Dissociable Contributions of Precuneus and Cerebellum to Subjective and Objective Neuropathy in HIV

  • Natalie M. ZahrEmail author
  • Kilian M. Pohl
  • Adolf Pfefferbaum
  • Edith V. Sullivan


Neuropathy, typically diagnosed by the presence of either symptoms or signs of peripheral nerve dysfunction, remains a frequently reported complication in the antiretroviral (ART)-treated HIV population. This study was conducted in 109 healthy controls and 57 HIV-infected individuals to investigate CNS regions associated with neuropathy. An index of objective neuropathy was computed based on 4 measures: deep tendon ankle reflex, vibration sense (great toes), position sense (great toes), and 2-point discrimination (feet). Subjective neuropathy (self-report of pain, aching, or burning; pins and needles; or numbness in legs or feet) was also evaluated. Structural MRI data were available for 126/166 cases. The HIV relative to the healthy control group was impaired on all 4 signs of neuropathy. Within the HIV group, an objective neuropathy index of 1 (bilateral impairment on 1 measure) or 2 (bilateral impairment on at least 2/4 measures) was associated with older age and a smaller volume of the cerebellar vermis. Moderate to severe symptoms of neuropathy were associated with more depressive symptoms, reduced quality of life, and a smaller volume of the parietal precuneus. This study is consistent with the recent contention that ART-treated HIV-related neuropathy has a CNS component. Distinguishing subjective symptoms from objective signs of neuropathy allowed for a dissociation between the precuneus, a brain region involved in conscious information processing and the vermis, involved in fine tuning of limb movements.

Graphical Abstract

In HIV patients, objective signs of neuropathy correlated with smaller cerebellar vermis (red) volumes whereas subjective symptoms of neuropathy were associated with smaller precuneus (blue) volumes.


Magnetic resonance imaging (MRI) Position sense Vibration Reflex Aesthesiometer 



The authors would like to thank Priya Asok, Karen Jackson, and Anne-Lise Pitel for their help with data collection. The authors would also like to thank Ehsan Adeli for creating the regional brain atlas figure.


This study was supported with grant funding from the National Institute of Alcohol Abuse and Alcoholism (NIAAA): AA017347, AA010723, AA017168; and from the National Institute of Mental Health MH113406.

Compliance with Ethical Standards

Conflict of Interest

The authors report no competing interests.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Please also sees statement under Participant header in Material and Methods.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. Absinta M, Rocca MA, Colombo B, Falini A, Comi G, Filippi M (2012) Selective decreased grey matter volume of the pain-matrix network in cluster headache. Cephalalgia: An International Journal of Headache 32:109–115. Google Scholar
  2. Adoukonou TA, Kouna-Ndouongo P, Kpangon A, Gnonlonfoun D, Kpacha B, Dovonou A, Houinato D (2017) Distal sensory polyneuropathy among HIV-infected patients at Parakou University hospital, Benin, 2011. Medecine et Santé Tropicales 27:190–194. Google Scholar
  3. Andresen-Streichert H, Muller A, Glahn A, Skopp G, Sterneck M (2018) Alcohol biomarkers in clinical and forensic contexts. Deutsches Ärzteblatt International 115:309–315. Google Scholar
  4. Antinori A et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799. Google Scholar
  5. Arkkila PE, Koskinen PJ, Kantola IM, Ronnemaa T, Seppanen E, Viikari JS (2001) Diabetic complications are associated with liver enzyme activities in people with type 1 diabetes. Diabetes Research and Clinical Practice 52:113–118Google Scholar
  6. Asad A, Hameed MA, Khan UA, Ahmed N, Butt MU (2010) Reliability of the neurological scores for assessment of sensorimotor neuropathy in type 2 diabetics. JPMA 60:166–170Google Scholar
  7. Avants BB, Epstein CL, Grossman M, Gee JC (2008) Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 12:26–41. Google Scholar
  8. Avants BB, Tustison NJ, Song G, Cook PA, Klein A, Gee JC (2011) A reproducible evaluation of ANTs similarity metric performance in brain image registration. NeuroImage 54:2033–2044. Google Scholar
  9. Aziz-Donnelly A, Harrison TB (2017) Update of HIV-Associated Sensory Neuropathies. Curr Treat Options Neurol 19:36. Google Scholar
  10. Bauer LO, Ceballos NA, Shanley JD, Wolfson LI (2005) Sensorimotor dysfunction in HIV/AIDS: effects of antiretroviral treatment and comorbid psychiatric disorders. AIDS 19:495–502Google Scholar
  11. Beck AT, Steer RA, Brown GK (1996) Manual for the Beck depression inventory-II. Psychological Corporation, San AntonioGoogle Scholar
  12. Benevides ML, Filho SB, Debona R, Bergamaschi EN, Nunes JC (2017) Prevalence of Peripheral Neuropathy and associated factors in HIV-infected patients. J Neurol Sci 375:316–320. Google Scholar
  13. Berner K, Morris L, Baumeister J, Louw Q (2017) Objective impairments of gait and balance in adults living with HIV-1 infection: a systematic review and meta-analysis of observational studies. BMC Musculoskelet Disord 18:325. Google Scholar
  14. Boulton AJ (1998) Guidelines for diagnosis and outpatient management of diabetic peripheral neuropathy. European Association for the Study of Diabetes, Neurodiab. Diabetes Metab 24(Suppl 3):55–65Google Scholar
  15. Bozzette SA, Hays RD, Berry SH, Kanouse DE, Wu AW (1995) Derivation and properties of a brief health status assessment instrument for use in HIV disease. JAIDS and Human Retrovirology 8:253–265Google Scholar
  16. Brouwer BA, de Greef BT, Hoeijmakers JG, Geerts M, van Kleef M, Merkies IS, Faber CG (2015) Neuropathic pain due to small fiber neuropathy in aging: current management and future prospects. Drugs Aging 32:611–621. Google Scholar
  17. Buckalew N, Haut MW, Morrow L, Weiner D (2008) Chronic pain is associated with brain volume loss in older adults: preliminary evidence. Pain Med 9:240–248. Google Scholar
  18. Castillo LC, Gracia F, Roman GC, Levine P, Reeves WC, Kaplan J (2000) Spinocerebellar syndrome in patients infected with human T-lymphotropic virus types I and II (HTLV-I/HTLV-II): report of 3 cases from Panama. Acta Neurol Scand 101:405–412Google Scholar
  19. Cavanna AE, Trimble MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129:564–583. Google Scholar
  20. Center For Disease Control and Prevention (2017) Hepatitis C FAQs for health professionals. CDCGoogle Scholar
  21. Chen H et al (2013) Peripheral neuropathy in ART-experienced patients: prevalence and risk factors. J Neurovirol 19:557–564. Google Scholar
  22. Cherry CL, McArthur JC, Hoy JF, Wesselingh SL (2003) Nucleoside analogues and neuropathy in the era of HAART. J Clin Virol 26:195–207Google Scholar
  23. Cherry CL, Wesselingh SL, Lal L, McArthur JC (2005) Evaluation of a clinical screening tool for HIV-associated sensory neuropathies. Neurology 65:1778–1781. Google Scholar
  24. Cherry CL et al (2009) Age and height predict neuropathy risk in patients with HIV prescribed stavudine. Neurology 73:315–320. Google Scholar
  25. Cherry CL et al (2010) Hepatitis C seropositivity is not a risk factor for sensory neuropathy among patients with HIV. Neurology 74:1538–1542. Google Scholar
  26. Childs EA et al (1999) Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 52:607–613Google Scholar
  27. Cho HC (2010) The association between serum GGT concentration and diabetic peripheral polyneuropathy in type 2 diabetic patients. Korean Diabetes Journal 34:111–118. Google Scholar
  28. Chopra K, Tiwari V (2012) Alcoholic neuropathy: possible mechanisms and future treatment possibilities. Br J Clin Pharmacol 73:348–362. Google Scholar
  29. Coppieters I et al (2017) Decreased regional Grey matter volume in women with chronic whiplash-associated disorders: relationships with cognitive deficits and disturbed pain processing. Pain physician 20:E1025–E1051Google Scholar
  30. Corkin S, Milner B, Rasmussen T (1970) Somatosensory thresholds--contrasting effects of postcentral-gyrus and posterior parietal-lobe excisions. Arch Neurol 23:41–58Google Scholar
  31. Cornblath DR, Chaudhry V, Carter K, Lee D, Seysedadr M, Miernicki M, Joh T (1999) Total neuropathy score: validation and reliability study. Neurology 53:1660–1664Google Scholar
  32. Coupe P, Yger P, Prima S, Hellier P, Kervrann C, Barillot C (2008) An optimized blockwise nonlocal means denoising filter for 3-D magnetic resonance images. IEEE Trans Med Imaging 27:425–441. Google Scholar
  33. de Bresser J, Reijmer YD, van den Berg E, Breedijk MA, Kappelle LJ, Viergever MA, Biessels GJ (2010) Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes. Dement Geriatr Cogn Disord 30:381–386. Google Scholar
  34. Dejerine J, Roussy G (1906) Le syndrome thalamique. Revue Neurologique 14:521–532Google Scholar
  35. Ducic I, Short KW, Dellon AL (2004) Relationship between loss of pedal sensibility, balance, and falls in patients with peripheral neuropathy. Ann Plast Surg 52:535–540Google Scholar
  36. El Boghdady NA, Badr GA (2012) Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy. Cell Biochem Funct 30:328–334. Google Scholar
  37. Ellis RJ et al (2010) Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch Neurol 67:552–558. Google Scholar
  38. Endicott J, Spitzer RL, Fleiss JL, Cohen J (1976) The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance. Arch Gen Psychiatry 33:766–771Google Scholar
  39. Evans SR et al (2011) Peripheral neuropathy in HIV: prevalence and risk factors. AIDS 25:919–928. Google Scholar
  40. Feng Y, Schlosser FJ, Sumpio BE (2009) The Semmes Weinstein monofilament examination as a screening tool for diabetic peripheral neuropathy. J Vasc Surg 50:675-682, 682 e671
  41. First MB, Spitzer RL, Gibbon M, Williams JBW (1998) Structured clinical interview for DSM-IV Axis I disorders (SCID) version 2.0. Biometrics Research Department, New York State Psychiatric Institute, New YorkGoogle Scholar
  42. Fiset P et al (1999) Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study. J Neurosci 19:5506–5513Google Scholar
  43. Frokjaer JB, Brock C, Softeland E, Dimcevski G, Gregersen H, Simren M, Drewes AM (2013) Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study. Exp Clin Endocrinol Diabetes 121:354–360. Google Scholar
  44. Garcin R, Lapresle J (1954) Sensory syndrome of the thalamic type and with hand-mouth topography due to localized lesions of the thalamus. Rev Neurol (Paris) 90:124–129Google Scholar
  45. Ghosh S, Chandran A, Jansen JP (2012) Epidemiology of HIV-related neuropathy: a systematic literature review. AIDS Res Hum Retrovir 28:36–48. Google Scholar
  46. Gusnard DA, Raichle ME, Raichle ME (2001) Searching for a baseline: functional imaging and the resting human brain. Nat Rev Neurosci 2:685–694. Google Scholar
  47. Head H, Holmes G (1911) Sensory disturbances from cerebral lesions. Brain 34:102–254Google Scholar
  48. Hellmuth J et al (2016) Neurologic signs and symptoms frequently manifest in acute HIV infection. Neurology 87:148–154. Google Scholar
  49. Hollingshead A (1975) Four-factor index of social status. Department of Sociology, Yale University, New HavenGoogle Scholar
  50. Hsieh PC et al (2015) Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration. Pain 156:904–916. Google Scholar
  51. Kaku M, Simpson DM (2014) HIV neuropathy. Curr Opin HIV AIDS 9:521–526. Google Scholar
  52. Karnofsky DA (1949) The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM (ed) Evaluation of chemotherapeutic agents. Columbia University Press, New York, pp 191–205Google Scholar
  53. Keltner JR et al (2012) Health-related quality of life 'well-being' in HIV distal neuropathic pain is more strongly associated with depression severity than with pain intensity. Psychosomatics 53:380–386. Google Scholar
  54. Keltner JR et al (2014) HIV-associated distal neuropathic pain is associated with smaller total cerebral cortical gray matter. J Neurovirol 20:209–218. Google Scholar
  55. Keltner JR et al (2017) HIV distal neuropathic pain is associated with smaller ventral posterior cingulate cortex. Pain Med 18:428–440. Google Scholar
  56. Kjaer TW, Nowak M, Lou HC (2002) Reflective self-awareness and conscious states: PET evidence for a common midline parietofrontal core. NeuroImage 17:1080–1086Google Scholar
  57. Laureys S (2004) Functional neuroimaging in the vegetative state. NeuroRehabilitation 19:335–341Google Scholar
  58. Lee DH, Blomhoff R, Jacobs DR Jr (2004) Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res 38:535–539Google Scholar
  59. Lee AJ, Bosch RJ, Evans SR, Wu K, Harrison T, Grant P, Clifford DB (2015) Patterns of peripheral neuropathy in ART-naive patients initiating modern ART regimen. J Neurovirol 21:210–218. Google Scholar
  60. Lim JS, Yang JH, Chun BY, Kam S, Jacobs DR Jr, Lee DH (2004) Is serum gamma-glutamyltransferase inversely associated with serum antioxidants as a marker of oxidative stress? Free Radic Biol Med 37:1018–1023. Google Scholar
  61. Lin Y et al (2011) Serum gamma-glutamyltransferase and associated damage among a she Chinese population. Diabet Med 28:924–931. Google Scholar
  62. Lou HC et al (2004) Parietal cortex and representation of the mental self. Proc Natl Acad Sci U S A 101:6827–6832. Google Scholar
  63. Lou HC, Nowak M, Kjaer TW (2005) The mental self. Prog Brain Res 150:197–204. Google Scholar
  64. Lunetta M, Damanti AR, Fabbri G, Lombardo M, Di Mauro M, Mughini L (1994) Evidence by magnetic resonance imaging of cerebral alterations of atrophy type in young insulin-dependent diabetic patients. J Endocrinol Investig 17:241–245. Google Scholar
  65. Manor B, Newton E, Abduljalil A, Novak V (2012) The relationship between brain volume and walking outcomes in older adults with and without diabetic peripheral neuropathy. Diabetes Care 35:1907–1912. Google Scholar
  66. Mapoure NY, Budzi MN, Eloumou S, Malongue A, Okalla C, Luma HN (2018) Neurological manifestations in chronic hepatitis C patients receiving care in a reference hospital in sub-Saharan Africa: A cross-sectional study. PLoS One 13:e0192406. Google Scholar
  67. Mattis S (1998) Dementia rating scale (DRS) professional manual. Psychological Assessment Resources, Inc, OdessaGoogle Scholar
  68. McArthur JH (1998) The reliability and validity of the subjective peripheral neuropathy screen. J Assoc Nurses AIDS Care 9:84–94. Google Scholar
  69. Morgello S et al (2004) HIV-associated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: the Manhattan HIV Brain Bank. Arch Neurol 61:546–551. Google Scholar
  70. Mustapa A, Justine M, Mohd Mustafah N, Jamil N, Manaf H (2016) Postural control and gait performance in the diabetic peripheral neuropathy: a systematic review. Biomed Res Int 2016:9305025. Google Scholar
  71. Nelson D et al (2006) Comparison of conventional and non-invasive techniques for the early identification of diabetic neuropathy in children and adolescents with type 1 diabetes. Pediatr Diabetes 7:305–310. Google Scholar
  72. Nookala AR, Mitra J, Chaudhari NS, Hegde ML, Kumar A (2017) An overview of human immunodeficiency virus type 1-associated common neurological complications: does aging pose a challenge? J Alzheimers Dis 60:S169–S193. Google Scholar
  73. Pandya R, Krentz HB, Gill MJ, Power C (2005) HIV-related neurological syndromes reduce health-related quality of life. Can J Neurol Sci 32:201–204Google Scholar
  74. Periyasamy R, Manivannan M, Narayanamurthy VB (2008) Changes in two point discrimination and the law of mobility in diabetes mellitus patients. Journal of Brachial Plexus and Peripheral Nerve Injury 3:3. Google Scholar
  75. Perkins BA, Olaleye D, Zinman B, Bril V (2001) Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 24:250–256Google Scholar
  76. Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S (1982) Measurement of functional activities in older adults in the community. J Gerontol 37:323–329Google Scholar
  77. Pfefferbaum A, Rosenbloom M, Rohlfing T, Sullivan EV (2009) Degradation of association and projection white matter systems in alcoholism detected with quantitative fiber tracking. Biol Psychiatry 65:680–690. Google Scholar
  78. Pfefferbaum A, Zahr NM, Sassoon SA, Kwon D, Pohl KM, Sullivan EV (2018) Accelerated and premature aging characterizing regional cortical volume loss in human immunodeficiency virus infection: contributions from alcohol, substance use, and hepatitis C coinfection. Biol Psychiatry 3:844–859. Google Scholar
  79. Prodi E, Grisoli M, Panzeri M, Minati L, Fattori F, Erbetta A, Uziel G, D'Arrigo S, Tessa A, Ciano C, Santorelli FM, Savoiardo M, Mariotti C (2013) Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix-Saguenay. A comprehensive study of an Italian series. Eur J Neurol 20:138–146. Google Scholar
  80. Robinson-Papp J et al (2010) Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy. Pain 151:732–736. Google Scholar
  81. Rohlfing T, Zahr NM, Sullivan EV, Pfefferbaum A (2010) The SRI24 multichannel atlas of normal adult human brain structure. Hum Brain Mapp 31:798–819. Google Scholar
  82. Ruhdorfer AS et al (2015) Selecting a prospective test for early detection of diabetic polyneuropathy. Microsurgery 35:512–517. Google Scholar
  83. Saylor D, Nakigozi G, Nakasujja N, Robertson K, Gray RH, Wawer MJ, Sacktor N (2017) Peripheral neuropathy in HIV-infected and uninfected patients in Rakai, Uganda. Neurology 89:485–491. Google Scholar
  84. Schmidt-Wilcke T et al (2018) Structural changes in brain morphology induced by brief periods of repetitive sensory stimulation. NeuroImage 165:148–157. Google Scholar
  85. Schuster P (1937) Beitra¨ge zun Pathologie des Thalamus opticus. Mitteilung Archiv fu¨r Psychiatrie und Nervenkrakheiten 106:13-53Google Scholar
  86. Selvarajah D, Wilkinson ID, Davies J, Gandhi R, Tesfaye S (2011) Central nervous system involvement in diabetic neuropathy. Curr Diab Rep 11:310–322. Google Scholar
  87. Selvarajah D et al (2014) Magnetic resonance neuroimaging study of brain structural differences in diabetic peripheral neuropathy. Diabetes Care 37:1681–1688. Google Scholar
  88. Skinner HA, Sheu WJ (1982) Reliability of alcohol use indices. The Lifetime Drinking History and the MAST. J Stud Alcohol 43:1157–1170Google Scholar
  89. Sommer C (2018) Nerve and skin biopsy in neuropathies. Curr Opin Neurol 31:534–540. Google Scholar
  90. Sugimine S, Ogino Y, Kawamichi H, Obata H, Saito S (2016) Brain morphological alternation in chronic pain patients with neuropathic characteristics. Mol Pain 12.
  91. Sullivan EV, Rosenbloom MJ, Pfefferbaum A (2000) Pattern of motor and cognitive deficits in detoxified alcoholic men. Alcohol Clin Exp Res 24:611–621Google Scholar
  92. Szmulewicz DJ, Waterston JA, Halmagyi GM, Mossman S, Chancellor AM, McLean CA, Storey E (2011a) Sensory neuropathy as part of the cerebellar ataxia neuropathy vestibular areflexia syndrome. Neurology 76:1903–1910. Google Scholar
  93. Szmulewicz DJ et al (2011b) Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis. Ann N Y Acad Sci 1233:139–147. Google Scholar
  94. Taki M et al (2018) Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Auris Nasus Larynx 45:866–870. Google Scholar
  95. Tate JP et al (2013) An internationally generalizable risk index for mortality after one year of antiretroviral therapy. AIDS 27:563–572. Google Scholar
  96. Tesfaye S, Boulton AJ, Dickenson AH (2013) Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 36:2456–2465. Google Scholar
  97. Tesfaye S, Selvarajah D, Gandhi R, Greig M, Shillo P, Fang F, Wilkinson ID (2016) Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging. Pain (Suppl 1):157, S72–180.
  98. Tourdias T, Saranathan M, Levesque IR, Su J, Rutt BK (2014) Visualization of intra-thalamic nuclei with optimized white-matter-nulled MPRAGE at 7T. NeuroImage 84:534–545 S1053-8119(13)00934-8. Google Scholar
  99. Vermeer S, van de Warrenburg BP, Kamsteeg EJ (1993) Arsacs. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). Seattle (WA)Google Scholar
  100. Vermeer S et al (2008) ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. Neurogenetics 9:207–214. Google Scholar
  101. Vogt BA, Laureys S (2005) Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness. Prog Brain Res 150:205–217. Google Scholar

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Authors and Affiliations

  1. 1.Neuroscience ProgramSRI InternationalMenlo ParkUSA
  2. 2.Department of Psychiatry and Behavioral SciencesStanford University School of MedicineStanfordUSA

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