Clinical Neurophysiology 111 (2000) 504±512

www.elsevier.com/locate/clinph

Magnetoelectric brain stimulation in the assessment of brain physiology

and pathophysiology
Laura S. Boylan a,*, Harold A. Sackeim b, c, d
a
Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
b
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA
c
Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
d
Department of Biological Psychiatry, New York Psychiatric Institute, New York, NY, USA
Accepted 13 October 1999

Abstract
Objective: To review ®ndings from transcranial magnetic stimulation (TMS)-induced motor evoked potentials in normal subjects, in
various neurological diseases and with pharmacologic manipulation.
Methods: MEDLINE was searched to identify pertinent articles and articles referenced therein were also reviewed.
Results: TMS is a safe and non-invasive technique which has been used widely in the study of corticospinal and corticocortical
connectivity as well as in the assessment of basal ganglia disorders, diffuse diseases, and neuropharmacology.
Conclusions: TMS motor measures have utility in examination of brain structure and function within and beyond the corticospinal tract.
These measures have both research and clinical applications. q 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Magnetoelectric brain stimulation; Transcranial magnetic stimulation; Electrical brain stimulation; Motor evoked potentials; Cortical excitability

1. Introduction interruption of visual and cognitive brain processing in

The transcranial magnetic brain stimulator was intro-
duced in 1985 by Barker and colleagues (Barker et al.,
1985). Today technology is available for delivering single
or paired pulses as well as repetitive transcranial magnetic
stimulation. This review will cover ®ndings from the use of
motor evoked potentials induced by transcranial magnetic
stimulation (TMS) techniques. A review of these transcra-
nial magnetic stimulation (TMS) ®ndings in brain assess-
ment indicates that these measures may prove useful in the
study of neural excitability and plasticity, in rationalizing
the approach to medical therapy in neurologic disease, and
in prognosis following brain injury.
Not covered are stimulation with repetitive trains of TMS
currently under study as a therapeutic intervention, primar-
ily in mood disorders (Pascual-Leone et al., 1996; George et
al., 1997). Single pulse techniques have been used to stimu-
late areas beyond the primary motor cortex including the
occipital cortex and association areas of the brain. Visual
phenomena are produced with occipital stimulation and
psychophysical experiments has been demonstrated (Amas-
sian et al., 1989b; MuÈri et al., 1996). These interesting
studies are beyond the scope of this review.
Single and paired pulse TMS measures are safe and non-
invasive (Rossini et al., 1994). Stimulation is accomplished
with a ¯at coil held against the head. An electric current,
which passes through the wires of the coil, induces a
magnetic ®eld, which, in turn, induces electrical current in
the underlying brain. Unlike transcranial electrical stimula-
tion, this technique is painless. Also unlike transcranial elec-
trical stimulation, the induced electrical ®eld preferentially
excites neural elements oriented parallel to the surface of the
brain, i.e. primarily interneurons (Amassian et al., 1989a,
1990; Day et al., 1989). Lesional and pharmacological
studies demonstrate that TMS measures provide insight
into multiple areas of brain function within and beyond
the corticospinal tract, which is most directly assessed.
2. Techniques

2.1. MEP amplitude, latency, and threshold

* Corresponding author. Neurological Institute Box 43, 710 West 168th
Street, New York, NY, USA. Tel.: 11-212-543-5879; fax: 11-212-543-
5854. The upper and lower motor neurons and the motor unit
E-mail address: lsb21@columbia.edu (L.S. Boylan) constitute the ®nal common pathway of TMS motor
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. CLINPH 99070
PII: S13 88-2457(99)0028 0-1
 L.S. Boylan, H.A. Sackeim / Clinical Neurophysiology 111 (2000) 504±512 505

measures. Measures of motor evoked potential (MEP) at approximately 80% of a peripherally-induced M wave
latency and amplitude are thought to most directly measure (Pascual-Leone et al., 1994). Stimulus intensity is expressed
the integrity of this pathway and the membrane excitability as a percent of the device's maximum output.
characteristics of upper motor neurons. A related measure is There are a number of technical challenges common to
the central motor conduction time. To obtain this measure measures of MEPs. Particularly at near threshold intensities,
the coil is placed over the spine and cervical roots are stimu- MEPs show substantial trial to trial variation. These may
lated transcutaneously. Subtraction of this latency from the occur even without movements of either coil or head.
cortical stimulation latency provides a measure of central However, MEPs are extremely sensitive to even small
transmission with elimination of transmission time distal to head movements and variations in coil angle or position
the proximal root. Another technique used to separate out that are dif®cult to completely eliminate. Determinations
anatomic levels of involvement is measurement of F waves. of MT with serial stimuli given too rapidly may be inaccu-
As will be explained below, MEPs are in¯uenced by various rate as the pulses themselves have short-term effects on
factors including stimulus intensity, presence of condition- cortical excitability. These considerations highlight the
ing pulses, and muscle facilitation. A suprasegmental origin importance of skilled personnel in acquisition and interpre-
of changes induced in MEPs by these can be inferred by tation of TMS motor measures.
demonstration of unchanged F waves under the same stimu-
lus conditions. 2.2. Recruitment and facilitation
Peristimulus time histograms obtained with single ®ber
recordings after cortical stimulation reveal several peaks. Motor thresholds are lowered and MEP amplitudes
The ®rst of these peaks, referred to as the D wave, is consid- increased by muscle activation (see Fig. 1). Facilitation by
ered to represent direct activation of the upper motor muscle activation is also associated with decreased latencies
neuron. Subsequent peaks, termed I waves, are thought to (Hess et al., 1987). Mechanisms for this facilitation may
result from indirect excitation of upper motor neurons via include an increased number and greater synchronization
cortical interneurons. Interpeak intervals corresponding to of descending impulses from the motor cortex as well as
synaptic transmission support this interpretation (Amassian reafferent facilitation at the segmental level (Rossini et al.,
et al., 1989a, 1990; Day et al., 1989; Berardelli et al., 1990). 1994).
As compared with transcranial electrical stimulation, I Recruitment is measured by plotting a stimulus-response
waves predominate in responses to TMS while D waves
are dependent on careful coil positioning (Amassian et al.,
1989a, 1992).
The optimal site for obtaining motor evoked potentials
(MEPs) in a target muscle is determined by moving the
coil across the scalp and stimulating at suprathreshold
intensity. The site at which the largest contralateral
MEPs are produced is called the optimal site. Ipsilateral
MEPs and silent periods (see below) can be evoked, parti-
cularly in proximal muscles. The optimal sites for evoking
ipsilateral MEPs and silent periods may differ from the
optimal site for contralateral MEPs (Wassermann et al.,
1991, 1994; Wilson et al., 1993). This latter observation
suggests that there are separate mechanisms underlying
these different measures.
MEPs evoked off the optimal site have prolonged laten-
cies and lower amplitudes. Topographic mapping has been
used to demonstrate neural plasticity following task perfor-
mance and insults to the motor and sensory ®elds (Cohen et
al., 1991; Classen et al., 1998). The topographic representa-
tion of muscles is enlarged by motor utilization, ischemic
nerve block, and insults to the brain's motor and sensory
®elds including amputation, paralysis and peripheral nerve
block (Cohen et al., 1991; Rossini et al., 1996; Classen et al.,
1998).
By convention, motor threshold (MT) is de®ned as the
Fig. 1. MEPs evoked from a relaxed (a) and facilitated (b) FDI in the same
lowest stimulus intensity that evokes MEPs of 50 mV in subject. MEP amplitudes are equivalent but in (a) stimulus intensity was
amplitude in ®ve of ten trials. MEP amplitude is measured 76% machine output and in (b) stimulus intensity was 40% machine output.
peak to peak, increases with stimulus intensity, and plateaus Note the silent period following the MEP in (b). Arrows indicate stimuli.
506 L.S. Boylan, H.A. Sackeim / Clinical Neurophysiology 111 (2000) 504±512
curve of stimulus intensity versus MEP amplitude. The
slope of this curve is normally increased by facilitation as
well as by maneuvers that enlarge cortical representation of
muscles (Ridding and Rothwell, 1997).
Temporal summation can also be shown with stimuli
delivered repeatedly (Pascual-Leone et al., 1994). Immedi-
ately following trains at low (1 Hz) and high (10 Hz)
frequencies, respectively, decreases and increases of single
pulse MEP amplitudes have been demonstrated (Chen et al.,
1997; Pascual-Leone et al., 1994). These latter phenomena
bear some resemblance to long-term depression and facil-
itation.
2.3. Silent period
The silent period is measured with the muscle in the
activated state. The silent period is a suppression of volun-
tary EMG activity occurring from approximately100±200
ms following a stimulus (see Fig. 1b). The silent period is
typically seen following an MEP, however, it may also be
induced by stimuli subthreshold to produce an MEP
(Rossini et al., 1995). This latter characteristic provides
strong support for the idea that this `negative effect' is
mechanistically distinct from the positive effect seen in
MEP induction. At least the latter part of this silent period
is determined by central mechanisms (Hallett, 1995; Berar-
delli et al., 1996a; Brasil-Neto et al., 1995).
2.4. Paired pulse measures
Measures of MEPs using paired pulse techniques can
demonstrate changes in cortical excitability that cannot be
measured using other techniques. The ®rst pulse is known as
the conditioning stimulus, and the second pulse is the test
pulse. At short intervals (1±15 ms) the conditioning stimulus
is subthreshold and the test pulse is suprathreshold (Kujarai
et al., 1993). At 1±6 ms interstimulus intervals (ISI) an
inhibition of the MEP amplitude is normally seen, while
facilitation of amplitude may occur at ISIs between 6 and
15 ms (see Fig. 2). Performance of these paired pulse
measures requires two time-locked stimulators. The
measures are technically challenging as it is necessary
during the assessment to continually readjust the intensity
of the test pulse in order to produce an MEP of constant size.
Also, maintaining constant head and coil position for the
duration of testing is dif®cult.
Less examined are the effects of paired pulse at longer
ISIs (100±200 ms). Using suprathreshold stimuli for both
conditioning and test pulses some investigators have found
that an inhibition or abolition of MEPs occurs at these
longer ISIs, even when the latter stimulus falls beyond the
end of the silent period induced by the prior stimulus (Berar-
delli et al., 1996a). Other paired pulse paradigms involve an
initial suprathreshold stimulus followed by a subsequent
subthreshold stimulus (Ziemann et al., 1998b) or two near
threshold stimuli (Tokimura et al., 1996). Facilitatory
effects seen at short ISIs in these paradigms likely re¯ect I
Fig. 2. Paired pulse curve. Test pulses are preceded by subthreshold condi-
tioning pulses by 1±11 ms. Interstimulus intervals of 1±3 ms are associated
with decreased MEP amplitude as compared with test pulse alone (intra-
cortical inhibition) while interstimulus intervals of 7±11 ms are associated
with increased MEP amplitude (intracortical facilitation).
wave interactions (Tokimura et al., 1996; Ziemann et al.,
1998b).
3. TMS measures in normal development and aging
MEPs have been demonstrated in children as young as
pre-term infants (Koh and Eyre, 1988). Up to two-thirds of
children have ipsilateral motor evoked responses, particu-
larly in proximal muscles, before the age of 9 years (MuÈller
et al., 1997). The latency of ipsilateral responses in children
is 12±14 ms longer than contralateral responses, a period of
time corresponding to transcallosal conduction. In contrast,
children with congenital lesions of the motor system have
equal latency to their bilateral responses, suggesting that the
normal pruning of motor neuron collaterals has not
occurred. Bilateral responses in adults are also found in
axial muscles (masseter, rectus abdominus, diaphragm)
(Carr et al., 1994). Some investigators using careful
mapping and positioning techniques have been able to
consistently elicit at least some ipsilateral MEPs from distal
hand muscles in adults as well. Silent periods, however, are
relatively easily elicited ipsilateral to the stimulated hemi-
sphere, even in the absence of an MEP (Wassermann et al.,
1994). Ipsilateral MEPs may be more easily evoked from
the dominant hemisphere (Caramia et al., 1998). Both MEPs
and silent periods evoked ipsilaterally have a prolonged
latency relative to contralateral responses (Wassermann et
al., 1991).
The higher frequency of ipsilateral responses seen in chil-
dren apparently reemerges in adults with acquired hemi-
spheric lesions. Patients with gliomas with total or near
total preservation of motor function are reported to have a
high frequency of ipsilateral MEPs evoked from the unaf-
 L.S. Boylan, H.A. Sackeim / Clinical Neurophysiology 111 (2000) 504±512
fected hemisphere. The prolonged latency of these
responses as compared to those evoked contralaterally is
consistent with a disinhibition or reestablishment of physio-
logic pathways seen commonly before the age of 9 years
(Caramia et al., 1998).
Children have higher motor thresholds, smaller MEPs,
and longer conduction times than adults and attain adult
values by the age of 13 years (Koh and Eyre, 1988; Nezu
et al., 1997). These differences likely re¯ect immature
myelination in children. TMS ®ndings in children with
malnutrition are consistent with a delay in normal develop-
mental processes (Tamer et al., 1997). In contrast to the
®nding of decreasing motor threshold with age in children,
an age over 50 years in adults is associated with a slight
increase in motor threshold and decrease in the silent period
(Prout and Eisen, 1994).
4. Physiologic facilitation
A variety of maneuvers beyond simple muscle activation
facilitate MEPs. Facilitation may also be accomplished by
sequential hand movements, by the imagination of sequen-
tial hand movements, by stimulation of afferent sensory
nerves, or by sequential administration of TMS pulses (Deli-
tis et al., 1987; Abbruzzese et al., 1996; Rossi et al., 1998).
Isometric contractions of arm muscles can induce a post-
exercise facilitation of MEPs. Interestingly, these isometric
contractions do not induce post-exercise facilitation in distal
hand muscles but precision grip movements do. Conversely,
proximal but not distal MEP facilitation was seen with
isometric contraction only (Rossi et al., 1999). The authors
suggest that this difference may re¯ect underlying differ-
ences in motor processing for postural and ®ne motor skills
at the level of the primary motor cortex. The various types
of facilitation seen support the idea of substantial short-term
plasticity not generally associated with the function of the
primary motor cortex (Scheiber, 1999).
It may be that the facilitation of MEPs by muscle activa-
tion or other maneuvers and enlargement of the motor repre-
sentation of a target muscle following insults to sensory and
motor ®elds (see above) both re¯ect the same plastic
changes (Fuhr et al., 1991; Ridding and Rothwell, 1997).
5. Disorders affecting the pyramidal system
5.1. Stroke
Hemiparetic stroke is associated with an increased motor
threshold, decreased MEP amplitude, and an increased
silent period. The magnitude of these changes in the acute
stage has prognostic value in stroke outcomes (Dominkus et
al., 1991; Nagao and Kawai, 1992; Cruz-Martinez et al.,
1998; Escudero et al., 1998).
Clinical pyramidal system involvement is not inevitably
re¯ected in MT or MEP (HoÈmberg et al., 1991; MuÈller et al.,
507
1992) and responses with normal latency (as compared with
the unaffected side) have been demonstrated following
degeneration of the pyramidal tract on MRI following stroke
(Fries et al., 1991). Abnormalities in the silent period may
be the most sensitive measures of abnormal function in
stroke, being often abnormal even following complete
recovery of motor function (Braune and Fritz, 1996; Ahonen
et al., 1998). These ®ndings highlight the role of intracor-
tical mechanisms and associated motor areas in the genesis
of motor dysfunction.
Classen et al. (1997) observed that patients with acute
hemiparetic stroke and a markedly prolonged silent period
but normal MEPs may have a several second period of
inability to initiate movement following a single TMS
stimulus which they term `motor arrest'. Further, subtle or
overt manifestations of motor neglect could be identi®ed in
patients with a prolonged silent period. The authors suggest
that poor motor function may be due to an excess of inhi-
bitory input to the corticospinal tract rather than injury to the
upper motor neuron itself (Classen et al., 1997). The clinical
correlate of neglect and the phenomenon of motor arrest
suggest that pre-motor areas of the brain in¯uence the silent
period. Cerebellar lesions increase the motor threshold and
the latency evoked from the contralesional hemisphere,
consistent with a hypothesis of a tonic facilitatory in¯uence
of the cerebellum on the cortex (Di Lazzaro et al., 1994;
Cruz-Martinez and Arpa, 1997).
5.2. Other pyramidal system pathology
In multiple sclerosis, as would be expected with demye-
lination, the most consistently reported abnormality is
prolongation of central motor conduction time (Berardelli
et al., 1988; Britton et al., 1991). Consistent with the
temporal dispersion one would see with peripheral demye-
lination, multiple sclerosis causes prolonged latency and
increased interpeak intervals as measured with single ®ber
recording (Boniface et al., 1991; Nielsen, 1997) and
increased duration of the compound MEP (Kukowski,
1993).
In amyotrophic lateral sclerosis (ALS) an increased
motor threshold and prolonged silent period have been
found. Findings vary with the stage of disease and variable
involvement of upper and lower motor neurons (Eisen et al.,
1993; Prout and Eisen, 1994). Upper motor neuron signs of
hyperre¯exia, spasticity and weakness of multiple etiologies
correlate with increased motor threshold and prolonged
silent period (Caramia et al., 1991). Abnormalities consis-
tent with corticospinal dysfunction can be demonstrated
even in early or clinically lower motor neuron presentations
of ALS (Triggs et al., 1999).
In hemiplegic cerebral palsy the MT is often elevated and
the MEP amplitude decreased. Furthermore, there are
frequently motor evoked responses from the undamaged
hemisphere to the ipsilateral paretic hand. The presence of
such bilateral responses is associated with better hand func-
508 L.S. Boylan, H.A. Sackeim / Clinical Neurophysiology 111 (2000) 504±512

tion as well as with the presence of mirror movements (Carr inhibition (Huag et al., 1992; Priori et al., 1994a; Hallett,
et al., 1993). 1995; Berardelli et al., 1996b). Dopaminergic therapy and
anticholinergic agents lengthen the abnormally short silent
period in patients with Parkinson's disease (Huag et al.,
6. Epilepsy and cortical myoclonus 1992; Priori et al., 1994a). The silent period appears to be
shorter and more dopa responsive contralateral to a patient's
Findings in epilepsy are con¯icting as regards to changes
most affected limbs and is lengthened following pallidot-
in motor threshold and silent period in unmedicated patients
omy (Priori et al., 1994a; Young et al., 1997). Some, but not
with idiopathic generalized epilepsy (Reutens et al., 1993;
all, investigators have found decreased intracortical inhibi-
Gianelli et al., 1994). Variable ®ndings regarding MT may
tion as measured in paired pulse paradigms (Ridding et al.,
be due to differences in patient and control characteristics
1995a; Berardelli et al., 1996b) and diminished facilitation
including wide age variation and seizure frequency. In a
of motor evoked potential (MEP) size with either muscle
study of 53 patients with mainly temporal lobe epilepsy
activation or increased stimulus intensity (Valls-Sole et al.,
on medications it was found that a high frequency of both
1994).
interictal epileptiform discharges and seizures was asso-
A decreased silent period has also been found in several
ciated with decreased central motor conduction time and
other movement disorders including Tourette's syndrome
motor thresholds (Hufnagel et al., 1990). These ®ndings
(Ziemann et al., 1997a) and focal or generalized dystonia
suggest that TMS excitability measures re¯ect a susceptibil-
(Mavroudakis et al., 1995; Filipovic et al., 1997; Odergren
ity to epileptogenesis. However, TMS measures have not
et al., 1997; Rona et al., 1998). Huntington's disease, on the
proved to be useful in categorization of the epilepsies (Cara-
other hand, is reported to be associated with a prolonged
mia et al., 1996).
silent period (Priori et al., 1994b). Reported changes in paired
The ®nding of increased MT in epileptic patients treated
pulse measures of intracortical inhibition are similar to those
with anticonvulsants, particularly valproate, is robust (Koh
reported in Parkinson's disease (Abbruzzese et al., 1997a).
and Eyre, 1988; Hufnagel et al., 1990; Gianelli et al., 1994;
Abnormalities of decreased intracortical inhibition on
Caramia et al., 1996; Nezu et al., 1997). Con®rming the
paired pulse measures are described in focal dystonia
current interpretation of the slow wave phase of spike and
(Ridding et al., 1995b) as well as in tic disorders (Ziemann
wave discharges as corresponding to a wave of inhibitory
et al., 1997a) and in obsessive compulsive disorder without
post-synaptic potentials, stimuli delivered time-locked to
tics (Greenberg et al., 1998). Low frequency repetitive TMS
the slow wave portion of 3 Hz spike and wave discharges
to the primary motor cortex has been shown to transiently
evoke signi®cantly reduced MEPs (Brown et al., 1996).
reverse the abnormalities of intracortical inhibition and
In apparent contradiction to ®ndings of an association
silent period in writer's cramp, and in some subjects results
between seizure frequency and reduced MT, Brown and
in transient improvement in writing (Siebner et al., 1999).
colleagues have found that the generalization of cortical
To date it seems that abnormalities on paired pulse testing
myoclonus is associated with an increased MT (Brown et
and silent period may re¯ect basal ganglia pathology with-
al., 1996). This study compared patients with purely focal
out being speci®c to etiology.
or multifocal myoclonus, whom they termed `non-sprea-
ders', and those with generalized myoclonus, whom they
termed `spreaders'. Regardless of medication status, 8. Diffuse diseases, other pathology
increased motor thresholds as well as decreased inhibition
by paired pulse measures were greatest in `spreaders', but Abnormalities in TMS measures have also been described
were still abnormal in `non-spreaders' as compared to in a number of diffuse diseases. In vitamin B12 de®ciency
controls. There was no association between the presence or there is a prolongation of the CMCT that is reversible with
absence of epilepsy and these measures of cortical inhibition. treatment (Wu and Chu, 1996). Patients with unilateral clas-
It is likely that ®ndings associated with epilepsy are variable sical migraine have an increased motor threshold in the
depending on the timing of testing vis-aÁ-vis paroxysmal affected hemisphere (Maertens de Noordhout et al., 1992).
events, the frequency of such events, as well as medication Absent MEPs have been reported in the akinetic rigid
status. syndrome of Wilson's disease associated with white matter
lesions (Chu, 1990).
Amongst psychiatric diseases, the ®rst report on patients
7. Basal ganglia disorders with schizophrenia found that unmedicated patients had
decreased latency to MEPs compared with age- and sex-
Diseases of the basal ganglia in general do not affect
matched controls (Puri et al., 1996).
motor threshold or latency. Abnormalities are found,
however, on paired pulse measures of intracortical excitabil-
ity and in the silent period. 9. Medication effects
In Parkinson's disease there is an abnormally short silent
period that is thought to be due to reduced intracortical The effects of medications on the brain can be character-
 L.S. Boylan, H.A. Sackeim / Clinical Neurophysiology 111 (2000) 504±512
ized by TMS measures. Typically, after the paradigm of
Ziemann and colleagues, an acute medication challenge of
a given medication is given to normal subjects (Ziemann et
al., 1996). Serial TMS studies are done following dosing
and changes that correlate with known medication pharma-
cokinetics are examined.
TMS pro®les created in this way distinguish drugs by
category. Pharmacologic studies in normal subjects have
demonstrated that anticonvulsant medications with Na 21/
Ca 21 blocking properties (carbamazepine, lamotrigine,
valproate, losigamone) and those with pro-GABA activity
(vigabatrin, baclofen) cause distinct changes in TMS
measures (Ziemann et al., 1996). Ion channel blockers
increase the motor threshold. This is thought to be due to
the critical role of ion in¯ux in eliciting action potentials in
corticospinal neurons. Pharmacologic enhancement of
GABA, on the other hand, dampens the facilitatory and
enhances the inhibitory effects of stimulation in paired
pulse paradigms with little or no effect on MT (Ziemann
et al., 1996).
While Na 21 channel blockers increase the motor thresh-
old, the potassium channel blocking agent 4-aminopyridine
has been reported to decrease the motor threshold as well as
increase MEP amplitude, at least in patients with spinal cord
injury (Qiao et al., 1997).
Glutamate antagonists dextromethorphan (acting at the
NMDA receptor) and riluzole have TMS pro®les similar
to those described for the GABA agonists (Liepert et
al., 1997; Ziemann et al., 1998a). Many of the directly or
indirectly pro-GABA agents, including lorazepam, gabapen-
tin, and ethanol, as well as dextromethorphan exhibit
enhancement of intracortical inhibition as expressed through
prolongation of the silent period (Ziemann et al., 1996,
1998a).
Dopamine exerts effects on TMS pro®les opposite to
those seen in Parkinson's disease. Levodopa prolongs the
silent period towards normal in patients with Parkinson's
disease and beyond normal in normal subjects (Priori et
al., 1994a). The dopamine agonist pergolide and the antic-
holinergic agent biperiden have similar effects (Priori et al.,
1994a; Ziemann et al., 1997b). On the other hand, neuro-
leptic dopamine receptor blockers shorten the silent period
in normal subjects as well as in patients with schizophrenia,
a change also seen in Parkinson's disease (Priori et al.,
1994a; Puri et al., 1996; Davey et al., 1997; Ziemann et
al., 1997b).
Just as individual drugs have characteristic spectrums of
action within their categories, individual medications have
particular effects: bromocriptine and pergolide but not dopa-
mine increase intracortical inhibition as measured with
paired pulse techniques (Ziemann et al., 1997b). Carbama-
zepine (thought to act primarily at Na 21 channels) enhances
paired pulse intracortical inhibition (Ziemann et al., 1996).
Adrenergic, cholinergic, and serotonergic agents have been
studied little or not at all with transcranial magnetic stimu-
lation (Werhahn et al., 1998).
509
10. Future directions
Measures of corticospinal and corticocortical function
with transcranial magnetic stimulation have potential
research and clinical applications. From a research perspec-
tive, TMS motor studies will likely provide insights into the
pathophysiology of disease, neural plasticity, and motor
control. Potential diagnostic clinical uses include the
demonstration of upper motor neuron/corticospinal tract
involvement in Parkinsonian and motor neuron syndromes
(Abbruzzese et al., 1997b; Triggs et al., 1999) and the early
distinction between early Parkinson's disease and essential
tremor (Pardal et al., 1999). A prognostic value in stroke
despite similar de®cits at presentation has already been
demonstrated (Dominkus et al., 1991; Nagao and Kawai,
1992; Cruz-Martinez et al., 1998; Escudero et al., 1998).
Ultimately TMS measures of brain neurochemistry might
be useful to guide pharmacotherapy in epilepsy or other
brain diseases. Mapping of motor function and reorganiza-
tion might be used to guide rehabilitation efforts following
neurological injury. Understanding and use of these safe,
non-invasive and functionally based in vivo assays of
brain physiology are likely to continue to increase.
Acknowledgements
We thank Drs. Sarah H. Lisanby and Bruce Luber and
Judy Louie for technical assistance.
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