Clinical short communication| Volume 398, P27-30, March 15, 2019

Superconditioning TMS unmasks latent voluntary innervation in MND – A case report

Published:January 16, 2019DOI:


      • TMS is used to elicit motor evoked potentials (MEPs) in normal muscle.
      • MEPs from certain target muscles may fail in persons with MND.
      • We describe a novel 4-pulse TMS method that can restore MEPs in a subject with MND.
      • This TMS pattern unmasked voluntary movement in a muscle previously paralyzed.
      • This method may be useful for studies of brain plasticity, or neuromodulation.


      Motor neuron disease (MND) includes both ALS and Progressive Muscular Atrophy (PMA) as variants. Abnormalities in brain excitability and upper motor neuron (UMN) function are characteristic of ALS, but by definition are absent in PMA. Transcranial magnetic stimulation (TMS) may be useful in demonstrating UMN pathology, but loss of muscle responsiveness with disease progression limits its usefulness in later stages of MND. We have developed a novel form of TMS comprised of 4 stimulating pulses that can enhance MEPs in target muscles already responding to traditional TMS inputs, in some cases even restoring MEPs in target muscles rendered unresponsive by the disease. An example of restored MEPs in response to this superconditioning TMS pattern (TMSsc) in a person with PMA is described, along with an unexpected finding. Despite a prolonged (> 5 year) history of movement paralysis in his right tibialis anterior (TA), immediately after cessation of TMSsc delivery the subject could now easily contract and relax this muscle; the presence of a latent pathway for voluntary innervation of his right TA was revealed. This modulation of central motor functional connectivity in response to TMSsc suggests a further, clinically-significant benefit of this form of noninvasive brain stimulation beyond its ability to enhance MEPs to traditional TMS inputs.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Barker A.T.
        • Jalinous R.
        • Freston I.L.
        Non-invasive magnetic stimulation of human motor cortex.
        Lancet. 1985; 1: 1106-1107
        • Kujirai T.
        • Caramia M.D.
        • Rothwell J.C.
        • Day B.L.
        • Thompson P.D.
        • Ferbert A.
        • Wroe S.
        • Asselman P.
        • Marsden C.D.
        Corticocortical inhibition in human motor cortex.
        J. Physiol. Lond. 1993; 471: 501-519
        • Ziemann U.
        • Rothwell J.C.
        • Ridding M.C.
        Interaction between intracortical inhibition and facilitation in human motor cortex.
        J. Physiol. Lond. 1996; 496: 873-881
        • Calancie B.
        • Wang D.
        • Young E.
        • Alexeeva N.
        Four-pulse transcranial magnetic stimulation using multiple conditioning inputs. Normative MEP responses.
        Exp. Brain Res. 2018; 236: 1205-1218
        • Vucic S.
        • Ziemann U.
        • Eisen A.
        • Hallett M.
        • Kiernan M.C.
        Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights.
        J. Neurol. Neurosurg. Psychiatry. 2013; 84: 1161-1170
        • Vucic S.
        • Kiernan M.C.
        Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease.
        Brain. 2006; 129: 2436-2446
        • Stefan K.
        • Kunesch E.
        • Benecke R.
        • Classen J.
        Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis.
        Ann. Neurol. 2001; 49: 536-539
        • Mills K.R.
        The natural history of central motor abnormalities in amyotrophic lateral sclerosis.
        Brain. 2003; 126: 2558-2566
        • Attarian S.
        • Pouget J.
        • Schmied A.
        Changes in cortically induced inhibition in amyotrophic lateral sclerosis with time.
        Muscle Nerve. 2009; 39: 310-317
        • Triggs W.J.
        • Menkes D.
        • Onorato J.
        • Yan R.S.H.
        • Young M.S.
        • Newell K.
        • Sander H.W.
        • Soto O.
        • Chiappa K.H.
        • Cros D.
        Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease.
        Neurology. 1999; 53: 605-611
        • Mills K.R.
        Motor neuron disease. Studies of the corticospinal excitation of single motor neurons by magnetic brain stimulation.
        Brain. 1995; 118: 971-982
        • de Carvalho M.
        • Scotto M.
        • Swash M.
        Clinical patterns in progressive muscular atrophy (PMA): a prospective study.
        Amyotroph. Lateral Scler. 2007; 8: 296-299
        • Brooks B.R.
        • Miller R.G.
        • Swash M.
        • Munsat T.L.
        • D. World Federation of Neurology Research Group on Motor Neuron
        El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.
        Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 2000; 1: 293-299
        • Calancie B.
        • Molano M.R.
        • Broton J.G.
        EMG for assessing the recovery of voluntary movement after acute spinal cord injury in man.
        Clin. Neurophysiol. 2004; 115: 1748-1759
        • Hamada M.
        • Hanajima R.
        • Terao Y.
        • Arai N.
        • Furubayashi T.
        • Inomata-Terada S.
        • Yugeta A.
        • Matsumoto H.
        • Shirota Y.
        • Ugawa Y.
        Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex.
        Clin. Neurophysiol. 2007; 118: 2672-2682
        • Alexeeva N.
        • Calancie B.
        Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: three case studies.
        J. Spinal Cord. Med. 2016; 39: 50-57
        • Ince P.G.
        • Evans J.
        • Knopp M.
        • Forster G.
        • Hamdalla H.H.
        • Wharton S.B.
        • Shaw P.J.
        Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS.
        Neurology. 2003; 60: 1252-1258
        • Van den Berg-Vos R.M.
        • Visser J.
        • Kalmijn S.
        • Fischer K.
        • de Visser M.
        • de Jong V.
        • de Haan R.J.
        • Franssen H.
        • Wokke J.H.
        • Van den Berg L.H.
        A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes.
        Arch. Neurol. 2009; 66: 751-757
        • Kim W.K.
        • Liu X.
        • Sandner J.
        • Pasmantier M.
        • Andrews J.
        • Rowland L.P.
        • Mitsumoto H.
        Study of 962 patients indicates progressive muscular atrophy is a form of ALS.
        Neurology. 2009; 73: 1686-1692