Person: Schmahmann, Jeremy
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Schmahmann
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Jeremy
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Schmahmann, Jeremy
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Publication as-PSOCT: Volumetric microscopic imaging of human brain architecture and connectivity(Elsevier BV, 2018-01) Wang, Hui; Magnain, Caroline; Wang, Ruopeng; Dubb, Jay; Varjabedian, Ani; Tirrell, Lee; Stevens, Allison; Augustinack, Jean; Konukoglu, Ender; Aganj, Iman; Frosch, Matthew; Schmahmann, Jeremy; Fischl, Bruce; Boas, DavidPolarization sensitive optical coherence tomography (PSOCT) with serial sectioning has enabled the investigation of 3D structures in mouse and human brain tissue samples. By using intrinsic optical properties of back-scattering and birefringence, PSOCT reliably images cytoarchitecture, myeloarchitecture and fiber orientations. In this study, we developed a fully automatic serial sectioning polarization sensitive optical coherence tomography (as-PSOCT) system to enable volumetric reconstruction of human brain samples with unprecedented sample size and resolution. The 3.5μm in-plane resolution and 50μm through-plane voxel size allow inspection of cortical layers that are a single-cell in width, as well as small crossing fibers. We show the abilities of as- PSOCT in quantifying layer thicknesses of the cerebellar cortex and creating microscopic tractography of intricate fiber networks in the subcortical nuclei and internal capsule regions, all based on volumetric reconstructions. as-PSOCT provides a viable tool for studying quantitative cytoarchitecture and myeloarchitecture and mapping connectivity with microscopic resolution in the human brain.Publication Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias(Columbia University Libraries/Information Services, 2017) Gan, Shi-Rui; Wang, Jie; Figueroa, Karla P.; Pulst, Stefan M.; Tomishon, Darya; Lee, Danielle; Perlman, Susan; Wilmot, George; Gomez, Christopher M.; Schmahmann, Jeremy; Paulson, Henry; Shakkottai, Vikram G.; Ying, Sarah H.; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael D.; Xia, Guangbin; Subramony, S. H.; Ashizawa, Tetsuo; Kuo, Sheng-HanBackground: Postural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known. Methods: We studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012. Results: Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = –0.91, p < 0.001; SCA6, β = –1.28, p = 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (β = 1.54, p = 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (β = –1.53, p = 0.037) and ATXN3 (β = 0.57, p = 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (β = 0.63, p = 0.041) and PPP2R2B (β = –0.40, p = 0.032). Discussion Postural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor.Publication Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency(BioMed Central, 2014) Lieber, Daniel S; Hershman, Steven G; Slate, Nancy G; Calvo, Sarah; Sims, Katherine Bustin; Schmahmann, Jeremy; Mootha, VamsiBackground: D-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia. Case presentation: An adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10–13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation. Conclusion: Our case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.Publication Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study(BioMed Central, 2013) Ashizawa, Tetsuo; Figueroa, Karla P; Perlman, Susan L; Gomez, Christopher M; Wilmot, George R; Schmahmann, Jeremy; Ying, Sarah H; Zesiewicz, Theresa A; Paulson, Henry L; Shakkottai, Vikram G; Bushara, Khalaf O; Kuo, Sheng-Han; Geschwind, Michael D; Xia, Guangbin; Mazzoni, Pietro; Krischer, Jeffrey P; Cuthbertson, David; Holbert, Amy Roberts; Ferguson, John H; Pulst, Stefan M; Subramony, SHBackground: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods: To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results: We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions: The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.Publication Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias(Columbia University Libraries/Information Services, 2015) Lo, Raymond Y.; Figueroa, Karla P.; Pulst, Stefan M.; Lin, Chi-Ying; Perlman, Susan; Wilmot, George; Gomez, Christopher M.; Schmahmann, Jeremy; Paulson, Henry; Shakkottai, Vikram G.; Ying, Sarah H.; Zesiewicz, Theresa; Bushara, Khalaf; Geschwind, Michael; Xia, Guangbin; Subramony, S. H.; Ashizawa, Tetsuo; Kuo, Sheng-HanBackground: The contributions of vascular risk factors to spinocerebellar ataxia (SCA) are not known. Methods: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA) for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account. Results: Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Discussion Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.Publication Consensus Paper: The Role of the Cerebellum in Perceptual Processes(Springer US, 2014) Baumann, Oliver; Borra, Ronald J.; Bower, James M.; Cullen, Kathleen E.; Habas, Christophe; Ivry, Richard B.; Leggio, Maria; Mattingley, Jason B.; Molinari, Marco; Moulton, Eric; Paulin, Michael G.; Pavlova, Marina A.; Schmahmann, Jeremy; Sokolov, Arseny A.Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.Publication Hypertrophic Pachymeningitis and Cerebral Venous Sinus Thrombosis in Inflammatory Bowel Disease(Elsevier BV, 2010-11) Xia, Zongqi; Chen-Plotkin, Alice; Schmahmann, JeremyHypertrophic pachymeningitis is rarely observed in inflammatory bowel disease. We report a woman with ulcerative colitis whose biopsy-confirmed hypertrophic pachymeningitis was complicated by cerebral venous sinus thrombosis and intracranial hypertension and required ventriculostomy and steroid therapy. This report highlights the challenge facing the diagnosis and management of hypertrophic pachymeningitis from an unusual primary cause.Publication Delayed Posthypoxic Leukoencephalopathy: Improvement with Antioxidant Therapy(S. Karger AG, 2015) King, Franklin; Morris, Nicholas A.; Schmahmann, JeremyIntroduction: Delayed posthypoxic leukoencephalopathy (DPHL) may result from a variety of hypoxic insults, including respiratory depression from an opiate overdose. The underlying pathophysiological mechanism of DPHL remains uncertain. We describe a patient with a typical case of DPHL who responded clinically to antioxidant treatment. Methods: Clinical, serological, and radiographic investigations were undertaken in the evaluation of the patient. Results: A 63-year-old man developed altered mental status 10 days following recovery from an opiate overdose and aspiration pneumonia that required intubation. The clinical course and brain imaging were consistent with DPHL. Initiation of antioxidant therapy with vitamin E, vitamin C, B-complex vitamins, and coenzyme Q10 coincided with the prompt reversal of clinical deterioration. Conclusions: The potential therapeutic effect of antioxidants on DPHL needs to be explored in future cases. If this relationship indeed holds true, it would be consistent with the hypothesis that formation of reactive oxygen species during reperfusion plays a role in the pathophysiology of this disorder.Publication Enhancing the Temporal Complexity of Distributed Brain Networks with Patterned Cerebellar Stimulation(Nature Publishing Group, 2016) Farzan, Faranak; Pascual-Leone, Alvaro; Schmahmann, Jeremy; Halko, MarkGrowing evidence suggests that sensory, motor, cognitive and affective processes map onto specific, distributed neural networks. Cerebellar subregions are part of these networks, but how the cerebellum is involved in this wide range of brain functions remains poorly understood. It is postulated that the cerebellum contributes a basic role in brain functions, helping to shape the complexity of brain temporal dynamics. We therefore hypothesized that stimulating cerebellar nodes integrated in different networks should have the same impact on the temporal complexity of cortical signals. In healthy humans, we applied intermittent theta burst stimulation (iTBS) to the vermis lobule VII or right lateral cerebellar Crus I/II, subregions that prominently couple to the dorsal-attention/fronto-parietal and default-mode networks, respectively. Cerebellar iTBS increased the complexity of brain signals across multiple time scales in a network-specific manner identified through electroencephalography (EEG). We also demonstrated a region-specific shift in power of cortical oscillations towards higher frequencies consistent with the natural frequencies of targeted cortical areas. Our findings provide a novel mechanism and evidence by which the cerebellum contributes to multiple brain functions: specific cerebellar subregions control the temporal dynamics of the networks they are engaged in.Publication Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination(New England Journal of Medicine (NEJM/MMS), 2013) Margolin, David H.; Kousi, Maria; Chan, Yee-Ming; Lim, Elaine T.; Schmahmann, Jeremy; Hadjivassiliou, Marios; Hall, Janet E.; Adam, Ibrahim; Dwyer, Andrew; Plummer, Lacey; Aldrin, Stephanie V.; O, Julia; Kirby, Andrew; Lage, Kasper; Milunsky, Aubrey; Milunsky, Jeff M.; Chan, Jennifer; Hedley-Whyte, E.; Daly, Mark; Katsanis, Nicholas; Seminara, StephanieIn recent years, we have seen great advances in the elucidation of genetic causes of cerebellar ataxia, with newly identified genes regulating a wide spectrum of cellular functions, including intracellular signaling, tau regulation, and mitochondrial function.1 However, a genetic defect cannot be found in approximately 40% of patients with ataxia,1 including those in whom ataxia is associated with reproductive endocrine failure, a syndrome first reported by Gordon Holmes in 1908.2 Most patients with this syndrome have a hypogonadotropic condition, with defective secretion of gonadotropins by the pituitary gland.3-12 Strikingly, genes associated with ataxia have little functional overlap with genes associated with hypogonadotropic hypogonadism, which encode proteins involved in the biologic function of the neurons that secrete gonadotropin-releasing hormone (GnRH).13 A decade ago, we described a consanguineous family with a syndrome of cerebellar ataxia, dementia, and hypogonadotropic hypogonadism.12 Here we report the results of whole-exome and targeted sequencing performed to identify mutations that underlie the syndrome in this kindred and in unrelated patients.