Experimental Brain Research

, Volume 232, Issue 7, pp 2255–2262 | Cite as

The subthalamic nucleus modulates the early phase of probabilistic classification learning

  • Daniel Weiss
  • Judith M. Lam
  • Sorin Breit
  • Alireza Gharabaghi
  • Rejko Krüger
  • Andreas R. Luft
  • Tobias WächterEmail author
Research Article


Previous models proposed that the subthalamic nucleus (STN) is critical in the early phase of skill acquisition. We hypothesized that subthalamic deep brain stimulation modulates the learning curve in early classification learning. Thirteen idiopathic Parkinson’s disease patients (iPD) with subthalamic deep brain stimulation (STN-DBS), 9 medically treated iPD, and 21 age-matched healthy controls were tested with a probabilistic classification task. STN-DBS patients were tested with stimulation OFF and ON, and medically treated patients with medication OFF and ON, respectively. Performance and reaction time were analyzed on the first 100 consecutive trials as early learning phase. Moreover, data were separated for low and high-probability patterns, and more differentiated strategy analyses were used. The major finding was a significant modulation of the learning curve in DBS patients with stimulation ON: although overall learning was similar to healthy controls, only the stimulation ON group showed a transient significant performance dip from trials ‘41–60’ that rapidly recovered. Further analysis indicated that this might be paralleled by a modulation of the learning strategy, particularly on the high-probability patterns. The reaction time was unchanged during the dip. Our study supports that the STN serves as a relay in early classification learning and directs attention toward unacquainted content. The STN might play a role in balancing the short-term success against strategy optimization for improved long-term outcome.


Learning Subthalamic nucleus Parkinson’s disease Deep brain stimulation Weather prediction task 



This work was supported by a research grant from Medtronic, Meerbusch, Germany.

Conflict of interest

Daniel Weiss is supported by a research grant of the German Research Council (DFG) WE5375/1-1 and was supported by a Research Grant of the Medical Faculty of the University of Tübingen (AKF 259-0-0). Daniel Weiss received speaker’s honoraria from Medtronic and travel grants from Medtronic, Abott Pharmaceutical, UCB, and the Movement Disorder Society. Judith Lam declares no competing financial interest. Sorin Breit declares no competing financial interest. Alireza Gharabaghi is supported by grants from Medtronic, the German Research Council [DFG GH 94/2-1, DFG EC 307], Federal Ministry for Education and Research [BFNT 01GQ0761, BMBF 16SV3783, BMBF 03160064B, BMBF V4UKF014], and European Union [ERC 227632]. Rejko Krüger serves as Editor of European Journal of Clinical Investigation, Journal of Neural Transmission and Associate Editor of BMC Neurology and has received research grants of the German Research Council (DFG; KR2219/2-3 and KR2119/8-1), the Michael J Fox Foundation, the Fritz Thyssen foundation (, and the Federal Ministry for Education and Research [BMBF, NGFNplus; 01GS08134], as well as speaker’s honoraria and/or travel grants from UCB Pharma, Cephalon, Abott Pharmaceutical, Takeda Pharmaceuticals and Medtronic. Andreas Luft is supported by grants from the EU FP7 program, the SNF and the McDonnell Foundation, and the KFSP Program of the University of Zurich. A. Luft is in the scientific advisory boards of Hocoma, Boehringer Ingelheim, Pfizer, Dynamic Devices. Tobias Wächter received speaker’s honoraria and travel reimbursement for scientific meetings from Medtronic, Solvay, Abbott Pharma, Cephalon, Merz Pharmaceuticals, Ipsen Pharma, and Schwarz Pharma. He has also received financial support for research from and conducted commissioned research for Medtronic, Abbott Pharma, Merz Pharmaceuticals, Ipsen Pharma, and Pharm-Allergan and worked on advisory boards for Ipsen Pharma, Merz Pharmaceuticals, and Medtronic.


  1. Angeli A, Mencacci NE, Duran R et al (2013) Genotype and phenotype in Parkinson’s disease: lessons in heterogeneity from deep brain stimulation. Mov Disord 28:1370–1375. doi: 10.1002/mds.25535 PubMedCentralPubMedGoogle Scholar
  2. Aron AR, Poldrack RA (2006) Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus. J Neurosci 26:2424–2433. doi: 10.1523/JNEUROSCI.4682-05.2006 PubMedCrossRefGoogle Scholar
  3. Ballanger B, van Eimeren T, Moro E et al (2009) Stimulation of the subthalamic nucleus and impulsivity: release your horses. Ann Neurol 66:817–824. doi: 10.1002/ana.21795 PubMedCentralPubMedCrossRefGoogle Scholar
  4. Brockmann K, Srulijes K, Hauser AK, Schulte C, Csoti I, Gasser T, Berg D (2011) GBA-associated PD presents with nonmotor characteristics. Neurology 77:276–280. doi: 10.1212/WNL.0b013e318225ab77 PubMedCrossRefGoogle Scholar
  5. Brown JW, Bullock D, Grossberg S (2004) How laminar frontal cortex and basal ganglia circuits interact to control planned and reactive saccades. Neural Netw 17:471–510. doi: 10.1016/j.neunet.2003.08.006 PubMedCrossRefGoogle Scholar
  6. Cooper SE, McIntyre CC, Fernandez HH, Vitek JL (2013) Association of deep brain stimulation washout effects with Parkinson disease duration. JAMA Neurol 70:95–99. doi: 10.1001/jamaneurol.2013.581 PubMedCrossRefGoogle Scholar
  7. Deuschl G, Schade-Brittinger C, Krack P et al (2006) A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 355:896–908PubMedCrossRefGoogle Scholar
  8. Flaherty AW, Graybiel AM (1991) Corticostriatal transformations in the primate somatosensory system. Projections from physiologically mapped body-part representations. J Neurophysiol 66:1249–1263PubMedGoogle Scholar
  9. Frank MJ (2006) Hold your horses: a dynamic computational role for the subthalamic nucleus in decision making. Neural Netw 19:1120–1136. doi: 10.1016/j.neunet.2006.03.006 PubMedCrossRefGoogle Scholar
  10. Frank MJ, O’Reilly RC (2006) A mechanistic account of striatal dopamine function in human cognition: psychopharmacological studies with cabergoline and haloperidol. Behav Neurosci 120:497–517. doi: 10.1037/0735-7044.120.3.497 PubMedCrossRefGoogle Scholar
  11. Frank MJ, Samanta J, Moustafa AA, Sherman SJ (2007) Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism. Science 318:1309–1312. doi: 10.1126/science.1146157 PubMedCrossRefGoogle Scholar
  12. Gluck MA, Shohamy D, Myers C (2002) How do people solve the “weather prediction” task?: Individual variability in strategies for probabilistic category learning. Learn Mem 9:408–418. doi: 10.1101/lm.45202 PubMedCentralPubMedCrossRefGoogle Scholar
  13. Graybiel AM, Aosaki T, Flaherty AW, Kimura M (1994) The basal ganglia and adaptive motor control. Science 265:1826–1831PubMedCrossRefGoogle Scholar
  14. Halbig TD, Gruber D, Kopp UA et al (2004) Subthalamic stimulation differentially modulates declarative and nondeclarative memory. NeuroReport 15:539–543PubMedCrossRefGoogle Scholar
  15. Jahanshahi M, Ardouin CM, Brown RG et al (2000) The impact of deep brain stimulation on executive function in Parkinson’s disease. Brain 123(Pt 6):1142–1154PubMedCrossRefGoogle Scholar
  16. Jahanshahi M, Wilkinson L, Gahir H, Dharmaindra A, Lagnado DA (2010) Medication impairs probabilistic classification learning in Parkinson’s disease. Neuropsychologia 48:1096–1103. doi: 10.1016/j.neuropsychologia.2009.12.010 PubMedCrossRefGoogle Scholar
  17. Knowlton BJ, Mangels JA, Squire LR (1996) A neostriatal habit learning system in humans. Science 273:1399–1402PubMedCrossRefGoogle Scholar
  18. Lam JM, Wachter T, Globas C, Karnath HO, Luft AR (2013) Predictive value and reward in implicit classification learning. Hum Brain Mapp 34:176–185. doi: 10.1002/hbm.21431 PubMedCrossRefGoogle Scholar
  19. Mahon S, Casassus G, Mulle C, Charpier S (2003) Spike-dependent intrinsic plasticity increases firing probability in rat striatal neurons in vivo. J Physiol 550:947–959. doi: 10.1113/jphysiol.2003.043125 PubMedCentralPubMedCrossRefGoogle Scholar
  20. Mink JW (1996) The basal ganglia: focused selection and inhibition of competing motor programs. Prog Neurobiol 50:381–425PubMedCrossRefGoogle Scholar
  21. Moody TD, Bookheimer SY, Vanek Z, Knowlton BJ (2004) An implicit learning task activates medial temporal lobe in patients with Parkinson’s disease. Behav Neurosci 118:438–442. doi: 10.1037/0735-7044.118.2.438 PubMedCrossRefGoogle Scholar
  22. Price AL (2009) Distinguishing the contributions of implicit and explicit processes to performance of the weather prediction task. Mem Cogn 37:210–222. doi: 10.3758/MC.37.2.210 CrossRefGoogle Scholar
  23. Sage JR, Anagnostaras SG, Mitchell S, Bronstein JM, De Salles A, Masterman D, Knowlton BJ (2003) Analysis of probabilistic classification learning in patients with Parkinson’s disease before and after pallidotomy surgery. Learn Mem 10:226–236. doi: 10.1101/lm.45903 PubMedCentralPubMedCrossRefGoogle Scholar
  24. Seger CA, Cincotta CM (2005) The roles of the caudate nucleus in human classification learning. J Neurosci 25:2941–2951. doi: 10.1523/JNEUROSCI.3401-04.2005 PubMedCrossRefGoogle Scholar
  25. Shohamy D, Myers CE, Kalanithi J, Gluck MA (2008) Basal ganglia and dopamine contributions to probabilistic category learning. Neurosci Biobehav Rev 32:219–236. doi: 10.1016/j.neubiorev.2007.07.008 PubMedCentralPubMedCrossRefGoogle Scholar
  26. Smith EE, Jonides J (1999) Storage and executive processes in the frontal lobes. Science 283:1657–1661PubMedCrossRefGoogle Scholar
  27. Thobois S, Hotton GR, Pinto S, Wilkinson L, Limousin-Dowsey P, Brooks DJ, Jahanshahi M (2007) STN stimulation alters pallidal-frontal coupling during response selection under competition. J Cereb Blood Flow Metab 27:1173–1184. doi: 10.1038/sj.jcbfm.9600425 PubMedCrossRefGoogle Scholar
  28. Uslaner JM, Robinson TE (2006) Subthalamic nucleus lesions increase impulsive action and decrease impulsive choice: mediation by enhanced incentive motivation? Eur J Neurosci 24:2345–2354. doi: 10.1111/j.1460-9568.2006.05117.x PubMedCrossRefGoogle Scholar
  29. Weiss D, Brockmann K, Srulijes K et al (2012) Long-term follow-up of subthalamic nucleus stimulation in glucocerebrosidase-associated Parkinson’s disease. J Neurol 259:1970–1972. doi: 10.1007/s00415-012-6469-7 PubMedCrossRefGoogle Scholar
  30. Weiss D, Walach M, Meisner C et al (2013) Nigral stimulation for resistant axial motor impairment in Parkinson’s disease? A randomized controlled trial. Brain 136:2098–2108. doi: 10.1093/brain/awt122 PubMedCentralPubMedCrossRefGoogle Scholar
  31. Wilkinson L, Lagnado DA, Quallo M, Jahanshahi M (2008) The effect of feedback on non-motor probabilistic classification learning in Parkinson’s disease. Neuropsychologia 46:2683–2695. doi: 10.1016/j.neuropsychologia.2008.05.008 PubMedCrossRefGoogle Scholar
  32. Wilkinson L, Beigi M, Lagnado DA, Jahanshahi M (2011) Deep brain stimulation of the subthalamic nucleus selectively improves learning of weakly associated cue combinations during probabilistic classification learning in Parkinson’s disease. Neuropsychology 25:286–294. doi: 10.1037/a0021753 PubMedCrossRefGoogle Scholar
  33. Williams ZM, Eskandar EN (2006) Selective enhancement of associative learning by microstimulation of the anterior caudate. Nat Neurosci 9:562–568. doi: 10.1038/nn1662 PubMedCrossRefGoogle Scholar
  34. Winstanley CA, Baunez C, Theobald DE, Robbins TW (2005) Lesions to the subthalamic nucleus decrease impulsive choice but impair autoshaping in rats: the importance of the basal ganglia in Pavlovian conditioning and impulse control. Eur J Neurosci 21:3107–3116. doi: 10.1111/j.1460-9568.2005.04143.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Daniel Weiss
    • 1
    • 2
    • 3
  • Judith M. Lam
    • 3
  • Sorin Breit
    • 1
    • 2
    • 3
  • Alireza Gharabaghi
    • 2
    • 4
  • Rejko Krüger
    • 1
    • 2
    • 3
  • Andreas R. Luft
    • 5
  • Tobias Wächter
    • 1
    • 2
    • 3
    • 6
    Email author
  1. 1.German Centre of Neurodegenerative DiseasesUniversity of TübingenTübingenGermany
  2. 2.Werner-Reichardt Center for Integrative NeuroscienceTübingenGermany
  3. 3.Department for Neurodegenerative DiseasesHertie Institute for Clinical Brain ResearchTübingenGermany
  4. 4.Division of Functional and Restorative Neurosurgery, Department of NeurosurgeryUniversity of TübingenTübingenGermany
  5. 5.Department of NeurologyClinical NeurorehabilitationZürichSwitzerland
  6. 6.Department of NeurologyCentre of RehabilitationBad GoeggingenGermany

Personalised recommendations