Mechanisms underlying training-related motor improvement in cerebellar ataxia.

• Applicant: Professorin Dr. Dagmar Timmann-Braun
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268201366

• Final Report Year: 2019

Final Report Abstract

Physical therapy remains the main clinical approach to patients suffering from cerebellar pathology with genetic therapies being at the horizon for only a subset of hereditary ataxias. In more recent years, well-controlled studies have been performed providing unequivocal proof that patients with cerebellar ataxia benefit from motor training. However, it is unknown what kind of training helps best in which kind of cerebellar patients, and whether neural stimulation might enhance training effects. Our main goal was to initiate a research program specifically designed to address this gap. More specifically, we aimed to substantiate the recent finding that slow adaptation processes may be preserved in cerebellar disease, and to investigate whether such slow learning is retained. We found that a high number of learning trials (that is overlearning) resulted in higher levels of slow learning in control subjects, but also in ataxia patients. However, whereas higher levels of slow learning were more resilient against forgetting in healthy controls, this was not the case in cerebellar patients. While memory resilience was reduced in cerebellar patients, retention was still amplified after extended training. We hypothesize that the mechanism underlying increased retention rates of the slow system is mediated via extra-cerebellar areas. A possible candidate for such an extra-cerebellar mechanism is use-dependent plasticity which is thought to rely primarily on the primary motor cortex. If use-dependent learning is spared in cerebellar patients, and extended training leads to higher retention of learned motor behavior, this may be leveraged to develop more effective therapy strategies in the future. Furthermore, we investigated whether non-invasive cerebellar or cerebral sensorimotor stimulation (transcranial direct current stimulation, tDCS) enhanced learning in patients with cerebellar degeneration. This was not the case. Our results require a critical re-evaluation of the clinical potential of tDCS in cerebellar patients.

Publications

• Cerebellar patients do not benefit from cerebellar or M1 transcranial direct current stimulation during forcefield reaching adaptation. J Neurophysiol. 2017 Aug 1;118(2):732-748
  Hulst T, John L, Küper M, van der Geest JN, Göricke SL, Donchin O, Timmann D
  
• Effects of transcranial direct current stimulation on grip force control in patients with cerebellar degeneration. Cerebellum Ataxias. 2017 Sep 15;4:15
  John L, Küper M, Hulst T, Timmann D, Hermsdörfer J
  
• Consensus Paper: Experimental Neurostimulation of the Cerebellum. Cerebellum. 2019 Jun 4
  Miterko LN, Baker KB, Beckinghausen J, Bradnam LV, Cheng MY, Cooperrider J, DeLong MR, Gornati SV, Hallett M, Heck DH, Hoebeek FE, Kouzani AZ, Kuo SH, Louis ED, Machado A, Manto M, McCambridge AB, Nitsche MA, Taib NOB, Popa T, Tanaka M, Timmann D, Steinberg GK, Wang EH, Wichmann T, Xie T, Sillitoe RV
  
• How to help cerebellar patients make the most of their remaining learning capacities. Brain. 2019 Mar 1;142(3):492-495
  Donchin O, Timmann D
  
• No effects of cerebellar transcranial direct current stimulation on force field and visuomotor reach adaptation in young and healthy subjects. J Neurophysiol. 2019 Jun 1;121(6):2112-2125
  Mamlins A, Hulst T, Donchin O, Timmann D, Claassen J