep brain stimulation (DBS) affords us a model for examining deglutition in humans with known impairment of the basal ganglia. The purpose of this study was to examine the effects of subthalamic nuclei (STN) DBS on the oral and pharyngeal stages of deglutition in individuals with Parkinson's Disease (PD). It was hypothesized that DBS would be associated with improved deglutition. Within participant, comparisons were made between DBS in the ON and OFF conditions using the dependent variables: pharyngeal transit time, maximal hyoid bone excursion, oral total composite score, and pharyngeal total composite score. Significant improvement occurred for the pharyngeal composite score and pharyngeal transit time in the DBS ON condition compared with DBS OFF. Stimulation of the STN may excite thalamocortical or brainstem targets to sufficiently overcome the bradykinesia/hypokinesia associated with PD and return some pharyngeal stage motor patterns to performance levels approximating those of "normal" deglutition. However, the degree of hyoid bone excursion and oral stage measures did not improve, suggesting that these motor acts may be under the control of different sensorimotor pathways within the basal ganglia.
- Sherman, S. J., Moustafa, A. A., & Frank, M. J. (2008). A dopaminergic basis for working memory, learning and attentional shifting in Parkinsonism.. Neuropsychologia, 46(13), 3144-56. doi:10.1016/j.neuropsychologia.2008.07.011More infoParkinson's disease (PD) patients exhibit cognitive deficits, including reinforcement learning, working memory (WM) and set shifting. Computational models of the basal ganglia-frontal system posit similar mechanisms for these deficits in terms of reduced dynamic range of striatal dopamine (DA) signals in both medicated and non-medicated states. Here, we report results from the first study that tests PD patients on and off dopaminergic medications in a modified version of the AX continuous performance (AX-CPT) working memory task, consisting of three performance phases and one phase requiring WM associations to be learned via reinforcement feedback. Patients generally showed impairments relative to controls. Medicated patients showed deficits specifically when having to ignore distracting stimuli during the delay. Our models suggest that this impairment is due to medication causing excessive WM updating by enhancing striatal "Go" signals that facilitate such updating, while concurrently suppressing "NoGo" signals. In contrast, patients off medication showed deficits consistent with an overall reduction in striatal DA and associated Go updating signals. Supporting this dichotomy, patients on and off medication both showed attentional shifting deficits, but for different reasons. Deficits in non-medicated patients were consistent with an inability to update the new attentional set, whereas those in medicated patients were evident when having to ignore distractors that had previously been task relevant. Finally, in the feedback-based WM phase, medicated patients were better than unmedicated patients, suggesting a key role of striatal DA in using feedback to update information into WM. These results lend further insight into the role of basal ganglia dopamine in WM and broadly support predictions from neurocomputational models.
- Østergaard, K., Wooten, G. F., Williamson, S., Wilk, J. B., Watts, R. L., Tobin, J. E., Suchowersky, O., Snow, B., Slevin, J. T., Singer, C., Shill, H. A., Sherman, S. J., Saint-hilaire, M. H., Roxburgh, R., Racette, B. A., Pramstaller, P. P., Pezzoli, G., Perlmutter, J. S., Ostergaard, K., , Nicholson, G. A., et al. (2008). Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study.. Neurology, 71(1), 28-34. doi:10.1212/01.wnl.0000304051.01650.23More infoMicrotubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum..Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR..After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT..This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.
- Østergaard, K., Zini, M., Wooten, G. F., Williamson, S., Wilk, J. B., Watts, R. L., Sun, M., Suchowersky, O., Snow, B., Slevin, J. T., Singer, C., Shill, H. A., Sherman, S. J., Saint-hilaire, M. H., Roxburgh, R., Racette, B. A., Pramstaller, P. P., Pezzoli, G., Perlmutter, J. S., , Ostergaard, K., et al. (2008). The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.. BMC medicine, 6(1), 32. doi:10.1186/1741-7015-6-32More infoWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD..A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample..Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families..Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.
- Frank, M. J., Scheres, A., & Sherman, S. J. (2007). Understanding decision making deficits in neurological conditions: Insights from models of natural action selection. Philos Trans R Soc Lond B Biol Sci, 362(1485), 1641-54. doi:doi: 10.1098/rstb.2007.2058.
- Sherman, S. J., Samanta, J., Moustafa, A. A., & Frank, M. J. (2007). Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism.. Science (New York, N.Y.), 318(5854), 1309-12. doi:10.1126/science.1146157More infoDeep brain stimulation (DBS) of the subthalamic nucleus markedly improves the motor symptoms of Parkinson's disease, but causes cognitive side effects such as impulsivity. We showed that DBS selectively interferes with the normal ability to slow down when faced with decision conflict. While on DBS, patients actually sped up their decisions under high-conflict conditions. This form of impulsivity was not affected by dopaminergic medication status. Instead, medication impaired patients' ability to learn from negative decision outcomes. These findings implicate independent mechanisms leading to impulsivity in treated Parkinson's patients and were predicted by a single neurocomputational model of the basal ganglia.
- Sherman, S. J., Scheres, A., & Frank, M. J. (2007). Understanding decision-making deficits in neurological conditions: insights from models of natural action selection.. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 362(1485), 1641-54. doi:10.1098/rstb.2007.2058More infoModels of natural action selection implicate fronto-striatal circuits in both motor and cognitive 'actions'. Dysfunction of these circuits leads to decision-making deficits in various populations. We review how computational models provide insights into the mechanistic basis for these deficits in Parkinson's patients and those with ventromedial frontal damage. We then consider implications of the models for understanding behaviour and cognition in attention-deficit/hyperactivity disorder (ADHD). Incorporation of cortical noradrenaline function into the model improves action selection in noisy environments and accounts for response variability in ADHD. We close with more general clinical implications.
- Xu, G., Wooten, G. F., Williamson, S., Wilk, J. B., Watts, R. L., Vieregge, P., Sun, M., Suchowersky, O., Singer, C., Shill, H. A., Sherman, S. J., Saint-hilaire, M. H., Racette, B. A., Pramstaller, P. P., Prakash, R., Pezzoli, G., Perlmutter, J. S., Parsian, A., Nicholson, G. A., , Myers, R. H., et al. (2006). Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study.. Archives of neurology, 63(6), 826-32. doi:10.1001/archneur.63.6.826More infoThe PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD)..To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members..Clinical and genetic study..Twenty collaborative clinical sites..Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2..Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion..Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04)..These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.
- Wooten, G. F., Williamson, J., Wilk, J. B., Watts, R. L., Vieregge, P., Tobin, S., Suchowersky, O., Singer, C., Shill, H. A., Sherman, S. J., Saint-hilaire, M., Racette, B. A., Pramstaller, P. P., Prakash, R., Pezzoli, G., Perlmutter, J. S., Parsian, A., Nicholson, G. A., Myers, R. H., , Mark, M. H., et al. (2005). BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study.. Neurology, 65(11), 1823-5. doi:10.1212/01.wnl.0000187075.81589.fdMore infoBrain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.
- Figueroa, C., Sherman, S. J., & Frank, M. (2012). Differential effects of levodopa and D2 agonists on reinforcement learning and the expression of learning in Parkinson's disease. Brain.
- Sherman, S. J., Semenchuk, M. R., & Davis, B. (2001). Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain.. Neurology, 57(9), 1583-8. doi:10.1212/wnl.57.9.1583More infoTo evaluate the effectiveness and safety of bupropion sustained-release (SR) for the treatment of neuropathic pain..This single-center, outpatient, randomized, double-blind, placebo-controlled, crossover study consisted of two phases. Forty-one nondepressed patients with neuropathic pain spent 6 weeks in each phase in random order and received identical tablets of 150 mg bupropion SR or placebo. Patients were instructed to take one tablet once daily for 1 week followed by one tablet twice daily for 5 weeks..While the patients took bupropion SR, neuropathic pain relief was improved or much improved in 30 (73%) patients, and one of these patients became pain-free. The mean average pain score at baseline was 5.7, which remained unchanged at the end of week 6 with placebo, but decreased by 1.7 points to 4.0 (p < 0.001) during therapy with bupropion SR. Pain relief with bupropion SR was significant at week 2 (p < 0.05) and continued throughout weeks 3 through 6 (p < 0.001). A significant decrease in interference of pain on quality of life was observed while patients were receiving bupropion SR compared with placebo. Side effects experienced with bupropion SR were not dose-limiting and consisted primarily of dry mouth, insomnia, headache, gastrointestinal upset, tremor, constipation, and dizziness..This placebo-controlled crossover trial showed that bupropion SR (150-300 mg daily) was effective and well tolerated for the treatment of neuropathic pain.
- Sherman, S. J., & Semenchuk, M. R. (2000). Effectiveness of tizanidine in neuropathic pain: an open-label study.. The journal of pain : official journal of the American Pain Society, 1(4), 285-92. doi:10.1054/jpai.2000.9435More infoThe purpose of this research trial is to assess the effectiveness and tolerability of tizanidine in neuropathic pain. In an open-label study, patients with neuropathic pain received 1 to 4 mg of tizanidine once daily for 7 days, followed by weekly dose escalation of 2 to 8 mg to his/her effective or maximum tolerated dose or a maximum of 36 mg over an 8-week period. Treatment effects were assessed, using average weekly pain scores as well as biweekly scores for patient global assessment of pain relief, the neuropathic pain scale, and wisconsin brief pain inventory. Frequency and severity of adverse events were examined also. Twenty-three patients were enrolled. The mean average weekly pain score at baseline was 6.9, which decreased by 1.7 points at the end of week 8 to 5.2 (p < or =.01). A total of 15 patients (68%) reported that their pain relief was improved or much improved with tizanidine therapy, and 2 of these patients became completely pain-free. The following neuropathic pain qualities were significantly lower at week 8 compared with baseline: intense, sharp, hot, dull, cold, sensitive, unpleasant, and deep pain. There was a significant decline in pain quantity and interference of pain on quality of life from baseline to week 8. The mean effective or maximum tolerated dose was 23 mg/day (range 6 to 36 mg/day). Side effects consisted primarily of dizziness/lightheadedness (52%), drowsiness (48%), fatigue/weakness (43%), dry mouth (39%), gastrointestinal upset (30%), and sleep difficulty (22%). One patient developed significant elevation in liver function tests (LFTS) With symptoms at week 4. Tizanidine therapy was discontinued. LFTS returned to normal in 3 weeks. Tizanidine might be an effective treatment for neuropathic pain, offering an alternative for patients poorly responsive to other medications. A larger, randomized placebo-controlled trial is recommended. In addition, comparative studies with alternative agents should be sought.
- Sherman, S. J., Boyer, L. V., Sibley, W. A., Sherman, S. J., & Boyer, L. V. (1994). Cerebral infarction immediately after ingestion of hydrogen peroxide solution.. Stroke, 25(5), 1065-7. doi:10.1161/01.str.25.5.1065More infoWe report the clinical and neuroimaging findings of a patient who sustained multiple cerebral infarcts after the ingestion of concentrated hydrogen peroxide solution sold as a "health food" product..An 84-year-old man sustained focal neurological deficits immediately after ingesting 30 mL of 35% hydrogen peroxide solution. Physical examination disclosed a left hemiparesis, frontal release signs, and cerebellar dysfunctions. Magnetic resonance imaging revealed multiple cerebral and cerebellar infarctions in the anterior, middle, and posterior vascular territories..The likely mechanism of pathogenesis involves cerebral oxygen gas embolization. The use of hyperbaric therapy should be considered in treating hydrogen peroxide poisoning.
- Sherman, S. J., Chrivia, J. C., & Catterall, W. A. (1985). Cyclic adenosine 3':5'-monophosphate and cytosolic calcium exert opposing effects on biosynthesis of tetrodotoxin-sensitive sodium channels in rat muscle cells. The Journal of Neuroscience, 5(6), 1570-1576. doi:10.1523/jneurosci.05-06-01570.1985More infoWe have previously presented evidence that electrical activity and increased cytosolic calcium reduce the density of sarcolemmal tetrodotoxin (TTX)-sensitive sodium channels in cultured rat muscle cells (Sherman, S. J., and W. A. Catterall (1984) Proc. Natl. Acad. Sci. U. S. A. 81: 262-266). We show here that growth of cells in ryanodine has a biphasic effect on sodium channel number. At low concentrations (0.3 to 10 microM) where this drug releases calcium from the sarcoplasmic reticulum into the cytoplasm, sodium channel number is reduced 62%; whereas, at higher concentrations where total cellular calcium is depleted, the density of sodium channels is increased 40% above control. These results provide further evidence for modulation of sodium channel number by cytosolic calcium. Growth of muscle cells in the presence of agents that mimic cyclic AMP (cAMP) action or increase intracellular cAMP levels including 8-bromo-cyclic AMP (8-BrcAMP), cyclic nucleotide phosphodiesterase inhibitors, and forskolin increased sodium channel density up to 125%. This action did not involve changes in spontaneous electrical activity. Dibutyryl cGMP had no effect. Measurement of the turnover rate of sodium channels after block of channel accumulation by tunicamycin (1.5 micrograms/ml) gave a half-time of 18 hr for exponential decay of TTX-sensitive sodium channels in cultured rat muscle cells after an initial 6-hr lag period. Treatments which modulate sodium channel number through changes in cytosolic calcium or cAMP had no effect on the rate of channel turnover. The increase of sodium channel number after inhibiton of electrical activity or treatment with 8-BrcAMP was half-maximal at 17 hr, consistent with an increase in the rate of sodium channel biosynthesis and/or incorporation into the sarcolemma without a change in channel turnover time. We conclude that cytosolic calcium decreases and cAMP increases sodium channel number by modulating the rate of biosynthesis and/or processing of channel components. The biochemical mechanisms of these regulatory effects are considered.
- Sherman, S. J., Gonoi, T., & Catterall, W. A. (1985). Voltage clamp analysis of tetrodotoxin-sensitive and -insensitive sodium channels in rat muscle cells developing in vitro.. The Journal of Neuroscience, 5(9), 2559-2564. doi:10.1523/jneurosci.05-09-02559.1985More infoSodium currents in cultured rat muscle cells converted to myoballs by treatment with colchicine were recorded using a giga-ohm seal voltage clamp procedure in the whole cell configuration. The mean peak Na+ conductance of the myoballs was 90 pS/microns2 of surface membrane. Half-maximal activation of Na+ currents was observed for test pulses to -31 mV and half-maximal inactivation was observed for prepulses to -74 mV. Titration of the inhibition of Na+ currents by tetrodotoxin (TTX) yielded a biphasic inhibition curve consistent with the presence of two classes of Na+ channels differing in affinity for TTX. The TTX-sensitive channels carried 28% of the Na+ current and had an apparent KD for TTX of 13 nM at 20 degrees C. The TTX-insensitive Na+ channels had an apparent KD for TTX of 3.2 microns. Inhibition of TTX-insensitive Na+ channels by TTX was enhanced by repetitive stimulation of the myoballs at 2 Hz, whereas the inhibition of TTX-sensitive Na+ channels by TTX was not frequency dependent. We conclude that rat muscle cells developing in vitro synthesize physiologically functional, TTX-sensitive Na+ channels in the absence of innervation. These channels, which are characteristic of adult skeletal muscle, function in parallel with TTX-insensitive Na+ channels that are present in embryonic muscle.
- Sherman, S. J., & Catterall, W. A. (1984). Electrical activity and cytosolic calcium regulate levels of tetrodotoxin-sensitive sodium channels in cultured rat muscle cells.. Proceedings of the National Academy of Sciences of the United States of America, 81(1), 262-6. doi:10.1073/pnas.81.1.262More infoPharmacological blockade of the spontaneous electrical activity present in primary cultures of rat myotubes by growth in bupivacaine, tetrodotoxin, or KCl was found to increase the number of voltage-sensitive Na+ channels 38-83% as measured by the specific binding of [3H]saxitoxin. The inhibition of spontaneous electrical activity and increase in channel density by bupivacaine displayed an identical dose response, with a half-maximal effect at 3.0 microM. Growth of myotubes in the presence of 1 microM A23187, a Ca2+-specific ionophore, resulted in a 30-60% decrease in the number of tetrodotoxin-sensitive channels with no change in affinity for [3H]saxitoxin. A23187 was able to overcome the increase in channel density produced by bupivacaine. These results suggest the presence of a Ca2+-mediated negative feedback system in which electrical excitability may be regulated by altering the number of tetrodotoxin-sensitive Na+ channels.
- Sherman, S. J., Messner, D. J., Lawrence, J. C., Jacoby, K., & Catterall, W. A. (1983). Tetrodotoxin-sensitive sodium channels in rat muscle cells developing in vitro.. Journal of Biological Chemistry, 258(4), 2488-2495. doi:10.1016/s0021-9258(18)32952-1
- Sherman, S. J., & Catterall, W. A. (1982). Biphasic regulation of development of the high-affinity saxitoxin receptor by innervation in rat skeletal muscle.. The Journal of general physiology, 80(5), 753-68. doi:10.1085/jgp.80.5.753More infoSpecific binding of 3H-saxitoxin (STX) was used to quantitate the density of voltage-sensitive sodium channels in developing rat skeletal muscle. In adult triceps surae, a single class of sites with a KD = 2.9 nM and a density of 21 fmol/mg wet wt was detected. The density of these high-affinity sites increased from 2.0 fmol/mg wet wt to the adult value in linear fashion during days 2-25 after birth. Denervation of the triceps surae at day 11 or 17 reduced final saxitoxin receptor site density to 10.4 or 9.2 fmol/mg wet wt, respectively, without changing KD. Denervation of the triceps surae at day 5 did not alter the subsequent development of saxitoxin receptor sites during days 5-9 and accelerated the increase of saxitoxin receptor sites during days 9-13. After day 13, saxitoxin receptor development abruptly ceased and the density of saxitoxin receptor sites declined to 11 fmol/wg wet wt. These results show that the regulation of high-affinity saxitoxin receptor site density by innervation is biphasic. During the first phase, which is independent of continuing innervation, the saxitoxin receptor density increases to 47-57% of the adult level. After day 11, the second phase of development, which is dependent on continuing innervation, gives rise to the adult density of saxitoxin receptors.
- Bartlett, M. J., Cristiani, S., Smidt, S. I., Farrell, D. C., Doyle, K., Heien, M. L., Sherman, S. J., & Falk, T. (2018, Fall). VEGF-B overexpression in PINK1 gene knock out rats improves motor function: Is this effect due to neuroprotection or to functional improvement of dopaminergic neurons?. Society for Neuroscience Meeting.
- Falk, T., Sherman, S. J., Heien, M. L., Doyle, K., Farrell, D. C., Smidt, S. I., Cristiani, S., & Bartlett, M. J. (2018, Fall). VEGF-B overexpression in PINK1 gene knock out rats improves motor function: Is this effect due to neuroprotection or to functional improvement of dopaminergic neurons?. Society for Neuroscience.
- Bartlett, M. J., Silashki, B. D., Muller, D. C., Tran, C. T., Sherman, S. J., & Falk, T. (2016, Fall). AAV-mediated over-expression of VEGF-B in PINK1 gene knockout rats: A behavioral evaluation.. Society for Neuroscience Abstracts.
- Bartlett, M., Bartlett, M., Caballero, B., Caballero, B., Zhang, S., Zhang, S., Mount, D., Mount, D., Sherman, S. J., Sherman, S. J., Falk, T., & Falk, T. (2015, spring). Neuroprotection of VEGF-B against mitochondrial toxins in culture and in vivo models of Parkinson’s disease: Mechanistic insights.. Blankenese Conference; Brain Repair: From Regeneration to Cellular Reprogramming. Hamburg, Germany.
- Bartlett, M., LePoidevin, L., Joseph, R., Parent, K., Laude, N., Lazarus, L., Heien, M., Estevez, M., Sherman, S. J., & Falk, T. (2015, fall). Long-term effect of sub-anesthetic ketamine-infusion in reducing L-DOPA-induced dyskinesia. Society for Neuroscience Abstracts.
- Sherman, S. J., Magill, A., Bartlett, M., Heien, M., Estevez, M., & Falk, T. (2015, spring). Case reports showing a long-term effect of sub-anaesthetic ketamine infusion in reducing L-DOPA-induced dyskinesias. American Neurologial Association Meeting AbstractsAmerican Neurological Association.
- Ye, T., Bartlett, M., Wiegand, J., Sherman, S. J., Falk, T., & Cowen, S. (2015, spring). Modulation of high-frequency oscillations and beta coherence in striato-cortico-limbic circuits following repeated sub-anesthetic ketamine exposure. Society for Neuroscience Abstracts.
- Bartlett, M. J., Stopera, C., Esqueda, A., Sherman, S. J., & Falk, T. (2021, Fall). Analysis of the role of opioid receptors in the anti-dyskinetic effects of sub-anesthetic ketamine.. Society for Neuroscience Meeting.
- Bernard, K., Falk, T., Bartlett, M. J., Heien, M. L., Liu, C., Polt, R. L., Molnar, G., Streicher, J. M., Apostol, C., Madhavan, L., Szabo, L., Sherman, S. J., Szabo, L., Sherman, S. J., Apostol, C., Madhavan, L., Molnar, G., Streicher, J. M., Liu, C., , Polt, R. L., et al. (2021, Spring). Evaluation of a neuroprotective PACAP glycopeptide as systemically delivered CNS active drug to treat motor and cognitive symptoms in two rodent models of Parkinson’s disease.. 15th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, AD/PD™.
- Cowen, S. L., Falk, T., Sherman, S. J., Jordan, G. A., Bartlett, M. J., & Vishwanath, A. (2021, January). Ketamine disrupts 80-Hz gamma oscillations in parkinsonian rats with L-DOPA-induced dyskinesia.. Society for Neuroscience Global Connectome Conference.
- Falk, T., Falk, T., Sherman, S. J., Sherman, S. J., Morrison, H. W., Morrison, H. W., Esqueda, A., Esqueda, A., Sexauer, M. R., Sexauer, M. R., Bernard, K., Bernard, K., Bartlett, M. J., Bartlett, M. J., Stopera, C., & Stopera, C. (2021, January). Behavioral analysis in the progressive unilateral 6-OHDA-lesion rat model indicate a neuroprotective effect of sub-anesthetic ketamine-treatment.. Society for Neuroscience Global Connectome Conference.
- Falk, T., Heien, M. L., Polt, R. L., Streicher, J. M., Madhavan, L., Sherman, S. J., Szabo, L., Apostol, C., Molnar, G., Liu, C., Bartlett, M. J., & Bernard, K. (2021, January). Evaluation of a neuroprotective PACAP glycopeptide as systemically delivered CNS active drug to treat Parkinson’s disease.. Society for Neuroscience Global Connectome Conference.
- Falk, T., Heien, M. L., Polt, R. L., Streicher, J. M., Madhavan, L., Sherman, S. J., Szabò, L., Apostol, C. R., Molnar, G., Liu, C., Bartlett, M. J., Morrison, H. W., Lujan, A., & Bernard, K. (2021, Fall). Evaluation of a systemically delivered PACAP glycopeptide as a neuroprotective agent in 2 rodent models of Parkinson’s Disease.. Society for Neuroscience Meeting.
- Sherman, S. J., Cowen, S. L., Heien, M. L., Liu, C., Ye, T., Stopera, C., Bartlett, M. J., & Falk, T. (2021, Spring). Update on preclinical and clinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia. 6th Annual ABRC-Flinn Research Conference. Phoenix, AZ.
- Stopera, C., Bartlett, M. J., Sexauer, M. R., Bernard, K., Stancati, J., Sherman, S. J., Steece-Collier, K., Morrison, H. W., & Falk, T. (2021, November). Analysis of neuroprotective and anti-inflammatory activity of sub-anesthetic ketamine-treatment in the progressive unilateral 6-OHDA-lesion rat model.. Society for Neuroscience Meeting.
- Sherman, S. J., Cowen, S. L., Heien, M. L., Farrell, D. C., Ye, T., Bartlett, M. J., & Falk, T. (2020, Spring). Preclinical and clinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.. 5th Annual ABRC-Flinn Research Conference, Phoenix, AZ.
- Sherman, S. J., Cowen, S. L., Steece-Collier, K., Heien, M. L., Farrell, D. C., Ye, T., Bartlett, M. J., & Falk, T. (2020, Summer). Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia.. European Neuroscience Virtual Forum Abstracts, 2020..
- Bartlett, M. J., Cristiani, S., Silashki, B. D., Muller, D. C., Farrell, D. C., Parent, K. L., Doyle, K., Heien, M. L., Sherman, S. J., & Falk, T. (2018, Summer). AAV2/1-hVEGF-B overexpression improves motor outcomes in PINK1 gene knockout rat: An insight into potential mechanisms.. 2nd Pan American Parkinson's Disease and Movement Disorders Congress.
- Falk, T., Porreca, F., Sherman, S. J., Heien, M. L., Siegenthaler, J., Sexauer, M. R., Bartlett, M. J., Flores, A. J., & Nava, R. (2018, Fall). The kappa opioid receptor antagonist nor-BNI accelerates development of L-DOPA-induced dyskinesia in a model of mild Parkinson’s disease. Society for Neuroscience.
- Falk, T., Sherman, S. J., Steece-Collier, K., Doyle, K., Dollish, H. K., Flores, A. J., & Bartlett, M. J. (2018, Summer). Sub-anesthetic ketamine prevents levodopa-induced dyskinesia and improves motor function in a 6-OHDA rat model of Parkinson’s disease. 2nd Pan American Parkinson's Disease and Movement Disorders Congress.
- Sherman, S. J., Steece-Collier, K., Heien, M. L., Doyle, K., Stancati, J. A., Dollish, H. K., Flores, A. J., Bartlett, M. J., & Falk, T. (2018, Fall). Neuroplastic effects in the striatum contribute to the suppression of L-DOPA-induced dyskinesia by sub-anesthetic ketamine. Society for Neuroscience.
- Bartlett, M. J., Flores, A. J., Ye, T., Dollish, H. K., Doyle, K., Cowen, S. L., Sherman, S. J., & Falk, T. (2017, Summer). Mechanisms of sub-anesthetic ketamine infusions to reduce levodopa-induced dyskinesia: effects on striatal mTOR signaling and beta band oscillations in striatum and motor cortex.. International Parkinson and Movement Disorders Society Abstracts.
- Falk, T., Falk, T., Sherman, S. J., Sherman, S. J., Cowen, S. L., Cowen, S. L., Doyle, K., Doyle, K., Dollish, H. K., Dollish, H. K., Ye, T., Ye, T., Flores, A. J., Flores, A. J., Bartlett, M. J., Bartlett, M. J., Falk, T., Sherman, S. J., Cowen, S. L., , Doyle, K., et al. (2017, Summer). Mechanisms of sub-anesthetic ketamine infusions to reduce levodopa-induced dyskinesia: effects on striatal mTOR signaling and beta band oscillations in striatum and motor cortex.. International Parkinson and Movement Disorders Society Abstracts.
- Falk, T., Sherman, S. J., Doyle, K., Dollish, H. K., Bartlett, M. J., Flores, A. J., Falk, T., Sherman, S. J., Doyle, K., Dollish, H. K., Bartlett, M. J., & Flores, A. J. (2017, November). Role of BDNF and mTOR pathways in the suppression of L-DOPA-induced dyskineasis by sub-anesthetic ketamine.. Society for Neuroscience Abstracts.
- Falk, T., Sherman, S. J., Heien, M. L., Doyle, K., Farrell, D. C., Parent, K. L., Silashki, B. D., Muller, D. C., Bartlett, M. J., Falk, T., Sherman, S. J., Heien, M. L., Doyle, K., Farrell, D. C., Parent, K. L., Silashki, B. D., Muller, D. C., & Bartlett, M. J. (2017, November). AAV2/1 VEGF-B overexpression improves motor function and prevents dopamine loss in PINK1 gene knock out rats.. Society for Neuroscience Abstracts.
- Falk, T., Sherman, S. J., Morrison, H. W., Pottinger, A., Doyle, K., Dollish, H. K., Flores, A. J., Bartlett, M. J., Falk, T., Sherman, S. J., Morrison, H. W., Pottinger, A., Doyle, K., Dollish, H. K., Flores, A. J., Bartlett, M. J., Falk, T., Sherman, S. J., Morrison, H. W., , Pottinger, A., et al. (2017, December). Neuroplastic effects contribute to the suppression of L-DOPA-induced dyskineasis by sub-anesthetic ketamine. Neurobiology, Aging, Dementias and Movement Disorders Division Meeting. Scottsdale, Arizona: Arizona Wellbeing Commons Division.
- Sherman, S. J., Goldstone, L. W., Alrabiah, Z., Bhattacharjee, S., Sherman, S. J., Goldstone, L. W., Alrabiah, Z., & Bhattacharjee, S. (2017, May). Patterns And Predictors of Depression Treatment among Older Adults with Parkinson’s Disease and Depression in Ambulatory Care Settings in the United States. ISPOR 22nd Annual International Meeting. Boston, MA, USA.
- Sherman, S. J., Heien, M. L., Parent, K. L., Farrell, D. C., Silashki, B. D., Muller, D. C., Bartlett, M. J., & Falk, T. (2017, Summer). AAV-mediated over-expression of VEGF-B in PINK1 gene knockout rats increases striatal dopamine content.. International Parkinson and Movement Disorders Society Abstracts.
- Bartlett, M. J., Flores, A. J., Zehri, A., Sherman, S. J., & Falk, T. (2016, Fall). Low-Dose Sub-Anesthetic Ketamine Infusions Reduce the Development of L-DOPA-Induced Dyskinesias in a Preclinical Model.. 4th World Parkinson Congress Abstracts.
- Flores, A. J., Bartlett, M. J., Zehri, A. H., Parent, K. L., Heien, M. L., Sherman, S. J., & Falk, T. (2016, Fall). Development of L-DOPA-induced dyskinesias is reduced in a rat model after sub-anesthetic ketamine infusions.. Society for Neuroscience Abstracts.
- Ye, T., Bartlett, M. J., Schmit, M. B., Sherman, S. J., Falk, T., & Cowen, S. L. (2016, Fall). Alterations of oscillatory activity in the striatal-cortical circuit following repeated sub-anesthetic ketamine administration in 6-OHDA-lesioned rats.. Society for Neuroscience Abstracts.
- Ye, T., Bartlett, M. J., Schmit, M., Sherman, S. J., Falk, T., & Cowen, S. L. (2016, Fall). Gamma-band oscillatory activity in the motor cortex is progressively enhanced following repeated ketamine administration in 6-OHDA-lesioned rats.. 4th World Parkinson Congress Abstracts.
- Falk, T., Sherman, S. J., Caballero, B., Falk, T., Sherman, S. J., & Caballero, B. (2017. Insights into mechanism of the protective effects of VEGF-B in dopaminergic neurons.(pp Article ID 4263795, 13 pages).