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Frank Middleton, PhD

3711 Institute For Human Performance (IHP)
505 Irving Avenue
Syracuse, NY 13210
Frank Middleton's email address generated as an image





Biochemistry and Molecular Biology
Biomedical Sciences Program
Medical Genetics Research Center
Neuroscience and Physiology
Neuroscience Program
Physiology Program


  • Genetic, epigenetic, and neuroanatomical basis of neurological and psychiatric disorders
  • Basal ganglia and cerebellar circuitry in normal and disease states
  • Neural-immune and gut-brain interactions
  • Machine learning approaches for biomarker discovery
  • Next generation sequencing for multiomic data analysis (genome, transcriptome, microbiome, methylome) 


Research in the Middleton lab focuses on defining substrates of normal and abnormal motor and cognitive function. This is accomplished by performing high-throughput genetic, epigenetic, and functional genomic studies involving human subjects or animal and cellular models of various neuropsychiatric, neurodegenerative, and addictive disorders. The specific disorders of most interest include autism, schizophrenia, ADHD, Parkinson's disease, alcohol abuse, and traumatic brain injury. In addition to the use of similar analytical methods to study these conditions, another common underlying theme is the attempt to define their relationship to neural-immune responses. Thus, the neural-immune axis forms a major lab interest as well, and this has been pursued through several collaborative efforts in studies of central and peripheral inflammatory and immune system alterations in these and other conditions, such as lupus, multiple sclerosis, and Zika virus infection. While in the past, it might have been nearly impossible for one lab to simultaneously pursue research on so many different topics, with the advent of modern bioinformatic tools and systems biological methods, these integrated approaches are now seen as highly valuable. Indeed, comparisons across disorders can help define the specificity of the changes that are seen and may lead to the identification of novel biomarkers or therapeutic agents. As examples, recent publications from the lab describe several novel discoveries of DNA mutations causally linked to schizophrenia, or microRNA biomarkers in peripheral blood or saliva that are strongly associated with alcohol abuse or autism spectrum disorder. Students and postdoctoral fellows who are interested in the research performed in the lab will likely become well-versed in next generation sequencing, comparative anatomical analysis, and statistical data mining.


Selected Publications

Hicks SD, Jacob P, Middleton FA, Perez O, Gagnon Z. Distance running alters peripheral microRNAs implicated in metabolism, fluid balance, and myosin regulation in a sex-specific manner. Physiol Genomics. 2018 Jun 8. doi: 10.1152/physiolgenomics.00035.2018. [Epub ahead of print]PMID:29883262

Fernandes S, Srivastava N, Sudan R, Middleton FA, Shergill AK, Ryan JC, Kerr WG. SHIP1 Deficiency in Inflammatory Bowel Disease Is Associated With Severe Crohn's Disease and Peripheral T Cell Reduction. Front Immunol. 2018 May 22;9:1100. doi: 10.3389/fimmu.2018.01100. eCollection 2018.PMID:29872435

Hausmann L, Schweitzer B, Middleton FA, Schulz JB. Reviewer selection biases editorial decisions on manuscripts. J Neurochem. 2018 Jan 27. doi: 10.1111/jnc.14314. [Epub ahead of print] PMID:29377133

Afshari P, Yao WD, Middleton FA. Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia. PLoS One. 2017 Sep 8;12(9):e0183854. doi: 10.1371/journal.pone.0183854. eCollection 2017.PMID:28886095

Safi S, Rahimi A, Raeesi A, Safi H, Aghazadeh Amiri M, Malek M, Yaseri M, Haeri M, Middleton FA, Solessio E, Ahmadieh H. Contrast sensitivity to spatial gratings in moderate and dim light conditions in patients with diabetes in the absence of diabetic retinopathy. BMJ Open Diabetes Res Care. 2017 Aug 8;5(1):e000408. doi: 10.1136/bmjdrc-2017-000408. eCollection 2017.PMID:28878937

Somasundaram R, Fernandes S, Deuring JJ, de Haar C, Kuipers EJ, Vogelaar L, Middleton FA, van der Woude CJ, Peppelenbosch MP, Kerr WG, Fuhler GM. Analysis of SHIP1 expression and activity in Crohn's disease patients. PLoS One. 2017 Aug 2;12(8):e0182308. doi: 10.1371/journal.pone.0182308. eCollection 2017. PMID:28767696

Camargo Moreno M, Mooney SM, Middleton FA. Heterogeneity of p53 dependent genomic responses following ethanol exposure in a developmental mouse model of fetal alcohol spectrum disorder. PLoS One. 2017 Jul 19;12(7):e0180873. doi: 10.1371/journal.pone.0180873. eCollection 2017.PMID:28723918

Lammert DB, Middleton FA, Pan J, Olson EC, Howell BW. The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression. J Neurochem. 2017 Jul;142(1):89-102. doi: 10.1111/jnc.14045. Epub 2017 May 18.PMID:28419454

Bodea CA, Middleton FA, Melhem NM, Klei L, Song Y, Tiobech J, Marumoto P, Yano V, Faraone SV, Roeder K, Myles-Worsley M, Devlin B, Byerley W. Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31.Mol Neuropsychiatry. 2017 Feb;2(4):173-184. doi: 10.1159/000450726. Epub 2016 Oct 12. PMID:28277564

Thompson CA, Karelis J, Middleton FA, Gentile K, Coman IL, Radoeva PD, Mehta R, Fremont WP, Antshel KM, Faraone SV, Kates WR. Associations between neurodevelopmental genes, neuroanatomy, and ultra high risk symptoms of psychosis in 22q11.2 deletion syndrome. Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):295-314. doi: 10.1002/ajmg.b.32515. Epub 2017 Jan 31.PMID:28139055

Cohen OS, Weickert TW, Hess JL, Paish LM, McCoy SY, Rothmond DA, Galletly C, Liu D, Weinberg DD, Huang XF, Xu Q, Shen Y, Zhang D, Yue W, Yan J, Wang L, Lu T, He L, Shi Y, Xu M, Che R, Tang W, Chen CH, Chang WH, Hwu HG, Liu CM, Liu YL, Wen CC, Fann CS, Chang CC, Kanazawa T, Middleton FA, Duncan TM, Faraone SV, Weickert CS, Tsuang MT, Glatt SJ. A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. Mol Psychiatry. 2016 Jul;21(7):975-82. PubMed PMID: 26347318

Hicks SD, Ignacio C, Gentile K, Middleton FA. Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment. BMC Pediatr. 2016 Apr 22;16(1):52. PubMed PMID: 27105825

Ignacio C, Hicks SD, Burke P, Lewis L, Szombathyne-Meszaros Z, Middleton FA. Alterations in serum microRNA in humans with alcohol use disorders impact cell proliferation and cell death pathways and predict structural and functional changes in brain. BMC Neurosci. 2015 Sep 5;16:55. PubMed PMID: 26341662

Kates WR, Olszewski AK, Gnirke MH, Kikinis Z, Nelson J, Antshel KM, Fremont W, Radoeva PD, Middleton FA, Shenton ME, Coman IL. White matter microstructural abnormalities of the cingulum bundle in youths with 22q11.2 deletion syndrome: associations with medication, neuropsychological function, and prodromal symptoms of psychosis. Schizophr Res. 2015 Jan;161(1):76-84. PubMed PMID: 25066496

Afshari P, Myles-Worsley M, Cohen OS, Tiobech J, Faraone SV, Byerley W, Middleton FA. Characterization of a novel mutation in SLC1A1 associated with schizophrenia. Mol Neuropsychiatry. 2015;1(3):125-144. PubMed PMID: 26380821

Radoeva PD, Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA, Antshel KM, Fremont W, Shprintzen RJ, Morrow BE, Kates WR. Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes. Psychiatr Genet. 2014 Dec;24(6):269-72. PubMed PMID: 25325218

Melhem NM, Lu C, Dresbold C, Middleton FA, Klei L, Wood S, Faraone SV, Vinogradov S, Tiobech J, Yano V, Roeder K, Byerley W, Myles-Worsley M, Devlin B. Characterizing runs of homozygosity and their impact on risk for psychosis in a population isolate. Am J Med Genet B Neuropsychiatr Genet. 2014 Sep;165B(6):521-30. PubMed PMID: 24980794.

Zhang-James Y, Yang L, Middleton FA, Yang L, Patak J, Faraone SV. Autism-related behavioral phenotypes in an inbred rat substrain. Behav Brain Res. 2014 Aug 1;269:103-14. doi: 10.1016/j.bbr.2014.04.035. Epub 2014 Apr 26. PubMed PMID

Perlstein MD, Chohan MR, Coman IL, Antshel KM, Fremont WP, Gnirke MH, Kikinis Z, Middleton FA, Radoeva PD, Shenton ME, Kates WR. White matter abnormalities in 22q11.2 deletion syndrome: preliminary associations with the Nogo-66 receptor gene and symptoms of psychosis. Schizophr Res. 2014 Jan;152(1):117-23. PubMed PMID: 24321711

Ignacio C, Mooney SM, Middleton FA. Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment. Front Pediatr. 2014 Sep 24;2:103. PubMed PMID: 25309888

Myles-Worsley M, Tiobech J, Browning SR, Korn J, Goodman S, Gentile K, Melhem N, Byerley W, Faraone SV, Middleton FA. Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Am J Med Genet B Neuropsychiatr Genet. 2013 Mar;162B(2):87-95. PubMed PMID: 23341099

Hicks SD, Lewis L, Ritchie J, Burke P, Abdul-Malak Y, Adackapara N, Canfield K, Shwarts E, Gentile K, Meszaros ZS, Middleton FA. Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations. BMC Neurosci. 2012 Oct 25;13:128. PubMed PMID: 23095216


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