Jonathan W. Mink - US grants

The basal ganglia comprise several nuclei in the forebrain, diencephalon, and midbrain that are thought to play a significant role in the control of posture and movement. It is well known that human patients with certain degenerative diseases of the basal ganglia (e.g., Parkinson's, Wilson's, and Huntington's diseases) suffer from rigidly held abnormal body postures, slowing of movement, involuntary movements, or a combination of these abnormalities. However, it is not known exactly what features the basal ganglia contribute to normal movement, nor is it known how their dysfunction causes the associated movement abnormalities. There are several current models of basal ganglia function, but many of these lack specificity and no one mode is widely accepted. The proposed experiments will test the hypothesis that the basal ganglia act during voluntary movement to inhibit motor programs that would otherwise compete with the one which has been selected. The basal ganglia will be mapped carefully by injecting small amounts of the GABA agonist muscimol in awake, behaving monkeys to temporarily inactivate discrete areas of these nuclei. The hypothesis predicts that inactivation of the basal ganglia output will 'release' motor programs which would normally be suppressed during an intended movement. This will be assessed in four ways. First, monkeys will perform step-tracking wrist movements before and after inactivation. Movement velocity and amplitude, EMG of agonist, antagonist, and other muscles, and the presence or absence of adventitious movements will be measured before and after inactivation with muscimol. Second, torque pulse and torque step perturbations will be applied during maintained wrist position and prompt wrist movement. The perturbations will allow the measurement of resistance to stretch (tone) and the latency and magnitude of the monosynaptic and transcortical stretch reflexes. Third, unit activity will be recorded in downstream structures (e.g., motor cortex, supplementary motor cortex) during maintained posture and movement of the wrist before and after basal ganglia inactivation. Fourth, multijoint reaching will be evaluated with a two-dimensional video-based digital movement analysis system.

Chorea is a movement disorder that results from basal ganglia injury due to a variety of causes in children. Chorea is characterized by sudden, brief, involuntary muscle contractions causing movements that appear to flow from body part to body part in an unpredictable manner. Disorders associated with chorea include CNS infections, post-infectious and other autoimmune diseases, ischemia during cardiopulmonary bypass, 'extrapyramidal' cerebral palsy, a variety of toxic and acute metabolic processes, degenerative conditions, and inborn errors of metabolism. In many cases the cause is unknown. In diseases with well defined neuropathology, chorea has been associated with abnormalities in the striatum (caudate and putamen) and the subthalamic nucleus (STN). However, the fundamental pathophysiology of chorea is not known. This is due in part to the lack of non-primate models and in part to the difficulty of measuring involuntary movements in the primate models that do exist. Current medical treatment options for chorea are few, may have significant side effects, and are often ineffective. The proposed experiments will develop quantitative 3-dimensional kinematic measures of chorea and use them measure spatial and temporal properties of chorea in adults and children with different disorders. Focal pharmacologic manipulation of basal ganglia nuclei will be used in monkeys to produce chorea. The resulting chorea will be measured in the monkeys and compared to human chorea in order to validate the monkey models, especially with respect to childhood chorea. The monkey models will then be used to investigate the fundamental pathophysiology of chorea by recording the activity of individual globus pallidus internal segment neurons before and during chorea. Through a combination of neurophysiologic and kinematic techniques to study experimentally produced chorea, the prevailing hypotheses of chorea pathophysiology can be tested rigorously. There is strong potential to identify the fundamental mechanisms of chorea. Development of a non-invasive method to quantify chorea in children and in monkeys will be an important advance toward better characterization of the pathophysiology of involuntary movements and development of more effective medical therapies.

[unreadable] DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects nearly one million people and dystonia affects up to 500,000 people in North America. It is generally accepted that the motor manifestations of PD are due to degeneration of nigrostriatal dopamine neurons with resulting striatal dopamine depletion. The causes of dystonia are more numerous. Recent evidence has indicated that dystonia (involuntary muscle contractions that produce twisting postures) can also be associated with deficiencies in striatal dopamine neurotransmission. In monkeys, it has been shown that unilateral striatal dopamine depletion induced by intracarotid injection of MPTP causes a biphasic disorder with transient dystonia followed by stable parkinsonism. The association of both dystonia and parkinsonism with equivalent degrees of striatal dopamine deficiency raises questions about the fundamental pathophysiology of these conditions. The purpose of this project is to investigate the pathophysiology of parkinsonism and dystonia by recording the activity of globus pallidus neurons before and after the administration of MPTP in monkeys trained to perform a reaching task. Quantitative behavioral methods and PET imaging will be used to measure the severity of dystonia, parkinsonism, and dopamine depletion. The activity of single neurons in globus pallidus internal segment (GPi) and external segment (GPe) will be recording in monkeys before MPTP and in the transient dystonic phase and chronic parkinsonian phase after MPTP. The specific aims are: 1) to determine to determine the relationship of resting pallidal discharge rates, patterns, and synchronization to dystonia and parkinsonism; 2) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism; 3) to determine whether there is loss of somatotopic selectivity in the sensorimotor region of putamen and whether the loss of somatotopic selectivity in globus pallidus is due to abnormal signal processing in the putamen. These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will advance our understanding of the pathophysiology of parkinsonism and dystonia in ways not possible from studies in rodent models or in human subjects. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies. [unreadable] [unreadable] [unreadable]

The basal ganglia are important components of the motor system. Diseases of the basal ganglia cause impaired voluntary movement, abnormal involuntary movements, or both. It is generally agreed that the basal ganglia function in concert with cerebral cortical mechanisms in the control of many aspects of behavior. A large portion of the basal ganglia-thalmocortical circuitry is devoted to the control of movement. Despite substantial advances in understanding the contributions of these circuits to motor control, there is still no consensus as to how the basal ganglia output influences cortical motor areas. The proposed experiments will investigate the function of basal ganglia-thalamocortical circuits in the control of limb movement in primates. Selective inactivation of basal ganglia output neurons in globus pallidus, pars interna (GPi) will be combined with recording neuronal activity in cortical targets of that output while monkeys perform a wrist movement task. We have hypothesized that a key function of the basal ganglia in voluntary movement is to facilitate the desired motor pattern and to simultaneously inhibit potentially competing motor patterns so that they do not interfere with the one that has been selected. We will test this overall hypothesis in 2 specific aims. We will determine how movement-related neuronal signals in supplementary motor area (SMA) and primary motor cortex (MC) change after reversible inactivation of GPi and how those signal changes relate to the resulting motor impairment. We will also determine if GPi activity correlates with suppression of an "automatic" movement response and whether inactivation of GPi prevents suppression of that response and interferes with performance of a movement in the opposite direction from the "automatic" response. These experiments will directly test the effect on cortical motor physiology of inactivating the basal gangia output for limb movements. They will provide important new information on how the basal ganglia interact with motor areas of cerebral cortex. This results of this project will enhance understanding of normal basal ganglia function in motor control and will provide important clues to the pathophysiology of movement disorders resulting from basal ganglia diseases. Better understanding of these mechanisms will have potential significant impact on development of better therapies for those movement disorders.

DESCRIPTION (provided by applicant): The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited, autosomal recessive lysosomal storage diseases. Although the NCLs are relatively rare, the childhood variants represent the most common neurodegenerative disorders of childhood, affecting approximately 1:25,000 in the U.S. and with an incidence worldwide as high as 1:12,500. NCL variants are distinguished mainly by their different ages of onset and the rate at which symptoms progress. Juvenile NCL (JNCL), due to the CLN-3 mutation, is one of the more common forms of NCL. Symptom onset for JNCL is between ages 5 to 8, with slow progression until death in the 2nd or 3rd decade of life. The most common early symptoms of JNCL are vision loss, seizures dementia, behavioral difficulties, and impaired motor skills. As the disease progresses, the child becomes increasingly disabled and there is a substantial caregiver burden. There are few quantitative data on the natural history of JNCL. It is known that JNCL includes a broad range of neurological, neuropsychological, and behavioral/psychiatric symptoms. There is progressive loss of speech, language, motor skills, and self-care skills as the disease progresses. In some individuals, aggressive behavior, anxiety, hallucinations, obsessions, or personality changes are prominent. However, it is not known to what degree each type of symptoms contributes to the overall disability and caregiver burden. It is also not known to what degree the seizures and seizure control contributes to disability. Further, it is not known to what extent genotype influences phenotypic variability. We propose three specific aims to determine the natural history of JNCL quantitatively, to characterize the neuropsychological and behavioral phenotype of JNCL, to establish validity and reliability of a rating scale for JNCL, and to determine correlations between phenotype and genotype of individual JNCL subjects. Successful completion of this project will provide the necessary framework for moving forward with clinical trials in this devastating disease. Although JNCL is a rare disease, our research has implications that can be generalized to the study of other degenerative neurologic disorders in children and for preparing translational clinical trials in these diseases.

Project Summary/Abstract Tourette's syndrome (TS) is a childhood-onset tic disorders that is associated with a spectrum of co-occurring neuropsychiatric problems (particularly ADHD and OCD) and that has been found to be much more common than once thought. Taken together, the features of TS can be disabling and have significant impacts on individuals with the condition, their families and their communities. Systematic collection of accurate data regarding these impacts is a prerequisite for the development of interventions and for changes in health care policies and services aimed at reducing the negative consequences of TS. In keeping with the RFA, we propose to recruit 100 youth probands with TS (and their parents and siblings) and 100 matched healthy control youth (and their parents and siblings). The subjects will be administered a standardized battery of validated self-report, interview-based and teacher-report instruments in order to: 1) obtain demographic information, 2) define the tic disorder and its severity, 3) define the presence and severity of co-occurring neuropsychiatric conditions, 4) assess the impacts on individuals with TS (quality of life [QoL], and overall, school and social functioning), 5) assess the impacts on families (parent QoL, family functioning, socioeconomic, sibling QoL, and overall, school and social functioning), and 6) assess the impacts on the community (estimated costs of additional educational, social, health care and economic resources). The impacts of TS will be assessed by comparing TS and control subjects/families. These groups will also be compared to national survey data. In order to identify the best targets for intervention, we will use regression analysis to determine which demographic and clinical features and measured impacts most closely correlate with (predict) measured QoL in individuals with TS and their families (parents).

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited, autosomal recessive lysosomal storage diseases. Although the NCLs are relatively rare, the childhood variants represent the most common neurodegenerative disorders of childhood, affecting approximately 1:25,000 in the U.S. and with an incidence worldwide as high as 1:12,500. NCL variants are distinguished mainly by their different ages of onset and the rate at which symptoms progress. Juvenile NCL (JNCL), due to the CLN-3 mutation, is one of the more common forms of NCL. Symptom onset for JNCL is between ages 5 to 8, with slow progression until death in the 2nd or 3rd decade of life. The most common early symptoms of JNCL are vision loss, seizures dementia, behavioral difficulties, and impaired motor skills. As the disease progresses, the child becomes increasingly disabled and there is a substantial caregiver burden. There are few quantitative data on the natural history of JNCL. It is known that JNCL includes a broad range of neurological, neuropsychological, and behavioral/psychiatric symptoms. There is progressive loss of speech, language, motor skills, and self-care skills as the disease progresses. In some individuals, aggressive behavior, anxiety, hallucinations, obsessions, or personality changes are prominent. However, it is not known to what degree each type of symptoms contributes to the overall disability and caregiver burden. It is also not known to what degree the seizures and seizure control contributes to disability. Further, it is not known to what extent genotype influences phenotypic variability. We propose three specific aims to determine the natural history of JNCL quantitatively, to characterize the neuropsychological and behavioral phenotype of JNCL, to establish validity and reliability of a rating scale for JNCL, and to determine correlations between phenotype and genotype of individual JNCL subjects. Successful completion of this project will provide the necessary framework for moving forward with clinical trials in this devastating disease. Although JNCL is a rare disease, our research has implications that can be generalized to the study of other degenerative neurologic disorders in children and for preparing translational clinical trials in these diseases.

DESCRIPTION (provided by applicant): Project Summary: The University of Rochester Child Neurology Career Development Program will provide formal program- based career development support for promising junior faculty in child neurology. Our aims are: 1) to give junior faculty in this program the opportunity to transition from mentored trainees to independent investigators in clinical and/or basic neurobiology research;2) to foster thinking skills and a knowledge base that will allow supported candidates to apply basic neurobiological principles to achieve a mechanistic understanding of disease so they can translate them into therapeutic and diagnostic options for disorders of the developing nervous system;3) to foster the academic careers of these junior faculty by providing the guidance and framework necessary for the conduct of scientifically sound, ethical, and clinically relevant research in neurobiology with the mentoring necessary for long-term decision-making and career planning as future leaders in academic child neurology. These goals will be achieved during a 3-year program that provides the candidates with the necessary skills to formulate a research plan relevant to disease and design an implementation strategy under the guidance of faculty who have demonstrated research success and mentoring excellence. All supported candidates will participate in formal training in research ethics, career development, grant writing, and scientific communication. The goal is to provide the supported junior faculty members with the skills necessary to establish a research career in neurological science and to move toward independent funding as an investigator with the promise of vigorous professional growth. Support is sought for 3 positions, each for a three year period of support. Training facilities include: laboratories in the departments of Neurology, Pediatrics, Neurobiology &Anatomy, Physiology &Pharmacology, Brain &Cognitive Sciences, and the Center for Neural Development and Disease. The program will take full advantage of the resources and career development infrastructure of the UR Clinical and Translational Research Institute, including access to biostatistical, epidemiologic, and clinical research expertise and cutting-edge novel technologies developed in both academic and industry incubator settings. Public Health Relevance: It is increasingly difficult to attract, foster, and maintain a cadre of child neurologists whose interests are in the development of a translational body of knowledge and the dialogue between the laboratory bench and the clinic. This program will support the career development of talented individuals dedicated to academic research careers researchers at the interface between neurological sciences and child neurology.

The University of Rochester (UR) has a long and extraordinarily rich history of providing first-rate clinical services to persons with Intellectual and Developmental Disabilities (IDD), and in driving new discoveries through research that create increased opportunity for individuals with IDD to live their lives to the fullest of their potential. This proposed UR-IDDRC is founded upon a revolutionary philosophy of medicine, first introduced here at UR Medical Center by Profs. George Engel and Jon Romano in 1977: The Biopsychosocial Model. This simple, yet profound idea, that the person seeking treatment is not merely a product of their biology, but rather, is also an amalgam of their psychology and socio-economic circumstances, places the whole person in all their complexity at the center of medicine. If ever there was a population that deserves to be recognized and treated in this holistic humanistic manner, it is those with an IDD. This UR-IDDRC places persons with IDD at the center of our inclusive neurodiverse mission, and commits to providing excellence in our basic, translational and clinical research, with a singular focus on providing tractable clinical solutions for these individuals. In the pages of this program application, we describe the Center?s crucial scientific infrastructure, which supports four cutting-edge Cores that elevate and accelerate the work of our 105 UR-IDDRC investigators, providing the very latest available technologies and expertise with high efficiency and excellent cost-effectiveness. These Cores are: Human Phenotyping & Recruitment (HPR); Translational Neuroimaging & Neurophysiology (TNN); Cell & Molecular Imaging (CMI); and Animal Behavior and Neurophysiology (ABN). Through vigorous leadership and in close consultation with our UR-IDDRC community and the five key advisory committees that provide counsel to our Administrative Core (ADM), we articulate a set of five research foci that embrace key and established research strengths at our institution while also seeking to expand our program into important areas of concern to the larger IDD community. These are: (1) Rare and orphaned diseases of neurodevelopment; (2) Parental stress and early life exposure as determinants of brain development; (3) Neuroinflammatory mechanisms in pathological brain development; (4) Autism spectrum disorder; (5) Multisensory and sensorimotor integration. Some 202 ongoing IDD projects, and 9 associated training grants, are supported by this infrastructure, and the Center Leadership is committed to further growing this already thriving program by attracting and training new young investigators and clinicians in IDD research. Major efforts to disseminate the work of the Center through media outlets and culturally competent multilingual publications, oriented at our community, are in place. Outreach to our IDD community and the public at large is a central concern of the UR-IDDRC. Leveraging the enormous financial commitment of the University of Rochester?s leadership to developing the UR-IDDRC, and through a philanthropy-driven annual pilot grant fund of $400,000, UR-IDDRC leadership is strongly positioned to prosecute an innovative transformative IDD research agenda over the proposed five-year term of this program.