Transcranial Magnetic Stimulation in Alzheimers Disease and Cortical Dementias

Benussi A, Padovani A and Borroni B^*

Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy

Corresponding Author:

Barbara Borroni
MD, Clinica Neurologica, Università degliStudi di Brescia
P.le Spedali Civili 1, 25123, Brescia, Italy
Tel: 0039 0303995632
E-mail: bborroni@inwind.it

Received date: September 07, 2015; Accepted date: October 16, 2015; Published date: October 23, 2015

Citation: Benussi A, Padovani A, Borroni B (2015) Transcranial Magnetic Stimulation in Alzheimer’s Disease and Cortical Dementias. J Alzheimers Dis Parkinsonism 5:197. doi: 10.4172/2161-0460.1000197

Copyright: © 2015 Benussi A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Transcranial magnetic stimulation (TMS) has become a safe, noninvasive, and promising tool to assess specific cortical circuits in the central nervous system. Since its introduction, the use of TMS in clinical neurophysiology, neurology, neuroscience, and psychiatry has spread widely, leading to important findings on cortical function in physiological and pathological conditions. Indeed, numerous studies have described abnormalities in specific cortical circuits using particular TMS stimulation paradigms, which allow the indirect assessment of inhibitory and excitatory interneuronal activity, mainly dependent on GABA receptors, of central cholinergic activity, and of cortical plasticity. The objective of the present work is to examine the utility of TMS as a means to support and predict the clinical diagnosis of Alzheimer ’s disease and other cortical dementias, in a setting where our understanding of neurodegenerative diseases is far from adequate.

Keywords

Transcranial magnetic stimulation; Brain stimulation; Alzheimer’s disease; Dementia with Lewy bodies; Frontotemporal lobar degeneration

Abbreviations

AD: Alzheimer’s Disease; DLB: Dementia with Lewy bodies; PDD: Parkinson’s Disease Dementia; FTD: Frontotemporal Dementia; CBD: Corticobasal Degeneration; PSP: Progressive Supranuclear Palsy; rMT: Resting Motor Threshold; CSP: Cortical Silent Period; SICI: Short Interval Intracortical Inhibition; ICF: Intracortical Facilitation; LICI: Long Interval Intracortical Inhibition; SAI: Short Latency Afferent Inhibition

Introduction

Alzheimer’s disease (AD), Dementia with Lewy Bodies (DLB), Parkinson’s disease dementia (PDD) and frontotemporal lobar degeneration (FTLD), account for the predominant cause of dementia in the population aged ≥ 60 years, with an estimated prevalence of 5-7% in this age-group [1], escalating to about 30% in the people older than 85 [2]. With the progressive aging of the population, the prevalence of dementia is estimated to double every 20 years [3], thus becoming a health- and social-care priority for many high-income countries. Numerous studies have tried to address the challenge of identifying early biological or neuroimaging markers in order to unravel the physiopathological processes underlying these disorders and to correctly recognize the earliest stages of disease, when the neurodegenerative process is still limited and possibly reversible [4].

In this view, also neurophysiological techniques, particularly transcranial magnetic stimulation (TMS), have become promising tools to assess specific cortical circuits in the central nervous system. Since its introduction, the use of TMS in clinical neurophysiology, neurology, neuroscience, and psychiatry has spread widely, leading to important findings on cortical function in physiological and pathological conditions [5].Indeed, with the contribution of pharmacological studies, numerous TMS stimulation paradigms have been developed to assess, non-invasively and in-vivo, the function of GABAergic, glutamatergic and cholinergic cortical circuits [6]. Furthermore, specific paradigms of paired associative stimulation (PAS) [7] or repetitive TMS (rTMS) [8,9] have shown to increase or decrease the excitability of corticospinal projections of the primary motor cortex (M1), representing a form of long-term potentiation (LTP) or depression (LTD) and thus a method of assessing synaptic plasticity [10].

The objective of the present review is to examine the utility of TMS as a means to aid and predict the early diagnosis of AD and other cortical dementias, bearing in mind that a precise and prompt diagnosis will be critical in the prospect of future disease-modifying therapies.

Transcranial Magnetic Stimulation Techniques

Single-pulse stimulation

Motor threshold (MT): MT is defined as the minimal intensity of motor cortex stimulation required to elicit a reliable motor evoked potential (MEP) of minimal amplitude in the target muscle. It is considered a reliable global measure of corticospinal excitability and depends on the excitability of axons activated by the TMS pulse, as well as the excitability of synaptic connections at both the cortical and spinal level [11-14]. Resting MT (RMT) is determined while the target muscle is completely at rest, while the active MT (AMT) is usually determined during a slight tonic contraction of the target muscle at approximately 20% of the maximal muscle strength [11,12].

RMT is considered as a global parameter of human brain excitability as it mainly reflects the membrane excitability of corticospinal neurons, cortico-cortical axons and their excitatory synaptic contacts, mediated by voltage-gated sodium channels and by ionotropic glutamatergic non-NMDA receptors [15].

Motor evoked potential amplitude: The MEP is typically recorded over the target muscle using surface electrodes in a bipolar bellytendon arrangement, applying a single TMS pulse to the contralateral primary motor cortex (M1) at adequate stimulator intensity [16]. Extrinsic factors, as conditioning stimuli preceding a test TMS stimulus, and intrinsic factors, as mental activity, can modulate the cortico-motor excitability and change MEP amplitude [12]. MEP amplitude increases gradually with TMS intensity, with a relationship between stimulus intensity and MEP amplitude described by a sigmoid curve, also known as the “stimulus-response curve” or “recruitmentcurve”. MEP amplitude evoked by above threshold stimuli clearly reflects trans-synaptic activation of cortico-spinal neurons through a complex network of excitatory circuits controlled by inhibitory circuits. Pharmacological studies showed that this network is regulated by glutamatergic, GABAergic and neuromodulating (in particular noradrenergic and serotonergic) neurotransmitters [15]. The versatile modulation of the stimulus-response function by physiological variables explains why the measurement of MEP amplitude is the most widespread electrophysiological method to assess after-effects of repetitive TMS and other non-invasive brain stimulation protocols applied over M1 on corticospinal excitability [12,17,18].

Cortical silent period (CSP): The CSP is a period of electrical silence lasting up to 100-300 ms in the surface electromyographic activity [19], that can be evoked using TMS at suprathreshold intensities. The duration of the CSP gradually increases with the intensity of TMS and is mediated by intra-cortical inhibitory phenomena [20-25]. Pharmacological studies suggested that at the lower range of stimulus intensities, CSP duration reflects the activation of GABAA receptors, while at higher range of stimulus intensities, it reflects the activation of GABAB receptors [12,26-32].

Paired-pulse stimulation

Paired-pulse stimulation TMS usually involves a conditioning stimulus (CS) followed by a test stimulus (TS), and MEP amplitudes are compared to those produced by the TS alone as a reference condition. Many paradigms have been developed by varying the intensity of the CS and the interval between the pair of TMS pulses, or interstimulus interval (ISI). Different paired-pulse TMS paradigms allow the noninvasive assessment of inhibitory and excitatory interneuronal activity within the human cortex [12].

Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF): SICI is elicited when a subthreshold CS is followed by a suprathreshold TS at an ISI of 1-6 ms and likely reflects intracortical post-synaptic inhibition mediated by GABAA receptors, positively modulated by dopamine and nicotine, and decreased by noradrenaline [14,15,33-35]. ICF can be elicited with a similar protocol as SICI but at longer ISIs of 6-30 ms and, although poorly understood, may reflect excitatory glutamatergic circuits in M1 [12,15,33,36-38].

Long interval intracortical inhibition (LICI): LICI is tested by applying two suprathreshold stimuli at long ISIs of 50-200 ms, leading to inhibition of the TS by the CS, and is likely mediated by GABAB receptors [15,27,30,34,39-42].

Paired-associative stimulation (PAS): PAS involves a TMS stimulus preceded by a conditioning electrical stimulus of a peripheral nerve at different ISIs [43]. This paradigm, consisting of low-frequency repetitive stimulation of the median nerve (typically 90-200 stimuli) combined with a TMS stimulus over the contralateral motor cortex, may induce persistent and reversible excitability changes in the motor cortex [10,44]. PAS with an ISI of 25 ms (PAS25) leads to a strong facilitation of MEPs, mainly dependent on NMDA receptors, while an ISI of 10 ms (PAS10) causes inhibition [7,45]. It has been suggested that these effects represent, respectively, a form of associative LTP and LTD, and thus a method of assessing cortical synaptic plasticity [7,44-48].

Short latency afferent inhibition (SAI): SAI is elicited if median nerve stimulation precedes contralateral M1 TMS at ISIs around the latency of the N20 component of the somatosensory evoked potential, with a maximum inhibition occurring at about N20 latency plus 2 ms [43,49], and is likely mediated by cholinergic [50,51] and GABAAergic circuits [52]. SAI decreases with normal aging [53,54] and in neurodegenerative disorders of the central cholinergic system, such as AD [51,55-57].

Repetitive TMS

Repetitive TMS (rTMS) can be applied at various stimulation frequencies or as a patterned train of pulses, and has a modulatory effect on cortical excitability, which outlasts the stimulation period. Stimulation frequencies below 1 Hz are mainly inhibitory [8,58], while repetition rates above 5 Hz are mainly facilitatory [8,59]. Recently, newer patterned protocols such as theta burst stimulation (TBS) have been developed to modulate cortical excitability [60]. TBS consists of TMS pulses delivered as a 3-pulse 50-Hz burst applied at 5 Hz. Intermittent TBS (iTBS) involves 600 pulses delivered as 2-sec trains of TBS repeated every 10 sec for about 3 min, producing LTP-like plasticity in the cortex. In contrast, continuous stimulation for 40 sec of TBS (cTBS) results in a LTD-like decrease in motor cortex excitability [60]. Most rTMS paradigms are NMDA-receptor activity dependent [61] and are modulated by prior synaptic activation [62].

The Role of TMS in the Diagnosis of Dementia

Alzheimer’s disease

Several studies have identified an enhanced cortical excitability in AD, assessed by a reduction in the MT [55,63-83], even in the early phases of disease [31,55,56,64,66-75,77,78,81-88], albeit studies in patients with mild cognitive impairment (MCI) have reported contrasting results [87-89]. The gradual reduction in MT seems to correlate with disease progression [79,90], although a subsequent increase in MT has been identified in advanced stages of disease, possibly secondary to severe cortical atrophy [91].

Studies regarding the duration of the CSP have found contrasting results, with the majority of studies showing no significant alterations [55,64,74,75,82,86], while two studies showed a significant reduction in the duration of the CSP [63,91].

Contrasting results have been reported regarding SICI, with some studies showing normal inhibition [55,56,67,69-71,80,84,92], while others showing a reduction of SICI [73,78,86,87,93,94]. ICF seems to be unaffected in AD [31,55,56,71,78,80,84,86,87,92-94].

LICI was significantly reduced in one study in patients in therapy with memantine, thus no clear associations can be made on the role of the underlying pathology or the effect of the drug [65].

The dysfunction of the cholinergic system, highlighted by a reduction in SAI, has been widely reported in patients with AD [52,55,56,67-71,77,81,88,93,95]. Moreover, the restoration of SAI after the use of acetylcholinesterase inhibitors [51,55,67] and L-dopa [77] further supports this hypothesis, and seems to correlate with the response to treatment [51,55]. Cerebrospinal fluid (CSF) levels of amyloid beta42 and phosphorylated tau significantly correlate with the decrease in SAI, suggesting that these peptides may have some influence on the cholinergic dysfunction in AD [96]. Interestingly, as recently reported, a single session of cerebellar cTBS partially restored SAI in AD patients, suggesting that the cerebellum may have a direct influence on the cholinergic dysfunction in AD [71].

The decrease in SAI has also been reported in a single study on MCI patients, in particular in the amnestic presentations, while it was not significantly different in the non-amnestic form, thus suggesting possible at risk patients which will convert into dementia [57].

Cortical plasticity, as assessed by rTMS or PAS, also seems to be altered in patients with AD. Indeed, inhibitory and excitatory rTMS paradigms have shown reduced LTD- and LTP-like cortical plasticity, respectively [74,82,97]. The amount of rTMS-induced inhibition correlated with the CSF levels of total tau, but not with amyloid beta42, possibly suggesting an involvement of tau on the abnormal excitatory activity and thus on the mechanisms of cortical plasticity [98]. Likewise, iTBS and cTBS protocols have revealed a reduced LTP-like cortical plasticity with a normal LTD-like effect [99].

Pharmacological modulation of cortical plasticity could provide novel implications in disease pathophysiology; indeed, rotigotine administration was shown to restore LTP-like cortical plasticity in AD patients, as assessed by iTBS, thus providing novel implications for therapies based on dopaminergic stimulation [100].

Similarly to studies with rTMS, PAS protocols have shown impairment in cortical plasticity in mild and moderate AD, highlighting the involvement not only of the motor cortex but also of sensorimotor integration [81,85].

Dementia with lewy bodies and parkinson’s disease dementia

The rMT and SICI [70,93] seems to be unaffected in DLB. The cholinergic dysfunction, which is a hallmark of DLB and PDD, has been further corroborated by a series of studies that demonstrated a significant decrease in SAI, in both DLB [70,95] and PDD [101-103]. These findings have been confirmed also in patients with Parkinson’s disease and MCI [104-106].

In DLB patients, the defect of cholinergic activity, assessed by SAI, strongly correlated with visual hallucinations [95], while visual cortical excitability correlated with the severity of visual hallucinations [107].

Frontotemporal lobar degeneration

Frontotemporal dementia (FTD): Only five studies to date have assessed neurophysiological characteristics in patients with FTD. These studies have been hindered by the small number and by the selection of patients, which has been exclusively clinical and not taking into account the importance of CSF proteins (amyloid beta42, total and phosphorylated tau) to exclude possible focal variants of AD, or the genetic contribution of known pathogenic mutations.

These studies have shown central motor circuit abnormalities, even in cases without clinical evidence of motor involvement [31,68,75,84,108]. No significant alterations in MT [31,37,75,84,108], SICI or ICF [31,68,84], and SAI [68] have been shown in FTD.

However, recent studies have revealed a significant decrease in SICI, in particular in the progressive non-fluent aphasia subgroup, in contrast to the behavioral variant FTD and semantic dementia subgroups [84,108].

Corticobasal degeneration (CBD): Patients with CBD show significant higher MT, in agreement with the frequent involvement of motor areas in this disorder [84,109,110]. As a result, many cortical inhibitory mechanisms are altered in CBD, as CSP [109,111,112] and SICI [84,109,110,113,114]. No significant differences in ICF have been reported in CBD patients [84,109]. As with studies in FTD patients, diagnosis was exclusively made on clinical basis, not taking into account CSF values to exclude focal variants of AD, which have been reported in up to 50% of patients with corticobasal syndrome [115,116].

Progressive supranuclear palsy (PSP): Neurophysiological studies revealed a rMT within normal range and a reduced CSP in PSP patients [109,117]. Inhibitory mechanisms were also reduced, as assessed by SICI [109,117,118] and SAI [118], while ICF di not differ significantly from healthy subjects [117].

Cortical plasticity, as assessed by iTBS, elicited a significantly larger MEP facilitation in patients than in healthy subjects [117]. On the other hand, cTBS showed a paradoxical facilitation of MEPs in PSP patients, which correlated with disease progression [117].

The involvement of cerebellar structures and of the dentatothalamo- cortical pathway in PSP has been assumed based on the reduction in MEP inhibition following TMS of the cerebellum, accounting for the so called cerebellar brain inhibition (CBI) [118,119]. Moreover, cerebellar iTBS modulated this altered functional cerebellarmotor connectivity, as assessed by an increase in CBI [118].

Discussion

TMS is a non-invasive and effective methodology with the potential to assess the functional integrity of cortical networks, in particular with the use of paired-pulse paradigms, which selectively target precise neurotransmitters and receptors.

Several studies have shown that TMS techniques may represent an additional tool for the functional assessment of patients with dementia (Table 1). In summary, the studies reviewed so far have consistently found a significant reduction of SAI in patients with AD [55], DLB [69] and PDD [103], which all have an established cholinergic deficit that responds to cholinergic medications [120].

Table 1: Predominant neurophysiological parameters in dementias.

Conversely, in other non-cholinergic forms of dementia, as in FTD, SAI was found to be normal [68]. Therefore, SAI testing could be used as a non-invasive in vivo assessment for cholinergic dysfunction in patients with dementia, representing a useful tool in differentiating between the cholinergic and the non-cholinergic forms of dementia. Moreover, TMS could thus be used to identify patients at increased risk to convert into dementia [57], monitor disease progression and response to treatment [51].

Cortical hyperexcitability consistently found in AD patients, assessed by a reduction of the rMT [121], could be the result of a glutamatergic overactivation, possibly secondary to an imbalance between NMDA and non-NMDA neurotransmission [122].

Studies assessing intracortical inhibition (CSP and SICI) have reported contrasting results in many cases; these parameters seem to be more often altered in patients with dementia associated with parkinsonian features, as in DLB, PDD, PSP and CBD, suggesting an involvement of GABAergic circuits in these disorders [70,109,111,112,117,123]. The assessment of inhibitory circuits in FTD have led to conflicting results, possibly due to the wide variability of included patients, with different clinical phenotypes and without the assessment of CSF parameters or genetic contributors.

Finally, rTMS and TBS protocols both have the potential of inducing cortical plasticity, which can be useful in assessing deficient neuromodulation in neurodegenerative disorders, as in AD [74] and PSP [117], but also be a suitable rehabilitative tool to improve cognitive performance [124-129].

Future approaches with single-pulse and paired-pulse TMS will surely benefit from the integration of different stimulation paradigms in diagnostic algorithms, aiding in a more efficient differential diagnosis even at the single-subject level. While single TMS sessions currently carry a low specificity, a multi-paradigm approach can support the clinical diagnosis, predict progression and possibly identify at risk patients, providing the footprints of specific pathophysiological processes that affects motor and non-motor areas in the various form of dementia.

The future advances in technological development will further increase the potential of these techniques in accurately predicting the underlying neurodegenerative disorder, as recent studies have highlighted. Indeed, increased spatial sensitivity of the stimulation [130] and the development of more sophisticated paradigms, such as triple- [131] or quadro-pulse [132] stimulation techniques, will aid in detecting preclinical changes in brain connectivity.

Combined with other techniques, as EEG [133,134] and fMRI [135,136], TMS co-registration studies will be key in tracking temporal dynamics and of brain functional and effective connectivity, possibly clarifying some essential issues underlying brain physiology [137]. Future work with the application of these techniques promises to provide valuable advances in our understanding of the pathophysiology of a wide range of neurodegenerative disorders.

References

1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, et al. (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9: 63-75.
2. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, et al. (2007) Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29: 125-132.
3. Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ (2012) Epidemiology of dementias and Alzheimer's disease. Arch Med Res 43: 600-608.
4. Bredesen DE (2014) Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY) 6: 707-717.
5. Cantone M, Di Pino G, Capone F, Piombo M, Chiarello D, et al. (2014) The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia. ClinNeurophysiol 125: 1509-1532.
6. Paulus W, Classen J, Cohen LG, Large CH, Di Lazzaro V, et al. (2008) State of the art: Pharmacologic effects on cortical excitability measures tested by transcranial magnetic stimulation. Brain Stimul 1: 151-163.
7. Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J (2000) Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123 Pt 3: 572-584.
8. Fitzgerald PB, Fountain S, Daskalakis ZJ (2006) A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. ClinNeurophysiol 117: 2584-2596.
9. Thut G, Pascual-Leone A (2010) A review of combined TMS-EEG studies to characterize lasting effects of repetitive TMS and assess their usefulness in cognitive and clinical neuroscience. Brain Topogr 22: 219-232.
10. McKay DR, Ridding MC, Thompson PD, Miles TS (2002) Induction of persistent changes in the organisation of the human motor cortex. Exp Brain Res 143: 342-349.
11.  Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, et al. (1994) Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. ElectroencephalogrClinNeurophysiol 91: 79–92.
12. Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, et al. (2015) Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. ClinNeurophysiol 126: 1071-1107.
13. Rossini PM, Rossi S, Babiloni C, Polich J (2007) Clinical neurophysiology of aging brain: from normal aging to neurodegeneration. ProgNeurobiol 83: 375-400.
14. Ziemann U, Lönnecker S, Steinhoff BJ, Paulus W (1996) Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 40: 367-378.
15. Ziemann U, Reis J, Schwenkreis P, Rosanova M, Strafella A, et al. (2015) TMS and drugs revisited 2014. ClinNeurophysiol 126: 1847-1868.
16. Di Lazzaro V, Oliviero A, Profice P, Meglio M, Cioni B, et al. (2001) Descending spinal cord volleys evoked by transcranial magnetic and electrical stimulation of the motor cortex leg area in conscious humans. J Physiol 537: 1047-1058.
17. Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148: 1-16.
18. Ziemann U, Paulus W, Nitsche MA, Pascual-Leone A, Byblow WD, et al. (2008) Consensus: Motor cortex plasticity protocols. Brain Stimul 1: 164-182.
19. Merton PA, Morton HB (1980) Stimulation of the cerebral cortex in the intact human subject. Nature 285: 227.
20. Pierrot-Deseilligny E, Bussel B, Held JP, Katz R (1976) Excitability of human motoneurones after discharge in a conditioning reflex. ElectroencephalogrClinNeurophysiol 40: 279-287.
21. Person RS, Kozhina GV (1978) Study of orthodromic and antidromic effects of nerve stimulation on single motoneurones of human hand muscles. ElectromyogrClinNeurophysiol 18: 437-456.
22. Haug BA, Schönle PW, Knobloch C, Köhne M (1992) Silent period measurement revives as a valuable diagnostic tool with transcranial magnetic stimulation. ElectroencephalogrClinNeurophysiol 85: 158-160.
23. Inghilleri M, Berardelli A, Cruccu G, Manfredi M (1993) Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol 466: 521-534.
24. Rossini PM, Caramia MD, Iani C, Desiato MT, Sciarretta G, et al. (1995) Magnetic transcranial stimulation in healthy humans: influence on the behavior of upper limb motor units. Brain Res 676: 314-324.
25. Orth M, Rothwell JC (2004) The cortical silent period: intrinsic variability and relation to the waveform of the transcranial magnetic stimulation pulse. ClinNeurophysiol 115: 1076-1082.
26. Stetkarova I, Kofler M (2013) Differential effect of baclofen on cortical and spinal inhibitory circuits. ClinNeurophysiol 124: 339-345.
27. McDonnell MN, Orekhov Y, Ziemann U (2006) The role of GABA(B) receptors in intracortical inhibition in the human motor cortex. Exp Brain Res 173: 86-93.
28. Inghilleri M, Berardelli A, Marchetti P, Manfredi M (1996) Effects of diazepam, baclofen and thiopental on the silent period evoked by transcranial magnetic stimulation in humans. Exp Brain Res 109: 467-472.
29. Siebner HR, Dressnandt J, Auer C, Conrad B (1998) Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia. Muscle Nerve 21: 1209–1212.
30. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J (1999) Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol517 : 591-597.
31. Pierantozzi M, Panella M, Palmieri MG, Koch G, Giordano A, et al. (2004) Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia. ClinNeurophysiol 115: 2410-2418.
32. Kimiskidis VK, Papagiannopoulos S, Kazis DA, Sotirakoglou K, Vasiliadis G, et al. (2006) Lorazepam-induced effects on silent period and corticomotor excitability. Exp Brain Res 173: 603-611.
33. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, et al. (1993) Corticocortical inhibition in human motor cortex. J Physiol 471: 501-519.
34. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H (1997) Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol 498: 817-823.
35. Di Lazzaro V, Pilato F, Dileone M, Profice P, Ranieri F, et al. (2007) Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study. ClinNeurophysiol 118: 2207-2214.
36. Ziemann U, Rothwell JC, Ridding MC (1996) Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 496: 873-881.
37. Di Lazzaro V, Pilato F, Oliviero A, Dileone M, Saturno E, et al. (2006) Origin of facilitation of motor-evoked potentials after paired magnetic stimulation: direct recording of epidural activity in conscious humans. J Neurophysiol 96: 1765-1771.
38. Di Lazzaro V, Rothwell JC (2014) Corticospinal activity evoked and modulated by non-invasive stimulation of the intact human motor cortex. J Physiol 592: 4115-4128.
39. Valls-Solé J, Pascual-Leone A, Wassermann EM, Hallett M (1992) Human motor evoked responses to paired transcranial magnetic stimuli. ElectroencephalogrClinNeurophysiol 85: 355-364.
40. Wassermann EM, Samii A, Mercuri B, Ikoma K, Oddo D, et al. (1996) Responses to paired transcranial magnetic stimuli in resting, active, and recently activated muscles. Exp Brain Res 109: 158-163.
41. Sanger TD, Garg RR, Chen R (2001) Interactions between two different inhibitory systems in the human motor cortex. J Physiol 530: 307-317.
42. Florian J, Müller-Dahlhaus M, Liu Y, Ziemann U (2008) Inhibitory circuits and the nature of their interactions in the human motor cortex a pharmacological TMS study. J Physiol 586: 495-514.
43. Mariorenzi R, Zarola F, Caramia MD, Paradiso C, Rossini PM (1991) Non-invasive evaluation of central motor tract excitability changes following peripheral nerve stimulation in healthy humans. ElectroencephalogrClinNeurophysiol 81: 90-101.
44. Stefan K, Kunesch E, Benecke R, Cohen LG, Classen J (2002) Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J Physiol 543: 699-708.
45. Wolters A, Sandbrink F, Schlottmann A, Kunesch E, Stefan K, et al. (2003) A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. J Neurophysiol 89: 2339-2345.
46. Wolters A, Schmidt A, Schramm A, Zeller D, Naumann M, et al. (2005) Timing-dependent plasticity in human primary somatosensory cortex. J Physiol (Lond) 565: 1039–1052.
47. Feldman DE (2012) The spike-timing dependence of plasticity. Neuron 75: 556-571.
48. Classen J, Wolters A, Stefan K, Wycislo M, Sandbrink F, et al. (2004) Paired associative stimulation. SupplClinNeurophysiol 57: 563-569.
49. Tokimura H, Di Lazzaro V, Tokimura Y, Oliviero A, Profice P, et al. (2000) Short latency inhibition of human hand motor cortex by somatosensory input from the hand. J Physiol 523 Pt 2: 503-513.
50. Di Lazzaro V, Oliviero A, Profice P, Pennisi MA, Di Giovanni S, et al. (2000) Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex. Exp Brain Res 135: 455-461.
51. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, et al. (2005) Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J NeurolNeurosurg Psychiatry 76: 1064-1069.
52. Di Lazzaro V, Pilato F, Dileone M, Tonali PA, Ziemann U (2005) Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition. J Physiol 569: 315-323.
53. Young-Bernier M, Kamil Y, Tremblay F, Davidson PSR (2012) Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults. Behav Brain Funct 8: 17.
54. Young-Bernier M, Davidson PSR, Tremblay F (2012) Paired-pulse afferent modulation of TMS responses reveals a selective decrease in short latency afferent inhibition with age. Neurobiol Aging 33: 835.e1–.e11.
55. Di Lazzaro V, Oliviero A, Tonali PA, Marra C, Daniele A, et al. (2002) Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology 59: 392-397.
56. Nardone R, Bergmann J, Kronbichler M, Kunz A, Klein S, et al. (2008) Abnormal short latency afferent inhibition in early Alzheimer's disease: a transcranial magnetic demonstration. J Neural Transm 115: 1557-1562.
57. Nardone R, Bergmann J, Christova M, Caleri F, Tezzon F, et al. (2012) Short latency afferent inhibition differs among the subtypes of mild cognitive impairment. J Neural Transm 119: 463-471.
58. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, et al. (1997) Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48: 1398-1403.
59. Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M (1994) Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex.  Brain 117 : 847-858.
60. Huang Y-Z, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45: 201–206.
61. Cheeran B, Koch G, Stagg CJ, Baig F, Teo J (2010) Transcranial magnetic stimulation: from neurophysiology to pharmacology, molecular biology and genomics. Neuroscientist 16: 210-221.
62. Jung P, Ziemann U (2009) Homeostatic and nonhomeostatic modulation of learning in human motor cortex. J Neurosci 29: 5597-5604.
63. Alagona G, Bella R, Ferri R, Carnemolla A, Pappalardo A, et al. (2001) Transcranial magnetic stimulation in Alzheimer disease: motor cortex excitability and cognitive severity. NeurosciLett 314: 57-60.
64. Alagona G, Ferri R, Pennisi G, Carnemolla A, Maci T, et al. (2004) Motor cortex excitability in Alzheimer's disease and in subcortical ischemic vascular dementia. NeurosciLett 362: 95-98.
65. Brem AK, Atkinson NJ, Seligson EE, Pascual-Leone A (2013) Differential pharmacological effects on brain reactivity and plasticity in Alzheimer's disease. Front Psychiatry 4: 124.
66. de Carvalho M, de Mendonça A, Miranda PC, Garcia C, Luís ML (1997) Magnetic stimulation in Alzheimer's disease. J Neurol 244: 304-307.
67. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, et al. (2004) Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease. J NeurolNeurosurg Psychiatry 75: 555-559.
68. Di Lazzaro V, Pilato F, Dileone M, Saturno E, Oliviero A, et al. (2006) In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias. Neurology 66: 1111-1113.
69. Di Lazzaro V, Pilato F, Dileone M, Profice P, Marra C, et al. (2008) In vivo functional evaluation of central cholinergic circuits in vascular dementia. ClinNeurophysiol 119: 2494-2500.
70. Di Lazzaro V, Pilato F, Dileone M, Saturno E, Profice P, et al. (2007) Functional evaluation of cerebral cortex in dementia with Lewy bodies. Neuroimage 37: 422-429.
71. Di Lorenzo F, Martorana A, Ponzo V, Bonnì S, D'Angelo E, et al. (2013) Cerebellar theta burst stimulation modulates short latency afferent inhibition in Alzheimer's disease patients. Front Aging Neurosci 5: 2.
72. Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, et al. (2003) Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation study. Ann Neurol 53: 102-108.
73. Hoeppner J, Wegrzyn M, Thome J, Bauer A, Oltmann I, et al. (2012) Intra- and inter-cortical motor excitability in Alzheimer's disease. J Neural Transm 119: 605-612.
74. Inghilleri M, Conte A, Frasca V, Scaldaferri N, Gilio F, et al. (2006) Altered response to rTMS in patients with Alzheimer's disease. ClinNeurophysiol 117: 103-109.
75. Issac TG, Chandra SR, Nagaraju BC (2013) Transcranial magnetic stimulation in patients with early cortical dementia: A pilot study. Ann Indian AcadNeurol 16: 619-622.
76. Khedr EM, Ahmed MA, Darwish ES, Ali AM (2011) The relationship between motor cortex excitability and severity of Alzheimer's disease: a transcranial magnetic stimulation study. NeurophysiolClin 41: 107-113.
77. Martorana A, Mori F, Esposito Z, Kusayanagi H, Monteleone F, et al. (2009) Dopamine modulates cholinergic cortical excitability in Alzheimer's disease patients. Neuropsychopharmacology 34: 2323-2328.
78. Martorana A, Stefani A, Palmieri MG, Esposito Z, Bernardi G, et al. (2008) L-dopa modulates motor cortex excitability in Alzheimer's disease patients. J Neural Transm 115: 1313-1319.
79. Pennisi G, Alagona G, Ferri R, Greco S, Santonocito D, et al. (2002) Motor cortex excitability in Alzheimer disease: one year follow-up study. NeurosciLett 329: 293-296.
80. Pepin JL, Bogacz D, de Pasqua V, Delwaide PJ (1999) Motor cortex inhibition is not impaired in patients with Alzheimer's disease: evidence from paired transcranial magnetic stimulation. J NeurolSci 170: 119-123.
81. Terranova C, SantAngelo A, Morgante F, Rizzo V, Allegra R, et al. (2013) Impairment of sensory-motor plasticity in mild Alzheimer's disease. Brain Stimul 6: 62-66.
82. Trebbastoni A, Gilio F, D’Antonio F, Cambieri C, Ceccanti M, et al. (2012) Chronic treatment with rivastigmine in patients with Alzheimer’s disease: A study on primary motor cortex excitability tested by 5Hz-repetitive transcranial magnetic stimulation. ClinNeurophysiol 123: 902–909.
83. Wegrzyn M, Teipel SJ, Oltmann I, Bauer A, Thome J, et al. (2013) Structural and functional cortical disconnection in Alzheimer's disease: A combined study using diffusion tensor imaging and transcranial magnetic stimulation. Psychiatry Research: Neuroimaging 212: 192–200.
84. Alberici A, Bonato C, Calabria M, Agosti C, Zanetti O, et al. (2008) The contribution of TMS to frontotemporal dementia variants. ActaNeurolScand 118: 275-280.
85. Battaglia F, Wang HY, Ghilardi MF, Gashi E, Quartarone A, et al. (2007) Cortical plasticity in Alzheimer's disease in humans and rodents. Biol Psychiatry 62: 1405-1412.
86. Liepert J, Bär KJ, Meske U, Weiller C (2001) Motor cortex disinhibition in Alzheimer's disease. ClinNeurophysiol 112: 1436-1441.
87. Olazarán J, Prieto J, Cruz I, Esteban A (2010) Cortical excitability in very mild Alzheimer's disease: a long-term follow-up study. J Neurol 257: 2078-2085.
88. Sakuma K, Murakami T, Nakashima K (2007) Short latency afferent inhibition is not impaired in mild cognitive impairment. ClinNeurophysiol 118: 1460-1463.
89. Julkunen P, Jauhiainen AM, Westerén-Punnonen S, Pirinen E, Soininen H, et al. (2008) Navigated TMS combined with EEG in mild cognitive impairment and Alzheimer's disease: a pilot study. J Neurosci Methods 172: 270-276.
90. Ferreri F, Pasqualetti P, Määttä S, Ponzo D, Guerra A, et al. (2011) Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation follow-up study. NeurosciLett 492: 94-98.
91. Perretti A, Grossi D, Fragassi N, Lanzillo B, Nolano M, et al. (1996) Evaluation of the motor cortex by magnetic stimulation in patients with Alzheimer disease. J NeurolSci 135: 31-37.
92. Martorana A, Di Lorenzo F, Esposito Z, Giudice Lo T, Bernardi G, et al. (2013) Dopamine D2-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients. Neuropharmacology 64: 108–113.
93. Nardone R, Bratti A, Tezzon F (2006) Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer's disease. J Neural Transm 113: 1679-1684.
94. Olazarán J, Hernández-Tamames JA, Molina E, García-Polo P, Dobato JL, et al. (2013) Clinical and anatomical correlates of gait dysfunction in Alzheimer's disease. J Alzheimers Dis 33: 495-505.
95. Marra C, Quaranta D, Profice P, Pilato F, Capone F, et al. (2012) Central cholinergic dysfunction measured "in vivo" correlates with different behavioral disorders in Alzheimer's disease and dementia with Lewy body. Brain Stimul 5: 533-538.
96. Martorana A, Esposito Z, Di Lorenzo F, Giacobbe V, Sancesario GM, et al. (2012) Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer's disease patients. J Neural Transm 119: 771-778.
97. Koch G, Esposito Z, Codecà C, Mori F, Kusayanagi H, et al. (2011) Altered dopamine modulation of LTD-like plasticity in Alzheimer's disease patients. ClinNeurophysiol 122: 703-707.
98. Koch G, Esposito Z, Kusayanagi H, Monteleone F, Codecá C, et al. (2011) CSF tau levels influence cortical plasticity in Alzheimer's disease patients. J Alzheimers Dis 26: 181-186.
99. Koch G, Di Lorenzo F, Bonnì S, Ponzo V, Caltagirone C, et al. (2012) Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients. J Alzheimers Dis 31: 593-599.
100. Koch G, Di Lorenzo F, igrave SB, Giacobbe V, Bozzali M, et al. (2014) Dopaminergic Modulation of Cortical Plasticity in Alzheimer's Disease Patients. Neuropsychopharmacology: 1–8.
101. Sailer A, Molnar GF, Paradiso G, Gunraj CA, Lang AE, et al. (2003) Short and long latency afferent inhibition in Parkinson's disease. Brain 126: 1883-1894.
102. Celebi O, Temuçin CM, Elibol B, Saka E (2012) Short latency afferent inhibition in Parkinson's disease patients with dementia. MovDisord 27: 1052-1055.
103. Nardone R, Florio I, Lochner P, Tezzon F (2005) Cholinergic cortical circuits in Parkinson's disease and in progressive supranuclear palsy: a transcranial magnetic stimulation study. Exp Brain Res 163: 128-131.
104. Manganelli F, Vitale C, Santangelo G, Pisciotta C, Iodice R, et al. (2009) Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson's disease. Brain 132: 2350-2355.
105. Yarnall AJ, Rochester L, Baker MR, David R, Khoo TK, et al. (2013) Short latency afferent inhibition: a biomarker for mild cognitive impairment in Parkinson's disease? MovDisord 28: 1285-1288.
106. Nardone R, Bergmann J, Brigo F, Christova M, Kunz A, et al. (2013) Functional evaluation of central cholinergic circuits in patients with Parkinson's disease and REM sleep behavior disorder: a TMS study. J Neural Transm 120: 413-422.
107. Taylor JP, Firbank M, Barnett N, Pearce S, Livingstone A, et al. (2011) Visual hallucinations in dementia with Lewy bodies: transcranial magnetic stimulation study. Br J Psychiatry 199: 492-500.
108. Burrell JR, Kiernan MC, Vucic S, Hodges JR (2011) Motor neuron dysfunction in frontotemporal dementia. Brain 134: 2582-2594.
109. Kühn AA, Grosse P, Holtz K, Brown P, Meyer BU, et al. (2004) Patterns of abnormal motor cortex excitability in atypical parkinsonian syndromes. ClinNeurophysiol 115: 1786-1795.
110. Burrell JR, Hornberger M, Vucic S, Kiernan MC, Hodges JR (2014) Apraxia and motor dysfunction in corticobasal syndrome. PLoS One 9: e92944.
111. Leiguarda RC, Merello M, Nouzeilles MI, Balej J, Rivero A, et al. (2003) Limb-kinetic apraxia in corticobasal degeneration: clinical and kinematic features. MovDisord 18: 49-59.
112. Lu CS, Ikeda A, Terada K, Mima T, Nagamine T, et al. (1998) Electrophysiological studies of early stage corticobasal degeneration. MovDisord 13: 140-146.
113. Frasson E, Bertolasi L, Bertasi V, Fusina S, Bartolomei L, et al. (2003) Paired transcranial magnetic stimulation for the early diagnosis of corticobasal degeneration. ClinNeurophysiol 114: 272-278.
114. Okuma Y, Urabe T, Mochizuki H, Miwa H, Shimo Y, et al. (2000) Asymmetric cortico-cortical inhibition in patients with progressive limb-kinetic apraxia. ActaNeurolScand 102: 244-248.
115. Shelley BP, Hodges JR, Kipps CM, Xuereb JH, Bak TH (2009) Is the pathology of corticobasal syndrome predictable in life? MovDisord 24: 1593-1599.
116. Alladi S, Xuereb J, Bak T, Nestor P, Knibb J, et al. (2007) Focal cortical presentations of Alzheimer's disease. Brain 130: 2636-2645.
117. Conte A, Belvisi D, Bologna M, Ottaviani D, Fabbrini G, et al. (2012) Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy. Cereb Cortex 22: 693-700.
118. Brusa L, Ponzo V, Mastropasqua C, Picazio S, Bonnì S, et al. (2014) Theta burst stimulation modulates cerebellar-cortical connectivity in patients with progressive supranuclear palsy. Brain Stimul 7: 29–35.
119. Shirota Y, Hamada M, Hanajima R, Terao Y, Matsumoto H, et al. (2010) Cerebellar dysfunction in progressive supranuclear palsy: a transcranial magnetic stimulation study. MovDisord 25: 2413-2419.
120. Emre M, Aarsland D, Albanese A, Byrne EJ, Deuschl G, et al. (2004) Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med 351: 2509-2518.
121. Pennisi G, Ferri R, Lanza G, Cantone M, Pennisi M, et al. (2011) Transcranial magnetic stimulation in Alzheimer's disease: a neurophysiological marker of cortical hyperexcitability. J Neural Transm 118: 587-598.
122. Paula-Lima AC, Brito-Moreira J, Ferreira ST (2013) Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease. J Neurochem 126: 191-202.
123. Ridding MC, Inzelberg R, Rothwell JC (1995) Changes in excitability of motor cortical circuitry in patients with Parkinson's disease. Ann Neurol 37: 181-188.
124. Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, et al. (2006) Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Arch Neurol 63: 1602-1604.
125. Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C (2008) Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. Eur J Neurol 15: 1286-1292.
126. Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, et al. (2011) Improved language performance in Alzheimer disease following brain stimulation. J NeurolNeurosurg Psychiatry 82: 794-797.
127. Cotelli M, Manenti R, Alberici A, Brambilla M, Cosseddu M, et al. (2012) Prefrontal cortex rTMS enhances action naming in progressive non-fluent aphasia. Eur J Neurol 19: 1404-1412.
128. Finocchiaro C, Maimone M, Brighina F, Piccoli T, Giglia G, et al. (2006) A case study of Primary Progressive Aphasia: improvement on verbs after rTMS treatment. Neurocase 12: 317-321.
129. Rektorova I, Megova S, Bares M, Rektor I (2005) Cognitive functioning after repetitive transcranial magnetic stimulation in patients with cerebrovascular disease without dementia: a pilot study of seven patients. J NeurolSci 229-230: 157–161.
130. Pennimpede G, Spedaliere L, Formica D, Di Pino G, Zollo L, et al. (2013) Hot Spot Hound: a novel robot-assisted platform for enhancing TMS performance. ConfProc IEEE Eng Med BiolSoc 2013: 6301-6304.
131. Cash RF, Ziemann U, Murray K, Thickbroom GW (2010) Late cortical disinhibition in human motor cortex: a triple-pulse transcranial magnetic stimulation study. J Neurophysiol 103: 511-518.
132. Hamada M, Hanajima R, Terao Y, Arai N, Furubayashi T, et al. (2007) Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex. ClinNeurophysiol 118: 2672-2682.
133. Cracco RQ, Amassian VE, Maccabee PJ, Cracco JB (1989) Comparison of human transcallosal responses evoked by magnetic coil and electrical stimulation. ElectroencephalogrClinNeurophysiol 74: 417-424.
134. Ilmoniemi RJ, Kicić D (2010) Methodology for combined TMS and EEG. Brain Topogr 22: 233-248.
135. Bohning DE, Shastri A, Nahas Z, Lorberbaum JP, Andersen SW, et al. (1998) Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation. Invest Radiol 33: 336-340.
136. Roberts DR, Vincent DJ, Speer AM, Bohning DE, Cure J, et al. (1997) Multi-modality mapping of motor cortex: comparing echoplanar BOLD fMRI and transcranial magnetic stimulation. Short communication. J Neural Transm 104: 833–843.
137. Ferreri F, Rossini PM (2013) TMS and TMS-EEG techniques in the study of the excitability, connectivity, and plasticity of the human motor cortex. Rev Neurosci 24: 431-442.