Cognitive Neuroscience Homework

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This is homework about TMS & Perception. I attached the related homework (question) below. It is a total of 9 questions. I would appreciate it if you could answer these questions by referring to the materials I attached below. Thank you again for your help

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Topic 1 (Part 3). TMS & Perception
Example
Outline:
 Journal articles
 Visual awareness of motion
(Pascual-Leone & Walsh, 2001)
 Introduction
 Methods
 First Experiment
 Methods
 Results
 Discussion
 Second Experiment
 Methods
 Results
 Discussion
 General Discussion
2
Journal articles
4
Journal hierarchy & impact factors
 General
 Nature (41.456)
 Science (33.611)
 Field
 Behavioral and Brain Science (20.771)
 Nature Neuroscience (16.095)
 Neuron (15.054)
 Sub-field
 Social, Cognitive, and Affective Neuroscience (7.372)
 Neuroimage (6.357)
 Journal of Cognitive Neuroscience (4.085)
 Specialized
 Hippocampus (4.162)
 Neurobiology of Learning and Memory (3.652)
 Attention, Perception, & Psychophysics (2.168)
Journal distribution models
 Traditional
 Free for researchers to submit
articles
 Cost for libraries to receive
online/offline access
 Examples:
 Science, Nature, JCogNeuro, etc…
 Pros:
 Incentive for rigorous peer-review &
high quality to boost desirability/sales
 Cons:
 Expensive, limited access to scientific
output (particularly for those outside
the academy or in less wealthy
countries)
 Alternatives
5
 Open-access
 Cost for researchers to submit
articles
 Free for anyone to receive online
 Examples:
 Public Library of Science, Frontiers,
etc…
 Pros:
 Unlimited free access for everyone!
 Cons:
 Incentive to accept submissions in
order to attract more submissions and
thus increase collected fees
 Funding agencies (e.g. NIH in USA, NSERC/SSHRC/CIHR in Canada) require
open access after 12 months
 Institutionally funded open-access journals
Organization of an
original research article
IMRaD hourglass organization
6
Visual awareness of motion
(Pascual-Leone & Walsh, 2001)
(Pascual-Leone & Walsh, 2001)
8
Introduction:
Research question
What role do backprojections from the motion
area to primary visual cortex play in the visual
awareness of motion?
 backprojections from the motion area to primary
visual cortex
 visual awareness of motion
9
Introduction:
Organization of visual system
Serial, parallel, and recurrent processing
in the visual system
10
What is represented by the blue pathway in this
diagram?
A. Pathway from eyes to visual cortex
B. Overall visual system
C. Overall auditory system
D. “Where/how” stream
E. “What” stream
Introduction:
Organization of visual system
MT/V5: Motion area
backprojection
V1: Primary visual cortex
15
Introduction:
Visual awareness
 What is it?
 How do we operationalize it?
16
Methods
Methods:
Calibration
19
 V5
 Identified scalp location for induction of moving
phosphenes
 Identified minimum field strength for consistent
induction of moving phosphenes
 V1
 Identified scalp location for induction of stationary
phosphenes in same perceived location as moving
phosphenes
 Identified minimum field strength for consistent
induction of stationary phosphenes
Methods:
TMS to V5
V5 stimulated to induce moving phosphenes
V5
20
What planes of section are used in X and Y
respectively?
A. sagittal and coronal
B. horizontal and sagittal
C. horizontal and coronal
D. coronal and sagittal
E. coronal and horizontal
X
Y
Methods:
TMS to V1
24
V1 stimulated to induce stationary phosphenes
V1
First Experiment (V5 to V1)
Methods:
V5 to V1 experiment
 Single-pulse test stimulus at 100% of
threshold applied to V5
 Induces moving phosphene
 Single-pulse conditioning stimulus at 80% of
threshold applied to V1
 Does not induce stationary phosphene
 Time between V5 pulse and V1 pulse is the
“V5-V1 asynchrony” aka “Conditioning to test
asynchrony”
26
Methods:
V5 to V1 experiment
27
Methods:
V5 to V1 experiment
28
On each trial, report visual experience
(phosphene report):
 1 = moving phosphene, same as with single V5 TMS
 2 = moving phosphene, but not as clearly moving
as with single V5 TMS
 3 = phosphene in same location as with single V5
TMS but not moving
 4 = no phosphene
Methods:
V5 to V1 experiment
 Independent variable:
 V5-V1 asynchrony
 Dependent variable:
 Phosphene report
29
Results:
V5 to V1 experiment
Results represented by circles in this graph
30
Discussion:
V5 to V1 experiment
31
Why does TMS to V1 disrupt visual awareness of
motion?
Discussion:
V5 to V1 experiment
32
Why does TMS to V1 disrupt visual awareness of
motion?
 Feedback to V1 necessary for visual awareness of
motion
 Interference in V5 due to forward projections from
V1 to V5
 Backward masking of motion phosphenes by later
stationary phosphenes
Second Experiment (V5 to V5)
Methods:
V5 to V5 experiment
34
 Single-pulse test stimulus at 100% of
threshold applied to V5
 Induces moving phosphene
 Single-pulse conditioning stimulus at 80% of
threshold applied to V5
 Does not induce moving phosphene
 Time between suprathreshold V5 pulse and
subthreshold V5 pulse is “Conditioning to test
asynchrony”
Results:
V5 to V5 experiment
Results represented by squares in this graph
35
Discussion:
V5 to V5 experiment
 Seems to rule out interference in V5 due to
forward projections from V1 to V5
 Why doesn’t TMS to V5 disrupt visual
awareness of motion?
36
General Discussion
General Discussion:
Conclusion?
38
“Our results highlight the importance of the fast
feedback projections from V5 to V1 in visual
awareness of motion and document the
chronometry of the phenomenon.” (p. 512)
General Discussion:
Potential issues
39
What are possible issues with this experiment?
General Discussion:
Follow-up questions
What are follow-up questions raised by this
experiment?
41
Topic 1 (Part 3). TMS & Perception
Example
Outline:
 Journal articles
 Visual awareness of motion
(Pascual-Leone & Walsh, 2001)
 Introduction
 Methods
 First Experiment
 Methods
 Results
 Discussion
 Second Experiment
 Methods
 Results
 Discussion
 General Discussion
43
Neuron
Primer
Transcranial Magnetic Stimulation: A Primer
Mark Hallett1,*
1
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda,
MD 20892, USA
*Correspondence: [email protected]
DOI 10.1016/j.neuron.2007.06.026
Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human
brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief
electric current through a magnetic coil. The field can excite or inhibit a small area of brain below the
coil. All parts of the brain just beneath the skull can be influenced, but most studies have been of the
motor cortex where a focal muscle twitch can be produced, called the motor-evoked potential. The
technique can be used to map brain function and explore the excitability of different regions. Brief
interference has allowed mapping of many sensory, motor, and cognitive functions. TMS has
some clinical utility, and, because it can influence brain function if delivered repetitively, it is being
developed for various therapeutic purposes.
Principles of Magnetic Stimulation
Almost 30 years ago, Merton asked Morton to build a
high-voltage electrical stimulator able to activate muscle
directly rather than through the small nerve branches in
the muscle. When built, he had the idea that this device
could also stimulate the motor areas of the human brain
through the intact scalp (transcranial electrical stimulation
[TES]), and it worked (Merton and Morton, 1980). A brief,
high-voltage electric shock over the primary motor cortex
(M1) produced a brief, relatively synchronous muscle
response, the motor-evoked potential (MEP). It was immediately clear that this would be useful for many different
purposes, but a problem with TES is that it is painful. Five
years later, Barker et al. (Barker et al., 1985) solved a
number of technical problems and showed that it was
possible to stimulate brain (as well as peripheral nerve)
with magnetic stimulation (transcranial magnetic stimulation [TMS]), and this could be accomplished with little or
no pain. TMS has now come into wide use, and TES is still
used for selective purposes. TMS is most frequently used
as a research tool to study brain physiology, but it has
some clinical utility and is also being developed as a
therapeutic tool.
For electrical stimulation between two electrodes
placed on the scalp, current flows from anode to cathode.
Near the scalp, the predominant direction of current flow is
radial, but there are return loops that are tangential to the
scalp. For magnetic stimulation, a brief, high-current pulse
is produced in a coil of wire, called the magnetic coil
(Figure 1). A magnetic field is produced with lines of flux
passing perpendicularly to the plane of the coil, which ordinarily is placed tangential to the scalp. The magnetic
field can reach up to about 2 Tesla and typically lasts for
about 100 ms. An electric field is induced perpendicularly
to the magnetic field. The voltage of the field itself may excite neurons, but likely more important are the induced
currents. In a homogeneous medium, spatial change of
the electric field will cause current to flow in loops parallel
to the plane of the coil, which will be predominantly tangential in the brain. The loops with the strongest current
will be near the circumference of the coil itself. The current
loops become weak near the center of the coil, and there
is no current at the center itself. Neuronal elements are activated by the induced electric field by two mechanisms. If
the field is parallel to the neuronal element, then the field
will be most effective where the intensity changes as a
function of distance. If the field is not completely parallel,
activation will occur at bends in the neural element.
Magnetic coils may have different shapes (Figure 2).
Round coils are relatively powerful. Figure-of-eightshaped coils are more focal, producing maximal current
at the intersection of the two round components. A
figure-of-eight-shaped coil with the two components at
an angle, the cone-shaped coil, increases the power at
the intersection. Another configuration is called the Hcoil, with complex windings that permit a slower fall-off
of the intensity of the magnetic field with depth (Zangen
et al., 2005). In another design, the windings of a coil are
around an iron core rather than air; this focuses the field
and allows greater strength and depth of penetration
(Epstein and Davey, 2002).
The results of TMS over M1 appear similar to those
of TES. One difference, however, is that the latency of
response is slightly shorter with TES, and explaining this
difference opens the door to understanding the excitation
mechanism of the two types of stimulation. It is likely that
the mechanism of stimulation is similar in many parts of
the brain, but we have detailed information only from
M1, since the results can be measured in such detail.
The difference in latency appears to be related to the
nature of the descending volley in the corticospinal tract
produced by the two types of stimulation (Figure 3)
(Di Lazzaro et al., 1998). With TES, but typically not with
TMS, there is an early D wave (direct wave) that reflects
Neuron 55, July 19, 2007 ª2007 Elsevier Inc. 187
Neuron
Primer
Figure 1. Illustration of Direction of Current Flows in
a Magnetic Coil and the Induced Current in the Brain
From Hallett (2000), with permission.
direct activation of descending axons. With both types of
stimulation, there is a series of later I waves (indirect
waves) that reflect synaptic activation of the corticospinal
neurons. The mechanism of I wave production is not completely clear. I waves come at intervals of about 1.5 ms
and are either generated by increasingly long polysynaptic
networks or recurrent synaptic networks. Comparing the
responses from rotating the magnetic coil in different angles, the largest MEPs are produced when the current in
the brain is directed in the posterior-anterior direction (optimally at an angle perpendicular to the central sulcus),
and the first wave produced is typically the I1 wave (at
about a 1.5 ms interval from the D wave). When brain current is lateral-medial, there can be a D wave produced
first. When the brain current is anterior-posterior, the I3
wave (at about a 4.5 ms interval from the D wave) can
be produced first. MEPs are also larger and earlier when
the muscle is contracting at baseline as opposed to
when it is at rest. This is largely due to the fact that the motor neuron pool is at a higher level of activity and it is easier
to provoke an increase of activation.
Delivering a single pulse of TMS to the brain is very safe.
Devices are now available that are capable of delivering
high-frequency (1–50 Hz), repetitive TMS (rTMS). This can
produce powerful effects that outlast the period of stimulation, inhibition with stimulation at about 1 Hz, and excitation
with stimulation at 5 Hz and higher. rTMS, however, has the
potential to cause seizures even in normal individuals.
Safety guidelines describing limits for combinations of frequency, intensity, and train length have been developed,
which should prevent most problems (Wassermann, 1998).
Corticomotor Conduction Time
One of the obvious measurements that can be made with
TMS is central motor conduction time. This is the time
from motor cortex to the motor neuron pool in the spinal
cord or brainstem. It is calculated by taking the latency
of the MEP and subtracting the peripheral conduction
time. Peripheral conduction time may be obtained in two
188 Neuron 55, July 19, 2007 ª2007 Elsevier Inc.
Figure 2. Magnetic Coil Shape Determines the Pattern of the
Electric Field
Two magnetic coils with different shapes (A and B) and their resultant
electric fields (C and D). Modified from Cohen et al. (1990), with
permission.
ways. The first is to stimulate over the spine that activates
the nerve roots in the intravertebral foramina. This is
slightly in error since it misses the segment from the spinal
cord to the foraminal region. The second method is to use
the F wave, using the formula (F wave latency + M wave
latency – 1)/2. Upon stimulating a motor nerve, the
M wave is the direct muscle response, and the F wave is
the muscle response produced by activation of the alpha
motoneuron by the antidromic volley. This is more accurate, but a bit more time consuming (and painful).
Activation, Inhibition, and Mapping
Using TMS, the brain can be briefly activated or briefly
inhibited; in fact, likely both occur with each stimulus in
differing amounts and with different time courses. This effect can be used to localize brain functions in both space
and time. Applications were first in the motor system but
have now been used to map sensory processes and cognitive function.
Mapping the motor cortex by moving the coil over the
surface of the scalp and recording MEPs from different
muscles has been fairly straightforward. MEP mapping
is an example of mapping in space with activation. Different body parts, such as arm and leg, are completely separate, but there is overlapping of muscles in the same
body part (Wassermann et al., 1992) (Figure 4). Such studies have also allowed the demonstration of weak ipsilateral pathways to upper extremity muscles as well as the
more powerful contralateral ones. Mapping of cranial
nerve muscles has also been done, revealing innervations
that are bilateral, bilaterally asymmetric, and unilateral,
and also allowed confirmation of the innervation of orbicularis oculi by the cingulate cortex (Sohn et al., 2004). The
patterns of muscle activity provoked by TMS have some
physiological relevance, as these can be recognized as
principal components of natural movement (Gentner and
Classen, 2006).
Neuron
Primer
Figure 4. TMS Mapping of Upper Extremity Muscles in Right
and Left Sides of One Normal Subject after Stimulation of the
Contralateral M1s
From Wassermann et al. (1992), with permission.
Figure 3. Descending Volleys Recorded from the Spinal Cord
and the Resultant MEPs after Different Types of TES and TMS
Anodal stimulation is from TES, and TMS is delivered in both lateralmedial (LM) and posterior-anterior (PA) directions in various intensities.
AMT is active motor threshold, and other intensities are at percentages
above that. The vertical timeline for the descending volleys is at the D
wave and, for the MEPs, at the onset of the MEP from TES. Note that
a D wave is produced by anodal TES and that a small D wave is produced by LM TMS at low intensity of stimulation. For the PA stimulation, the I1 wave is first produced by low-intensity stimulation, and
a D wave, as well as later I waves, is produced at higher stimulation
intensity. From Rothwell (2004), as modified from Di Lazzaro et al.
(1998), with permission.
While TMS of occipital cortex can produce phosphenes,
it can also produce a transient scotoma. Scotoma mapping is an example of mapping in time with inhibition. In
the first demonstration of this, subjects were shown briefly
presented, randomly generated letters on a visual monitor,
and TMS was delivered after the visual stimulus (Amassian
et al., 1989). When delivered at an interval less than
40–60 ms or more than 120–140 ms, letters were correctly
reported; but at intervals of 80–100 ms, a blur or nothing
was seen. Presumably this indicates important visual processing during that time interval. Subsequent studies with
more sensitive techniques indicate also an earlier period
of suppression at about 30 ms, likely indicating the initial
arrival of visual information to occipital cortex (Figure 5)
(Corthout et al., 1999b). Additionally, TMS of V5 can selectively interfere with the perception of motion of a stimulus
without impairing its recognition (Beckers and Zeki, 1995;
Walsh et al., 1998). Such data provide support to the concept arising from imaging studies that V5 is the motion
perception region of the brain.
Studies of vision have also revealed the importance of
backprojections for perception. For example, there appears to be an important projection from V5 to V1. TMS
over V5 can produce a moving phosphene, but when the
V5 stimulus is followed by a TMS over V1 at an interval
of 5–45 ms, the phosphene is degraded (Pascual-Leone
and Walsh, 2001). Moreover, a similar backprojection
exists from the frontal eye field (FEF) to V5. TMS over
FEF impairs visual target discrimination (independent of
its role in eye movements) (O’Shea et al., 2004) and, at
an interval of 20–40 ms, can modify the phosphene threshold of TMS over V5 (Silvanto et al., 2006).
High-frequency rTMS, at about 5–10 Hz, has been used
as a more powerful stimulus to produce a brief period of
inhibition in space and time. One example in the motor
system is the study of the role of the supplementary motor
cortex (SMA; more exactly, the mesial frontocentral cortex) in the production of sequential finger movements
(Gerloff et al., 1997). Stimulation over the SMA induced
accuracy errors in complex, but not simple, sequences.
Additionally, the errors occurred in subsequent elements
of the sequence rather than those occurring at the time
of the stimulation itself. The data support a critical role of
the SMA in the organization of forthcoming movements
in complex motor sequences.
When patients who are blind from early life read Braille,
they activate their occipital cortex, as demonstrated by
functional neuroimaging (Sadato et al., 1996). This is a
striking example of transmodal plasticity, where somatosensory information gets routed to the visual cortex. The
observation from neuroimaging alone, however, did not
prove that the activity in visual cortex was being used
for actual useful analysis of the information. Using rTMS
during the reading showed that function was impaired
when the visual cortex was disrupted (Cohen et al.,
1997). Hence, TMS showed that the occipital activity
was a necessary component of the processing. In a similar
situation, studies with fMRI showed that the ventral
premotor cortex was activated with counting of large
numbers, but not small ones (up to 4) (Kansaku et al.,
2007). Correlative studies with rTMS showed that disruption of the ventral premotor cortex interfered with this
counting behavior, showing that this region appears to
be necessary for it.
TMS has helped localize memory processes. For example, several studies give evidence for a role of the left
dorsolateral prefrontal cortex (DLPFC) in working memory.
Neuron 55, July 19, 2007 ª2007 Elsevier Inc. 189
Neuron
Primer
Figure 5. Mapping Visual Processing in Time
The x axis shows magnetic-visual stimulus onset asynchrony (SOA),
i.e., time of onset of the magnetic stimulus minus time of onset of
the visual stimulus (positive values thus indicate that the magnetic
stimulus came after the visual stimulus). The y axis shows proportion
of letters correctly identified as a function of magnetic-visual SOA,
averaged across three subjects who showed the first visual dip. Error
bars denote ± 1 SEM. The thick horizontal line indicates that chance
level was 20%. Modified from Corthout et al. (1999a), with permission.
Single-pulse TMS between presentations of letters impaired ability to match letters on a three-back task (Mull
and Seyal, 2001). Low-frequency rTMS over the left
DLPFC interfered with short-term memory for words, but
not for faces (Skrdlantova et al., 2005). Double-pulse
TMS over DLPFC at 100 ms interval interfered with working memory for words after a reading task (Osaka et al.,
2007). Consolidation of a simple motor skill, phasic pinch
force, was disrupted by stimulation selectively over M1,
without disruption of other aspects of motor function
(Muellbacher et al., 2002). Another study confirmed this
finding, but failed to find a similar disruption of learning
of movement dynamics in a force field, suggesting that
only some types of motor consolidation occur in M1
(Baraduc et al., 2004). On the other hand, rTMS of M1 prior
to learning of movement dynamics did interfere with
consolidation without interfering with the learning itself
(Richardson et al., 2006).
There are numerous examples of how this technique
has helped localize a wide variety of other cognitive functions; a few other findings are noted here. Low-frequency
rTMS over either the right or left prefrontal cortex (but not
the parieto-occipital cortex) impaired behavior on a task
involving visuo-spatial planning (Basso et al., 2006). Disruption of the right (but not left) dorsolateral prefrontal
cortex reduced a subject’s willingness to reject an unfair
offer, even though they still could appreciate the offer
as unfair (Knoch et al., 2006). Selective stimulation over
Wernicke’s area improves cognitive function by shortening the latency for picture naming (Mottaghy et al., 2006).
Assessment of Cortical Excitability
Various TMS measures of the motor cortex can evaluate
different aspects of cortical excitability. Such measures
190 Neuron 55, July 19, 2007 ª2007 Elsevier Inc.
are useful in understanding changes in brain physiology
seen, for example, in the setting of cortical plasticity
and brain disorders. Some of the common measures are
listed here.
Threshold
The threshold for producing an MEP reflects the excitability of a central core of neurons that arises from the excitability of individual neurons and their local density. Since
it can be influenced by drugs that affect Na and Ca channels, it must indicate membrane excitability (Ziemann,
2004). Because the MEP is small, the threshold measure
(with posterior-anterior brain current flow) reflects the
influence of mainly the I1 wave.
Recruitment Curve
The recruitment curve is the growth of MEP size as a function of stimulus intensity and background contraction
force. This measurement is less well understood but
must involve neurons in addition to the core region activated at threshold. These neurons have higher threshold
for activation, either because they are intrinsically less
excitable or they are spatially further from the center of
activation by the magnetic stimulus. These neurons would
be part of the ‘‘subliminal fringe’’ and will contribute to
I2 and later I waves.
Short Intracortical Inhibition and Facilitation
Short intracortical inhibition (SICI) and facilitation (ICF) are
obtained with paired-pulse studies and reflect interneuron
influences in the cortex.(Ziemann et al., 1996) In such
studies, an initial conditioning stimulus is given—enough
to activate cortical neurons, but small enough so that no
descending influence on the spinal cord can be detected
and there is no MEP. A second test stimulus, at suprathreshold level, follows at a short interval. Intracortical influences initiated by the conditioning stimulus modulate
the amplitude of the MEP produced by the test stimulus.
At very short intervals, less than 5 ms, there is inhibition,
and at intervals between 8 and 30 ms, there is facilitation
(Figure 6). SICI is likely largely a GABAergic effect, specifically GABA-A (Di Lazzaro et al., 2000a).
Silent Period
The silent period (SP) is a pause in ongoing voluntary EMG
activity produced by TMS. While the first part of the SP is
due in part to spinal cord refractoriness, the latter part is
entirely due to cortical inhibition. This type of inhibition
seems to be mediated by GABA-B receptors (Werhahn
et al., 1999). SICI and the SP clearly reflect different
aspects of cortical inhibition.
Long Intracortical Inhibition
Long intracortical inhibition (LICI) is assessed with paired
suprathreshold TMS pulses at intervals from 50 to
200 ms. LICI and SICI differ, as demonstrated by the facts
that with increasing test pulse strength, LICI decreases
but SICI tends to increase, and that there is no correlation
between the degree of SICI and LICI in different individuals
(Sanger et al., 2001). Interestingly, LICI appears to inhibit
SICI and shows some interaction of inhibitory mechanisms within the human motor cortex (Sanger et al.,
2001). The mechanisms of LICI and the SP may be similar.
Neuron
Primer
Figure 6. Technique of Producing Short
Intracortical Inhibition and Intracortical
Facilitation
Paired magnetic pulses are given. In (A), from
top down: conditioning pulse alone, conditioning and test pulse at 3 ms interval, conditioning
and test pulse at 2 ms interval. The MEP from
the test pulse without the conditioning pulse
is indicated in the second and third traces
with dotted lines. This shows that the conditioning pulse, although not producing an MEP
itself, can lead to inhibition of the test pulse.
(B) illustrates the average effect on MEPs with
paired pulses at different intervals. Error bars
denote ± 1 SEM. There is inhibition at 1–5 ms
interval and facilitation at 10 and 15 ms interval.
From Kujirai et al. (1993), with permission.
Short and Long Afferent Inhibition
Short and long afferent inhibition (SAI and LAI) are
produced at latencies of about 20 ms and 200 ms, respectively, after somatosensory stimulation of the hand
(Di Lazzaro et al., 2000b). SAI has been demonstrated to
be mainly muscarinic by its selective blockage by scopolamine.
Transcallosal Inhibition
Transcallosal inhibition (TCI) is the inhibition produced in
the primary motor cortex in one hemisphere by stimulation
of the opposite primary motor cortex. Inhibition occurs at
intervals of 8–50 ms (Ferbert et al., 1992).
Premotor Cortex Inhibition
Premotor cortex inhibition is produced by stimulation of
the premotor cortex either in the same or opposite hemisphere (Civardi et al., 2001; Mochizuki et al., 2004).
Plasticity
TMS can be used in a variety of ways to induce plastic
changes in the brain, and this can be utilized to assess
the capability for plasticity (Table 1). Additionally, induced
plastic changes can be exploited therapeutically, and this
aspect will be discussed below. An effective way to modulate synaptic efficacy is to activate a cell with two or more
inputs at close to the same time. If the stimuli come on the
same synaptic pathway, this is called homosynaptic, and,
if on different synaptic pathways, this is called heterosynaptic. Increased synaptic strength is called long-term
potentiation (LTP); decreased synaptic strength is called
long-term depression (LTD).
rTMS at slow rates, approximately between 0.2 and
1 Hz, will cause a decrease in brain excitability (Chen
et al., 1997). rTMS at faster rates, approximately 5 Hz or
faster, will cause an increase in brain excitability (PascualLeone et al., 1994). In an animal model of these effects,
in the immediate period after rapid or slow rTMS to the
cat visuo-parietal cortex, the uptake of (14)C-2DG was increased or decreased, respectively (Valero-Cabre et al.,
2007). TMS can also be used repetitively in a mode where
very short, very high frequency trains of stimuli are delivered at theta frequency, about 5 Hz. This is called thetaburst stimulation (TBS) (Di Lazzaro et al., 2005; Huang
et al., 2005). A typical paradigm would be three stimuli at
50 Hz, repeated at 5 Hz. If given intermittently, say 2 s of
stimulation every 10 s, this leads to increased excitability.
If given continuously over 40 s, this leads to decreased
excitability.
Another method for influencing brain excitability is
a low-level continuous electric current, called transcranial
direct current stimulation (tDCS). This is becoming a popular technique as well but will not be emphasized here
since it is not magnetic. Anodal stimulation will facilitate
the motor cortex, and cathodal stimulation will inhibit it.
Heterosynaptic plasticity can be realized in humans with
a peripheral stimulus paired with a TMS brain stimulus. A
nice set of experimental paradigms has been developed
by Classen and collaborators and called paired associative stimulation (PAS) (Stefan et al., 2000; Wolters et al.,
2003). If a median nerve stimulus at the wrist is paired
with a TMS to the sensorimotor cortex at 25 ms, then
the two stimuli arrive at about the same time, and the
MEPs will be facilitated (Figure 7). If the interval is about
10 ms, the TMS comes about 15 ms before the median
nerve volley arrives, and the MEP will be depressed. The
former behaves like LTP and the latter like LTD (McDonnell
et al., 2007). As a simple motor learning task and PAS
interact with each other, it does appear that PAS is a highly
relevant model for brain plasticity (Ziemann et al., 2004).
Comparison with EEG/MEG and Functional
Imaging
There are several noninvasive techniques available to neuroscientists these days. Each method gives a different
view of brain function. One particular view might be best
in a particular situation, but often it will be better to get
multiple views for more complete understanding. EEG
and MEG are direct measures of neuronal activity, and
timing information is excellent, but spatial information is
not so good and is even ambiguous because of the
nonuniqueness of the inverse problem (determination of
sources from the scalp recordings). EEG measures voltage differences from different sites on the scalp. These
voltage differences are set up by transmembrane currents, mainly postsynaptic potentials of apical dendrites
of large pyramidal cells. Those that are oriented perpendicularly to the surface of the cortex have more influence
Neuron 55, July 19, 2007 ª2007 Elsevier Inc. 191
Neuron
Primer
Table 1. Summary of Noninvasive Methods for
Excitation and Inhibition
Method Excitatory Mode
Inhibitory Mode
rTMS
high frequency, R5 Hz low frequency, 0.2–1 Hz
TBS
intermittent
continuous
tDCS
anodal
cathodal
PAS
synchronous
heterosynaptic
stimulation
asynchronous
heterosynaptic
stimulation
than those oriented tangentially. Scalp potentials will be
measured only when a sufficient number of cells are active
synchronously, and this synchrony is facilitated by the
columnar organization of the cortex. MEG is similar to
EEG but measures more the intracellular currents. The
sources of MEG may be better localized than with EEG
because MEG is not distorted by the skull and scalp, but
MEG is blind to radial sources. PET and fMRI are techniques for functional neuroimaging and have good spatial
localization but less temporal resolution. PET using O-15
water measures regional cerebral blood flow, and this
is a reasonable measure since synaptic activity increases
local metabolism and stimulates changes in perfusion.
fMRI most commonly uses the BOLD technique, which
measures the oxidation state of hemoglobin in the blood.
Since with metabolism, blood flow increases more than
oxygen extraction, blood becomes more oxygenated. This
is a rather indirect measure of neuronal activity, but it
does correlate with perfusion measures, and like EEG and
MEG, it is most closely correlated with synaptic activity.
One example of how the techniques show different
views of a physiological process is what happens in the
motor cortex in the no-go trials in a go/no-go experimen