Transcranial magnetic stimulation (TMS)/repetitive magnetic stimulation (TMS)/repetitive TMS in mild cognitive ... 1Department of Neurology, ... thus shedding light on mechanisms of cor-

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  • Review Article

    Transcranial magnetic stimulation(TMS)/repetitive TMS in mild cognitiveimpairment and Alzheimers disease

    Nardone R, Tezzon F, Holler Y, Golaszewski S, Trinka E, Brigo F.Transcranial magnetic stimulation (TMS)/rTMS in mild cognitiveimpairment and Alzheimers disease.Acta Neurol Scand 2014: 129: 351366. 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    Several Transcranial Magnetic Stimulation (TMS) techniques can beapplied to noninvasively measure cortical excitability and brainplasticity in humans. TMS has been used to assess neuroplasticchanges in Alzheimers disease (AD), corroborating findings thatcortical physiology is altered in AD due to the underlyingneurodegenerative process. In fact, many TMS studies have providedphysiological evidence of abnormalities in cortical excitability,connectivity, and plasticity in patients with AD. Moreover, thecombination of TMS with other neurophysiological techniques, suchas high-density electroencephalography (EEG), makes it possible tostudy local and network cortical plasticity directly. Interestingly,several TMS studies revealed abnormalities in patients with early ADand even with mild cognitive impairment (MCI), thus enabling earlyidentification of subjects in whom the cholinergic degeneration hasoccurred. Furthermore, TMS can influence brain function if deliveredrepetitively; repetitive TMS (rTMS) is capable of modulating corticalexcitability and inducing long-lasting neuroplastic changes.Preliminary findings have suggested that rTMS can enhanceperformances on several cognitive functions impaired in AD andMCI. However, further well-controlled studies with appropriatemethodology in larger patient cohorts are needed to replicate andextend the initial findings. The purpose of this paper was to providean updated and comprehensive systematic review of the studies thathave employed TMS/rTMS in patients with MCI and AD.

    R. Nardone1,2, F. Tezzon2,Y. Holler1, S. Golaszewski1,E. Trinka1, F. Brigo2,31Department of Neurology, Christian Doppler Klinik,Paracelsus Medical University, Salzburg, Austria;2Department of Neurology, Franz Tappeiner Hospital,Merano, Italy; 3Department of Neurological,Neuropsychological, Morphological and MovementSciences, Section of Clinical Neurology, University ofVerona, Verona, Italy

    Key words: transcranial magnetic stimulation;Alzheimers disease; mild cognitive impairment; corticalplasticity; intracortical inhibition; afferent inhibition

    R. Nardone, Department of Neurology F. TappeinerHospital Meran/o, Via Rossini, 5 39012 Meran/o (BZ)ItalyTel.: 0473 264616Fax: 0473 264449e-mail:

    Accepted for publication January 8, 2014


    Alzheimers disease (AD) is a neurodegenerativeprocess characterized by progressive neuronal loss,reduced levels of several crucial neurotransmitters,and altered forms of synaptic plasticity. Mildcognitive impairment (MCI) is considered a transi-tional stage between normal aging and a diagnosisof clinically probable AD. Single and paired-pulsetranscranial magnetic stimulation (TMS) canassess cortical excitability, thus representing a

    useful co-adjuvant diagnostic tool to noninvasivelyassess in vivo neuroplastic changes. Pairedassociative stimulation and cortical response torepetitive TMS (rTMS) have provided usefulinformation about different aspects of corticalplasticity. The combination of TMS with electro-encephalography (EEG) or functional magneticresonance imaging (fMRI) can provide furtherinformation on local cortical excitability and func-tional connectivity between motor cortex andother cortical regions.


    Acta Neurol Scand 2014: 129: 351366 DOI: 10.1111/ane.12223 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd


  • We review the most important TMS studiesthat have demonstrated abnormal cortical excit-ability, plasticity, or connectivity in patients withAD and MCI.

    If delivered repetitively, TMS can also inducelong-lasting effects, noninvasively modulating thecortical excitability. rTMS was widely used toassess and modulate a variety of cognitive func-tions (sustained attention/concentration, executivefunctions/working memory verbal fluency/retrie-val, problem solving/reasoning) in patients withdegenerative diseases, patients with psychiatricdisorders and in healthy subjects (for a review,see 1). Memory impairment is usually the firstand more severe cognitive manifestation of theseneurodegenerative processes, and rTMS studieshave confirmed the role of the prefrontal cortex(PFC) during the encoding and retrieval of verbalor nonverbal material in healthy participants(26). By combining fMRI and rTMS, Manentiet al. (7) also provided evidence of a causal roleof not only the PFC but also parietal corticesduring word retrieval. It should be consideredthat the research in the field of memory is limitedby the poor penetration depth of TMS (8).

    In this review, we will also focus on the pres-ent, initial, findings showing that rTMS has thepotential to enhance performances in cognitivefunctions that are impaired in MCI and patientswith AD.

    We update here previous important reviews(i.e., 9, 10) because in the last few years, otherstudies have significantly expanded the previousfindings. We aimed thus to provide a comprehen-sive perspective of past and current research andto help guide future studies.

    The MEDLINE, Pubmed (1966July 2013), andEMBASE (1980July 2013) electronic databaseswere searched using the medical subject headings(MeSH) dementia, Alzheimers disease, mildcognitive impairment, transcranial magnetic stim-ulation, repetitive transcranial magnetic stimula-tion, cortical excitability, cortical plasticity,motor threshold, intracortical inhibition, affer-ent inhibition, and connectivity.

    Two review authors (SG and FB) screened thetitles and abstracts of the initially identified stud-ies to determine whether they satisfied the selec-tion criteria. Any disagreement was resolvedthrough consensus. Full-text articles wereretrieved for the selected titles, and reference listsof the retrieved articles were searched for addi-tional publications. In case of missing or incom-plete data, principal investigators of includedtrials were contacted and additional informationrequested. No language restrictions were applied.

    The two reviewers independently assessed themethodological quality of each study and risk ofbias, focusing on blinding and other potentialsources of bias. The search strategy describedpreviously yielded 48 results. Only articles report-ing data on studies using TMS techniques inpatients with AD or MCI were considered eligiblefor inclusion. We excluded 3 studies after readingthe full published papers; thus, 45 studies contrib-uted to this review: the earliest was published in1997 and the most recent in 2013.

    Transcranial magnetic stimulation techniques

    Measures of cortical excitability

    Resting motor threshold (RMT) is defined as theminimum stimulus intensity that produces amotor evoked potential (MEP) of more than50 lV in 50% of 10 trials in a relaxed muscle,whereas active motor threshold (AMT) is theminimum stimulus intensity required to generatea MEP (about 200 lV in 50% of 10 trials) duringisometric contraction of the tested muscle atabout 10% maximum. RMT provides informa-tion about a central core of neurons in the musclerepresentation in the motor cortex. RMT isincreased by drugs that block voltage-gatedsodium channels (11, 12), but is not affected bydrugs with effect on GABAergic transmission(11, 12), and is lowered by drugs that increasenon-N-methyl-D-aspartate (NMDA) glutamater-gic transmission (13, 14). Therefore, RMT isthought to reflect both neuronal membrane excit-ability and non-NMDA receptor glutamatergicneurotransmission. AMT differs from RMT inthat excitability of motoneurons in the spinalcord is enhanced by the voluntary muscle con-traction, and thus provides a measure of corti-cospinal excitability with greater dependence onthe spinal segmental-level excitability (1517).

    The amplitude of the MEP reflects not only theintegrity of the corticospinal tract and the excit-ability of motor cortex and spinal level, but alsothe conduction along the peripheral motor path-way to the muscles. That is, a dysfunction alongthe corticospinal tract may therefore revealabnormal MEPs, while the absence of MEPsabnormalities suggests integrity of the pyramidaltract (1517). It has been recently demonstrated(18) that changes in MEP amplitudes and motorthreshold represent two different indices of motorcortex plasticity. Whereas increases and decreasesin MEP amplitude are assumed to representLTP-like or LTD-like synaptic plasticity of motorcortex output neurons, changes in motor


    Nardone et al.

  • threshold may be considered as a correlate ofintrinsic plasticity.

    Transcranial magnetic stimulation enablesmapping of motor cortical outputs. Cortical map-ping procedures, performed through single TMSpulses applied on several scalp positions overlyingthe motor cortex, may be obtained with an accu-rate assessment of the number of cortical siteseliciting MEPs in a target muscle, the site of max-imal excitability (hot spot), and the center ofgravity of motor cortical output, as representedby the excitable scalp sites (19).

    Besides evoking MEPs, single TMS pulsesdelivered during voluntary muscle contractionproduce a period of EMG suppression known ascortical silent period (cSP). Moreover, throughsingle-pulse TMS, it is possible to investigateinhibitory motor cortical processes ipsilateral tothe stimulation side (ipsilateral silent period, iSP),which are considered to reflect the functionalintegrity of the callosal fibers connecting corre-sponding motor cortices (20).

    Transcranial magnetic stimulation may also beused to assess the intracortical facilitatory andinhibitory mechanisms that influence the corticalmotor output. Some of these TMS techniquesinvolve paired stimuli based on a conditioning-test paradigm (21). Stimulation parameters suchas the intensity of the conditioning (CS) and teststimulus (TS), together with the time betweenthem (interstimulus interval, ISI), determine inter-actions between stimuli. When the CS is belowand the TS is above the MT, the CS inhibits theresponse to TS at ISIs of 15 ms (short-latencyintracortical inhibition, SICI), inducing anincrease in the test MEP amplitude at ISIs of720 ms (intracortical facilitation, ICF). CS atsuprathreshold intensity inhibits the TS at ISIs of50200 ms and this is termed long-interval intra-cortical inhibition (LICI). Both SICI and cSP arethought to reflect the excitability of inhibitoryGABAergic cortical circuits (15), and SICI isconsidered to reflect mostly the GABAA-mediatedintracortical inhibitory interactions (22). Whereasspinal inhibition contributes to the early phase ofthe cSP (for its first 5075 ms), the late part ofthe SP, as well as LICI, reflect a long-lasting cor-tical inhibition mediated by GABAB most likelyin the motor cortex (23).

    Conversely, ICF is believed to reflect intracorti-cal excitatory neurotransmission, which is largelymediated by NMDA receptors (24).

    Short-latency afferent inhibition (SAI) refers tothe suppression of the amplitude of a MEP pro-duced by a conditioning afferent electrical stimu-lus, usually applied to the median nerve at the

    wrist approximately 20 ms prior to TMS of thehand area of the contralateral motor cortex (25).As SAI is decreased by the muscarinic receptorantagonist scopolamine in healthy individuals(26) and can be positively modulated by acetyl-choline (Ach) in healthy individuals (27, 28), thismeasure is thought to be a non-invasive way oftesting central cholinergic activity. However, SAImay also depend on the integrity of circuits con-necting sensory input with motor output (29),and other neurotransmitters, especially dopamine,are supposed to play a modulatory role on thecholinergic neurotransmission.

    Cortical connectivity and plasticity

    Real-time integration of TMS with electroencepha-lography (EEG) (3032) can provide further infor-mation on local cortical excitability andwidespread network dynamics. As a matter of fact,EEG has an excellent temporal resolution, whereasTMS can be applied to study local reactivity of thebrain and interactions between different brainregions with directional and precise chronometricinformation. The effects of several experimentalmanipulations including TMS in rodents on EEGrhythms have been recently reviewed to build aknowledge platform for innovative translationalmodels for drug discovery in AD (33).

    Several other TMS techniques are currentlyused to noninvasively modulate the cortical excit-ability, thus shedding light on mechanisms of cor-tical plasticity in humans.

    Paired associative stimulation (PAS) and corti-cal responses to rTMS also provide informationabout different aspects of cortical plasticity (34).Through PAS procedure, an electrical stimulus isdelivered to a peripheral nerve (usually the med-ian nerve), followed by a single TMS pulseapplied over the hand area of the primary motorcortex (M1) (35). When appropriately timed, PASinduces an increase in corticospinal excitabilityover a period of time which is interpreted as amarker of motor cortical plasticity, where long-term plasticity (LTP)-like processes are thoughtto play a major role (35). A new repetitive PAS(rPAS) protocol facilitates and prolongs theeffects of electrical peripheral nerve stimulationand rTMS on cortical excitability. Submotorthreshold 5-Hz repetitive electrical nerve stimula-tion of the right median nerve is synchronizedwith subthreshold 5-Hz rTMS of the left M1 at aconstant interval for 2 min. The ISI between theperipheral stimulus and the transcranial stimula-tion is set at 10 ms (5-Hz rPAS10 ms) or 25 ms(5-Hz rPAS25 ms) (36).


    TMS/rTMS in MCI and AD

  • If delivered repetitively, TMS can influencebrain function. Through rTMS, a train of TMSpulses of the same intensity are applied to a sin-gle brain area at a given frequency ranging from1 to 20 or more stimuli per second. Dependingon the stimulation parameters, particularly thefrequency of stimulation, cortical excitability canbe modulated, thus obtaining a facilitating orsuppressing effect. RTMS can be applied as con-tinuous trains of low-frequency (1 Hz) or burstsof higher-frequency ( 5 Hz) rTMS. Generally,low-frequency rTMS (stimulus rates 1 Hz)induces inhibitory effects on motor cortical excit-ability leading to a reversible virtual lesion (37,38), whereas high-frequency rTMS (520 Hz)usually promotes an increase in cortical excitabil-ity (39, 40). This modulation can last for severalminutes (depending on the overall duration of thetrain itself) and provides an index of corticalplasticity. A novel protocol of rTMS named thetaburst stimulation (TBS) (41) employs low intensi-ties and has a robust, long-lasting effect in nor-mal subjects (41, 42). Different patterns ofdelivery of TBS (continuous vs intermittent) pro-duce opposite effects on synaptic efficiency of...


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