Reduced volumes of the external and internal globus pallidus in male heroin addicts: a postmortem study

  • Ulf J. MüllerEmail author
  • Christian Mawrin
  • Thomas Frodl
  • Henrik Dobrowolny
  • Stefan Busse
  • Hans-Gert Bernstein
  • Bernhard Bogerts
  • Kurt Truebner
  • Johann SteinerEmail author
Original Paper


Deep brain stimulation (DBS) of the globus pallidus internus was recently proposed as a potential new treatment target for opioid addiction. DBS requires computer-assisted-3D planning to implant the stimulation electrode precisely. As volumes of brain regions may differ in addiction compared to healthy controls, our aim was to investigate possible volume differences in addicts compared to healthy controls. Volumes of the globus pallidus externus (PE) and internus (PI) in heroin addicts (n = 14) and healthy controls (n = 12) were assessed using morphometry of serial whole-brain sections. Total brain volume was larger in the heroin group (mean 1479 ± 62 cm3 vs. mean 1352 ± 103 cm3), as the heroin group was more than 10 years younger (p = 0.001). Despite larger mean whole brain volume, the mean relative volume of the PE and PI was smaller in addicted subjects compared to healthy controls (PE 0.658 ± 0.183 × 10−3 vs. 0.901 ± 0.284 × 10−3; ANOVA F(1, 24) = 6.945, p = 0.014, η2 = 0.224; PI 0.253 ± 0.095 × 10−3 vs. 0.345 ± 0.107 × 10−3; ANOVA F(1, 24) = 5.374, p = 0.029, η2 = 0.183). These findings were not significantly confounded by age, duration of autolysis, and fixation time. Our results provide further evidence for structural and not only functional deficits of the globus pallidus in addiction. In the context of previous studies, our findings support the idea of shared pathophysiological processes between comorbid depression and impulsivity in opioid addiction.


Heroin Addiction Globus pallidus internus Globus pallidus externus Postmortem Volumetry Morphometry Deep brain stimulation DBS 



Renate Stauch, Sieglinde Funke and Gabriela Meyer-Lotz provided excellent technical assistance.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

Sampling and preservation of the human brain material were done in accordance with the Declaration of Helsinki, German Law and approval by the local institutional review board.


  1. 1.
    Degenhardt L, Charlson F, Mathers B, Hall WD, Flaxman AD, Johns N, Vos T (2014) The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study. Addiction.109:1320–1333. CrossRefGoogle Scholar
  2. 2.
    Unick GJ, Ciccarone D (2017) US regional and demographic differences in prescription opioid and heroin-related overdose hospitalizations. Int J Drug Policy 46:112–119. CrossRefGoogle Scholar
  3. 3.
    Kuhn J, Lenartz D, Huff W, Lee S, Koulousakis A, Klosterkoetter J, Sturm V (2007) Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications? J Neurol Neurosurg Psychiatry 78:1152–1153. CrossRefGoogle Scholar
  4. 4.
    Müller U, Sturm V, Voges J, Heinze H-J, Galazky I, Büntjen L, Heldmann M, Frodl T, Steiner J, Bogerts B (2016) Nucleus accumbens deep brain stimulation for alcohol addiction—safety and clinical long-term results of a pilot trial. Pharmacopsychiatry 49:170–173. CrossRefGoogle Scholar
  5. 5.
    Kuhn J, Möller M, Treppmann JF, Bartsch C, Lenartz D, Gruendler TOJ, Maarouf M, Brosig A, Barnikol UB, Klosterkötter J, Sturm V (2014) Deep brain stimulation of the nucleus accumbens and its usefulness in severe opioid addiction. Mol Psychiatry 19:145–146. CrossRefGoogle Scholar
  6. 6.
    Muller UJ, Truebner K, Schiltz K, Kuhn J, Mawrin C, Dobrowolny H, Bernstein H-G, Bogerts B, Steiner J (2015) Postmortem volumetric analysis of the nucleus accumbens in male heroin addicts: implications for deep brain stimulation. Eur Arch Psychiatry Clin Neurosci. 265:647–653. CrossRefGoogle Scholar
  7. 7.
    Muller UJ, Schiltz K, Mawrin C, Dobrowolny H, Frodl T, Bernstein H-G, Bogerts B, Truebner K, Steiner J (2017) Total hypothalamic volume is reduced in postmortem brains of male heroin addicts. Eur Arch Psychiatry Clin Neurosci 268:243–248. CrossRefGoogle Scholar
  8. 8.
    Jaeger D, Kita H (2011) Review functional connectivity and integrative properties of globus pallidus neurons. Neuroscience 198:44–53. CrossRefGoogle Scholar
  9. 9.
    Goldberg JA, Bergman H (2011) Review computational physiology of the neural networks of the primate globus pallidus: function and dysfunction. Neuroscience 198:171–192. CrossRefGoogle Scholar
  10. 10.
    Moussawi K, Kalivas PW, Lee JW (2016) Abstinence from drug dependence after bilateral globus pallidus hypoxic-ischemic injury. BPS 80:e79–e80. Google Scholar
  11. 11.
    Isometsä ET (2001) Psychological autopsy studies—a review. Eur Psychiatry 16:379–385CrossRefGoogle Scholar
  12. 12.
    Bernstein HG, Stanarius A, Baumann B, Henning H, Krell D, Danos P, Falkai P, Bogerts B (1998) Nitric oxide synthase-containing neurons in the human hypothalamus: reduced number of immunoreactive cells in the paraventricular nucleus of depressive patients and schizophrenics. Neuroscience 83:867–875CrossRefGoogle Scholar
  13. 13.
    Bielau H, Trübner K, Krell D, Agelink MW, Bernstein HG, Stauch R, Mawrin C, Danos P, Gerhard L, Bogerts B, Baumann B (2005) Volume deficits of subcortical nuclei in mood disorders. Eur Arch Psychiatry Clin Neurosci 255:401–412. CrossRefGoogle Scholar
  14. 14.
    Baumann B, Danos P, Krell D, Diekmann S, Leschinger A, Stauch R, Wurthmann C, Bernstein HG, Bogerts B (1999) Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a postmortem study. J Neuropsychiatry Clin Neurosci 11:71–78CrossRefGoogle Scholar
  15. 15.
    Bernstein HG, Baumann B, Danos P, Diekmann S, Bogerts B, Gundelfinger ED, Braunewell KH (1999) Regional and cellular distribution of neural visinin-like protein immunoreactivities (VILIP-1 and VILIP-3) in human brain. J Neurocytol 28:655–662CrossRefGoogle Scholar
  16. 16.
    Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263CrossRefGoogle Scholar
  17. 17.
    Pollo C, Kaelin-Lang A, Oertel MF, Stieglitz L, Taub E, Fuhr P, Lozano AM, Raabe A, Schupbach M (2014) Directional deep brain stimulation: an intraoperative double-blind pilot study. Brain. 137:2015–2026. CrossRefGoogle Scholar
  18. 18.
    Andersen SN, Skullerud K (1999) Hypoxic/ischaemic brain damage, especially pallidal lesions, in heroin addicts. Forensic Sci Int 102:51–59CrossRefGoogle Scholar
  19. 19.
    Bernstein H-G, Trübner K, Krebs P, Dobrowolny H, Bielau H, Steiner J, Bogerts B (2014) Increased densities of nitric oxide synthase expressing neurons in the temporal cortex and the hypothalamic paraventricular nucleus of polytoxicomanic heroin overdose victims: possible implications for heroin neurotoxicity. Acta Histochem 116:182–190. CrossRefGoogle Scholar
  20. 20.
    Cadet JL, Bisagno V, Milroy CM (2013) Neuropathology of substance use disorders. Acta Neuropathol 127:91–107. CrossRefGoogle Scholar
  21. 21.
    Pearson J, Baden MB, Richter RW (1976) Neuronal depletion in the globus pallidus of heroin addicts. Drug Alcohol Depend 1:349–356CrossRefGoogle Scholar
  22. 22.
    Tolomeo S, Matthews K, Steele D, Baldacchino A (2018) Compulsivity in opioid dependence. Prog Neuropsychopharmacol Biol Psychiatry 81:333–339. CrossRefGoogle Scholar
  23. 23.
    Zippel-Schultz B, Specka M, Cimander K, Eschenhagen T, Golz J, Maryschok M, Nowak M, Poehlke T, Stover H, Helms TM, Scherbaum N (2016) Outcomes of patients in long-term opioid maintenance treatment. Subst Use Misuse 51:1493–1503. CrossRefGoogle Scholar
  24. 24.
    Gos T, Krell D, Bielau H, Steiner J, Trübner K, Brisch R, Bernstein H-G, Jankowski Z, Bogerts B (2009) Demonstration of disturbed activity of external globus pallidus projecting neurons in depressed patients by the AgNOR staining method. J Affect Disord 119:149–155. CrossRefGoogle Scholar
  25. 25.
    Ruitenberg MFL, Wu T, Averbeck BB, Chou KL, Koppelmans V, Seidler RD (2018) Impulsivity in Parkinson’s disease is associated with alterations in affective and sensorimotor striatal networks. Front Neurol 9:105–112. CrossRefGoogle Scholar
  26. 26.
    Saga Y, Hoshi E, Tremblay L (2017) Roles of multiple globus pallidus territories of monkeys and humans in motivation, cognition and action: an anatomical, physiological and pathophysiological review. Front Neuroanat 11:10612–10659. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ulf J. Müller
    • 1
    • 2
    • 3
    Email author
  • Christian Mawrin
    • 2
    • 4
  • Thomas Frodl
    • 1
    • 2
  • Henrik Dobrowolny
    • 1
    • 2
  • Stefan Busse
    • 1
  • Hans-Gert Bernstein
    • 1
    • 2
  • Bernhard Bogerts
    • 1
    • 2
  • Kurt Truebner
    • 5
  • Johann Steiner
    • 1
    • 2
    Email author
  1. 1.Department of Psychiatry and PsychotherapyUniversity of MagdeburgMagdeburgGermany
  2. 2.Center for Behavioral Brain SciencesMagdeburgGermany
  3. 3.Department of Psychiatry and PsychotherapySaarland UniversityHomburgGermany
  4. 4.Department of NeuropathologyUniversity of MagdeburgMagdeburgGermany
  5. 5.Institute of Legal MedicineUniversity of Duisburg-EssenEssenGermany

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