Oscillatory Contributions to Working Memory and Attention
Phase: NA
Conditions: Young Adults
Sponsor: University of Wisconsin, Madison

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Oscillatory Contributions to Working Memory and Attention 
 
PI: Bradley R. Postle, PhD, Departments of Psychology and Psychiatry, University of 
Wisconsin–Madison 
 
Protocol version date: 09/25/2023 
 
Sub-studies: L.3, O, Y, AA, AC, AD, AE 
 
Funding: NIH R01 MH095984-03S1 
 
NCT 03787134 
 

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Physiological and Behavioral Consequences of Brain Stimulation Renewal 
 
 
Principal Investigator:  
Bradley R. Postle, Ph.D.   
 
 
 
1. Title: Physiological and Behavioral Consequences of Brain Stimulation 
Renewal 
 
2. Summary of activities from protocol 2011-0608 and continuing studies 
for protocol 2016-0500:  
 
The approved sub-studies from the previous protocol, 2011-0608, fall into two 
categories, A or B. New sub-studies will be added to 2016-0500 in category B:  
 
A. The sub-study is either complete, or in the final stages of data 
analysis. No further enrollment of subjects or research will be 
conducted on these sub-studies. The study documents such as 
signed consent forms and screening materials will be maintained 
for 7 years to address potential audits/NIH follow-up. 
 
B. The sub-study is ongoing.  A portion of the subjects have been 
enrolled or the sub-study has not yet begun. The research activities for 
the sub-study are currently ongoing.  
 
 
A. The sub-study is complete or in the final stages of data analysis:   
Sub-study A 
Sub-study B 
Sub-study C 
Sub-study D 
Sub-study E 
Sub-study F 
Sub-study G  
Sub-study H 
Sub-study I 
Sub-study K 
Sub-study L.1 
Sub-study L.2 
Sub-study N 
Sub-study P 
Sub-study Q 
Sub-study R 
Sub-study J 
Sub-study S 
 

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B. The sub-study is ongoing: 
Sub-study L.3 
Sub-study M.1 
Sub-study M.2 
Sub-study T.1 
Sub-study T.2 
Sub-study O 
Sub-study U 
Sub-study V 
Sub-study W 
Sub-Study X 
Sub-Study Y 
Sub-Study Z 
Sub-Study AA 
Sub-Study AB 
Sub-Study AC 
 
Sub-Study AD 
Sub-Study AE 
 
Sub-Study AF 
  
 
3. Objectives of current sub-studies: 
 
The broad objective of the studies proposed under this protocol is to use 
transcranial brain stimulation, methods of non-invasive brain stimulation, to 
address questions about the functional anatomy of the human brain. Under this 
protocol These stimulation techniques offer advantages over measurement 
techniques, such as electroencephalography (EEG) and functional magnetic 
resonance imaging (fMRI), in that they support inferences about causation, as 
opposed to correlation. The stimulation techniques covered by this protocol 
include transcranial magnetic stimulation (TMS) and transcranial current 
stimulation (tCS).  Previous work carried out by the PI’s group under protocol 
2011-0608 (which the present protocol is intended to replace) indicates that 
TMS interacts in interesting ways with cortical oscillations, and therefore offers a 
unique way to study the function of these physiological phenomena. The 
experiments described in this protocol fall into several methodological 
categories: simultaneous TMS and fMRI; repetitive or single-pulse TMS, which 
is administered alone, simultaneously with EEG, or before fMRI scanning; and 
tCS, which is administered via a cap that also affords simultaneous EEG 
recording. In all cases, these studies follow from work that has been carried out 
by the PI’s group under protocol 2011-0608.  In all cases, the experiments 
carried out under this protocol will test hypotheses about the neural bases of 
human perception, attention, and memory. Specific experiments differ from one 
another in terms of the details of the cognitive task(s) that subjects perform, but 
not in terms of the general TMS and/or physiological measurement (i.e., fMRI or 
EEG) procedures that are used. For this reason, this protocol will follow the 

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convention used in 2011-0608, in which each experiment is described as a “sub-
study” of the protocol. 
Simultaneous TMS and fMRI studies will begin with an MRI scan in order to 
acquire information about the subject’s brain that is used for guiding the delivery 
of TMS (i.e., for “targeting”). On a different day, fMRI scanning is performed with 
a TMS coil that has been custom-designed to be compatible with the strong 
magnetic field generated by the MRI scanner. Repetitive TMS or Single-pulse 
TMS studies will also begin with an MRI or fMRI scan, followed, on a different 
day, by repetitive or single-pulse TMS that is delivered either alone. The EEG is 
recorded simultaneously, or before fMRI recordings. The initial scan is an MRI 
scan for experiments for which anatomical landmarks will be targeted by TMS. It 
is an fMRI scan of one or more areas of task-related activity are to be targeted 
with repetitive TMS. In such cases, subjects perform the cognitive task both 
during the initial fMRI scan and the subsequent repetitive TMS session. In some 
instances, high density EEG data (collected without concurrent TMS) can be 
recorded simultaneously with fMRI to obtain a higher temporal resolution, and to 
allow correlations between electrical activity and hemodynamic changes in the 
brain during tasks. EEG data can also be useful for pilot testing to refine EEG 
measurement and data processing procedures before a simultaneous repetitive 
TMS and EEG study is launched. Finally, tCS will be administered via a wireless 
hybrid EEG/tCS 8-channel neurostimulator system (model name “StarStim 8”) 
manufactured by Neuroelectrics. The system’s electrodes are held in a 
neoprene headcap that is worn by the subject. The cap is designed to allow for 
multiple configurations of tCS electrodes and EEG electrodes. This design 
affords the ability to record EEG signals prior to, during, and/or after stimulation. 
 
3. 
Rationale: 
 
 
In general, different substudies will utilize different approaches that rely on the 
various devices described in turn below. None of the substudies are intended to 
evaluate the safety/effectiveness of the devices. Rather, the devices are 
intended to be incorporated into this research as a tool to facilitate collection of 
data appropriate to address the over-arching research hypotheses. Any studies 
intended to evaluate device safety/effectiveness would be submitted under a 
separate protocol. 
 
3.A. The inferential limits of neuroimaging 
fMRI (as well as all other neurophysiological measurement methods, such 
as electrophysiology and positron emission tomography (PET)) is a correlative 
measure, and as such, data produced by fMRI alone are logically incapable of 
answering the question “does region X make a necessary contribution to 
function Y?” The only way to address conclusively questions about necessity is 
to alter the function of an area and to observe whether this perturbation has an 
effect on the function in question. The repetitive TMS experiment draws on this 
logic to ask questions of necessity that have arisen from previous neuroimaging 
studies. 

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3.B. Transcranial magnetic stimulation 
Transcranial magnetic stimulation (TMS) is a technique introduced in 1985 
(Barker, Jalinous, & al., 1985) that uses the principle of electromagnetic 
induction (the “right-hand rule” from high school physics) to get electrical energy 
across the scalp and skull in order to produce changes in neural activity in the 
brain. It involves placing a small coil of wire on the scalp and passing a very 
brief and powerful current through it. This produces a magnetic field that passes 
unimpeded through the tissues of the head. The magnetic field, in turn, induces 
a much weaker electrical current in the brain that is capable of activating nerve 
cells in the cerebral cortex. Thus, a TMS pulse produces a powerful but brief 
magnetic field that passes through the skin, soft tissue, and skull, and induces 
electrical current in neurons, causing depolarization that then may have 
behavioral effects. For example, if the hand area of primary motor area of the 
cortex is stimulated, twitches are easily recordable in hand muscles on the 
contralateral side of the body. TMS can be used to map the representation of 
body parts in the motor cortex on an individual basis, and is regularly used in 
neurology to determine central conduction times. (E.g., it is routinely used to 
track the progression of multiple sclerosis.) Subjectively, magnetic stimulation of 
motor cortex feels much like a tendon reflex movement (George, Lisanby, & al., 
1999). 
Applied as single pulses appropriately delivered in time and space, or 
applied in trains of repetitive stimuli at an appropriate frequency and intensity, 
TMS can be used to transiently alter the function of a given cortical target. In 
some applications it can have the effect of momentarily disrupting ongoing 
neural activity, thereby creating a temporary `virtual brain lesion' (Pascual-
Leone, Walsh et al. 2000). This makes it possible to study two aspects of the 
contribution of a given cortical region to a specific behavior: `what does it do?' 
and `when does it do it?' For example, functional imaging studies of early or 
congenitally blind subjects reveal that their primary visual cortex can be 
activated by Braille reading and other tactile discrimination tasks. However, this 
activation could be an epiphenomenon of tactile information processing in blind 
people. Using TMS, it was shown that disrupting neural activity in primary visual 
cortex induced reading errors and distorted the tactile perceptions of 
congenitally or early blind subjects, thus demonstrating that the visual cortex is 
actually required for tactile spatial processing by early blind subjects (Cohen et 
al., 1997). There is a large body of work that has used TMS to induce ‘virtual 
lesions’ in order to establish the causal role of a cortical region in a given 
function, such as primary visual cortex in visual imagery, motor cortex in mental 
rotation, parietal cortex in attention, neglect and extinction, and frontal cortex in 
random number generation and working memory (Pascual-Leone et al., 2000; 
Walsh & Cowey, 2000). Indeed, the PI’s group has published several such 
studies under protocol H-2003-033 and 2011-0608 (Feredoes, Tononi et al. 
2006; Postle, Ferrarelli et al. 2006; Feredoes, Tononi et al. 2007; Hamidi, 
Tononi et al. 2008; Hamidi, Tononi et al. 2009; Feredoes and Postle 2010). 
Interestingly, TMS can be used not only to induce virtual brain lesions, 
but also to enhance functioning. There are two classes of examples of this. The 

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first is the treatment of psychiatric disorders. For example, as demonstrated by a 
number of studies, both high-frequency and low-frequency stimulation with TMS 
can have antidepressant properties (George et al., 1999). TMS has also been 
applied in schizophrenic subjects (Boroojerdi, Topper, & al., 1999; Cohen et al., 
1999; Davey & Puri, 2000; Feinsod, Kreinin, Chistyakov, & Klein, 1998; Geller, 
Grisaru, Abarbanel, Lemberg, & Belmaker, 1997; Grisaru, Amir, Cohen, & 
Kaplan, 1998; Grisaru, Chudakov, Yaroslavsky, & Belmaker, 1998; Klein, Kolsky 
et al., 1999; Klein, Kreinin et al., 1999). For example, several studies have 
shown that TMS applied to temporal cortex of schizophrenic subjects can 
reduce the frequency and intensity of auditory hallucinations (Hoffman et al., 
1999; Hoffman et al., 2000). These studies have triggered great interest in the 
potential therapeutic applications of TMS. The second class of “enhancing” 
effects has been pioneered by the PI’s group, with the discovery (via 
simultaneous TMS-EEG) that repetitive TMS can have differing results on task-
related EEG for different subjects, with these effects predicting whether 
repetitive TMS will have performance-enhancing or performance-impairing 
effects for any given individual (Hamidi, Slagter et al. 2009; Johnson, Hamidi et 
al. 2010). More recently, repetitive TMS using a continuous theta burst 
stimulation paradigm (TBS, similar to sub-study G, which has been completed 
on the 2011-0608 protocol) has been shown to induce robust performance-
impairing effects during working memory tasks that can last up to one hour 
(Morgan et al, 2013; Lee and D’Esposito 2013). It has also been demonstrated 
that several daily sessions of TBS can have positive clinical effects in 
pathological disorders such as auditory hallucination (Kindler et al, 2013) and 
amblyopia (Clavagnier et al, 2013). These results are exciting, in that they 
suggest that it may be possible to tailor the delivery of repetitive TMS to an 
individual such that it can be used either therapeutically or diagnostically. 
However, the satisfactory development of such applications requires a 
better understanding of which brain circuits are activated or deactivated as a 
result of TMS of a given brain area (Pascual-Leone, Walsh et al. 2000). For 
example, investigators are only beginning to appreciate that whether repetitive 
TMS has disruptive or facilitative effects on cognitive task performance can 
depend on the frequency of repetitive TMS with respect to the subject’s IAF 
(Klimesch et al, 2003; Luber et al., 2007). In this context, recent work attempting 
to combine TMS with functional neuroimaging is particularly relevant. 
3.C. Transcranial magnetic stimulation and functional neuroimaging 
Paus et al. (Paus et al., 1997) were the first to introduce the combined 
techniques of TMS and functional neuroimaging as a means of mapping neural 
connections in the live human brain. They used TMS to stimulate directly a 
selected cortical area; simultaneously, they measured changes in brain activity, 
indexed by cerebral blood flow (CBF). Ilmoniemi et al. (Ilmoniemi, Virtanen et al. 
1997) used a similar approach for studying cerebral connectivity in humans 
using a combination of TMS and quantitative EEG. In their first study, Paus et al. 
(Paus et al., 1997) applied TMS to the left frontal eye fields of human subjects 
and found a significant positive correlation between the number of TMS pulses 

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and CBF at the stimulation site and, most importantly, in the superior parietal 
and medial parieto-occipital regions. The pattern of these distal effects was 
consistent with the known anatomical connectivity of monkey frontal eye fields. 
The authors concluded that the combination of TMS with functional 
neuroimaging offers an objective tool for assessing the state of effective 
connectivity without requiring the subject to engage in any specific behavior 
(Paus, 1999). Mottaghy et al.(Mottaghy, Krause et al. 2000) have combined 
TMS and PET in humans to investigate the role of prefrontal cortex in working 
memory. They found that, while both left and right prefrontal TMS affect 
performance in a working memory task, right-sided TMS has stronger and 
longer effects. Interestingly, the PET study showed that left dorsolateral 
prefrontal cortex TMS produced reductions in cortical activity only in the directly 
targeted prefrontal region. By contrast, TMS to the right prefrontal cortex 
significantly reduced activity in the right prefrontal region, the right fronto-
temporal pole, and bilateral parietal regions. This result indicates that, while the 
anatomical connectivity of left and right dorsolateral prefrontal cortex is similar, 
their effective connectivity may be quite different. 
In the first combined simultaneous fMRI/TMS study in humans, Bohning et 
al. showed that 18-second trains of TMS pulses at 1 Hz (18 pulses at 110% of 
motor threshold (MT)) induced 3%-4% increases in the blood oxygenation level-
dependent (BOLD)-fMRI signal in the area of stimulation (Bohning et al., 1999; 
Bohning et al., 1998). Although that study had an imaging time resolution of 3 
seconds rather than the approximately 60 seconds in the  PET studies, it used a 
block design stimulation pattern, so the hemodynamic response could not be 
directly compared with the hemodynamic response observed in cognitive task 
single-event studies. Bohning et al. also demonstrated BOLD-fMRI responses to 
single TMS pulses over human motor cortex in both the ipsilateral motor cortex 
under the TMS coil and the contralateral motor cortex (Bohning et al., 2000). 
The associated BOLD signal increase showed the typical fMRI hemodynamic 
response time course. More recently, using TBS on the prefrontal cortex before 
a working memory task performed in the MRI scanner, Lee and D’Esposito 
showed a decreased of the tuning of extrastriate cortex responses, coinciding 
with decrements in performance. They also found that activity in the 
homologous prefrontal region in the non-stimulated hemisphere predicted 
performance following disruption (Lee and D’Esposito, 2012). Similarly, TBS on 
the prefrontal or parietal cortices has been shown to selectively impair working 
memory for visual-spatial conjunctions (Morgan et al, 2013). The combination of 
TMS and fMRI technique is important because it allows the comparison of 
different TMS events using their associated BOLD responses. These studies 
demonstrate the feasibility of combined fMRI/TMS paradigms in humans to 
probe activity in different brain regions in a systematic manner. 
 
3.D. Combining TMS and EEG 
In TMS, the cerebral cortex is stimulated non-invasively by generating a 
brief but strong magnetic pulse (<1 ms, up to 2 Tesla) through a coil applied to 
the surface of the scalp. The rapid change in magnetic field strength induces a 

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current flow in the tissue, which results in the activation of underlying neuronal 
populations (Hallet, 2000). The synchronous volley of action potentials thus 
initiated propagates along the available connection pathways and can produce 
an evoked response in target cortical regions. Typically, if the primary motor 
area of the cortex is stimulated, twitches are recordable in muscles on the other 
side of the body. Most of the electrophysiological studies on TMS-evoked 
responses have been limited to the measurement of the motor output. Until 
recently, the effects of TMS on cortices other than motor cortex have been 
limited solely to the registration of the behavioral effects of the stimulation. The 
first studies of cortico-cortical responsiveness have used TMS and positron 
emission tomography (PET) in conjunction (Paus et al., 1997; Paus, 1999). This 
approach offers a good spatial resolution but suffers from a very low temporal 
resolution with respect to the actual dynamics of the response. 
The combination of TMS and EEG represents a unique tool for investigating 
the effects of repetitive TMS on endogenous oscillations in neuronal 
populations, a factor that may determine whether the effects of repetitive TMS 
on behavior are facilitatory or disruptive in any particular situation. The 
simultaneous use of TMS and EEG, however, is challenging and has required 
the solution of several technical problems. A major one is the EEG artifact 
induced by the magnetic pulse. During stimulation, the strong magnetic field 
generated by the coil can induce voltages between scalp electrodes that can 
reach several volts, i.e. six orders of magnitude larger than the typical EEG 
signal. The volt-level peak in the leads saturates the input stages of the 
standard EEG amplifier, requiring several seconds for the circuits to return in the 
linear operating range. To overcome this problem, Virtanen and collaborators 
have designed and built a 60-channel EEG acquisition system that prevents 
large artifacts thanks to gain-control and sample-and-hold circuits that pin the 
amplifier output to a constant level during the pulse (Virtanen et al., 1999). In a 
first study combining TMS/EEG, the motor cortex of normal volunteers was 
activated by single TMS pulses while recording electrical brain activity with 20 
scalp electrodes (Ilmoniemi, et al., 1997). After the pulse, an immediate 
response over the left sensory-motor area was followed by the spread of 
activation to adjacent ipsilateral motor areas within 5-10 ms and to homologous 
regions of the opposite hemisphere within 20 ms. In a more recent study by the 
same group (Komssi et al., 2002), TMS-evoked scalp potentials were recorded 
with a high-density array (60 leads) and superimposed on magnetic resonance 
images. The results confirmed specific ipsi- and contralateral EEG responses 
that varied depending on the precise site of stimulation in the left sensory-motor 
cortex. Using a similar technique, Paus et al. (2001) demonstrated that TMS in 
the human primary motor cortex induces both local synchronization and evoked 
waves at distant locations. Interestingly these responses were often detectable 
in single EEG traces. Altogether, these results indicate that the effects of TMS 
on endogenous oscillatory activity can now be studied in the human brain with 
high spatial resolution and on a millisecond time scale by combining TMS and 
EEG. As described in his HS-IRB protocol # 2003-238, Dr. Giulio Tononi’s group 
acquired the first commercially available version of the system used by Komssi 

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et al. (2002), which is manufactured and sold by Nexstim, Ltd. Dr. Postle’s group 
has now acquired an identical system, which is located at the HealthEmotions 
Research Institute (HERI), and the proposed repetitive TMS-EEG experiments 
will be performed with this system. 
 
3.E. Combining EEG and fMRI 
 
Simultaneous EEG-fMRI recordings offer the possibility of enriching the 
significance and the interpretation of results from single modality experiments 
because they provide simultaneous, complementary measures of the same 
neural processes underway in the same brain. The combination of EEG with 
fMRI has been successfully used by other investigators to observe changes in 
brain activity during working memory tasks (Scheeringa et al 2009, Michels et al 
2010, 2012, Chaudhary et al 2012, White et al 2012). For instance, Sheeringa et 
al (2009) identified the emergence of functional (MRI) networks related to alpha 
and theta EEG power increases during working memory maintenance, and 
showed that theta power during encoding predicted subsequent-memory 
performance and default mode network deactivation (White et al 2012). The 
coupling of frequency band oscillation and the BOLD signal in task-related areas 
permits the observation of changes with cognitive load, e.g., theta band power 
increased with load in frontal midline regions (Michels et al 2010). These studies 
demonstrate the feasibility of combined EEG-fMRI paradigms which provide 
complementary information: fMRI can show changes in blood flow and activity in 
deeper brain structures while EEG, which is limited to electrical activity at the 
brain surface, has the best temporal resolution and can measure changes in 
activity much more quickly than fMRI. Note that the EEG system (Brain Products 
GmBH, Germany) is compatible with the MRI equipment, and has been 
approved for use in the identical MRI conditions by the HS-IRB in previous 
protocols from Dr. Giulio Tononi’s group (H-2004-0023, H-2007-0150, H-2013-
0019), and the PI’s previous protocol, 2011-0608. 
 
3.F. tCS 
 
3.F.1.  
General description of method 
Transcranial current stimulation (tCS) is a non-invasive painless method to 
affect cortical excitability by using weak electrical currents (typically in the range 
of 1-to-2 mA) applied to the scalp of the subject. tCS can be administered in 
three modes: direct-current stimulation (tDCS); alternating-current stimulation 
(tACS); and random-noise stimulation (tRNS). The literature contains reports of 
thousands of tCS sessions that, when following standard procedures, have been 
carried out without any injury to skin or underlying tissue (Woods, Antal et al. 
2016). We will begin with tDCS, because its principles and application are 
easiest to explain.   
 
3.F.2.  Using tDCS involves passing current through the skin, skull, and 
brain with a direct-current device. By analogy, a battery is a device that we all 

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have experience with that delivers direct current. If one connects a fresh 9-volt 
battery to an oscilloscope, one will see the scope jump from 0 volts to 9 volts as 
soon as the battery terminals (the positive (i.e., the cathode) and the negative 
(i.e., the anode)) are attached to the two probes. When one of these probes is 
taken off, the circuit is “broken”, and the measured voltage returns to 0 volts. 
The method of tDCS entails passing precisely this same kind of constant current 
(albeit at markedly lower intensity) through a circuit, with the tissue of the brain 
serving as a part of the circuit, typically for a fairly long period of time (e.g., 20 
min). Importantly, the electrical currents from tDCS (typically 1-2mA on the 
scalp) are far too low to directly induce action potentials in cortical neurons. 
Instead, their effects are on cortical excitability via changing the transmembrane 
potential of neurons (Iyer et al., 2005; Nitsche & Paulus, 2000; Wagner et al., 
2007). This has the functional effect of modulating the processing carried out by 
the stimulated area. For example, Nitsche and Paulus (2000) showed that 
exciteability of primary motor cortex can be modulated by up to 40% with tDCS 
as measured by the size of motor evoked potentials induced with transcranial 
magnetic stimulation (TMS). That is, tDCS all by itself didn’t generate motor 
evoked potentials, but the amplitude of potentials evoked by a pulse of TMS was 
higher when TMS was delivered concurrently with tDCS. Similar results have 
been found for changes to TMS-evoked phosphenes when applying tDCS to 
primary visual cortex (Antal, Kincses, Nitsche, & Paulus, 2003). Importantly, the 
direction of the effect of tDCS – that is, excitation or suppression of exciteability 
-- depends on the polarity of the stimulation. Cortical excitability tends to be 
reduced in brain tissue nearest the cathode, whereas it is increased in tissue 
nearest the anode. In typical applications of tDCS, only the anode or the 
cathode of the stimulator is placed over cortex, with the other terminal placed on 
a part of the body away from the brain. Thus, a tDCS stimulation protocol is 
referred to as being “anodal” or “cathodal”. 
 
3.F.3. 
tACS also involves passing current through the skin, skull, and 
brain with an electrical stimulator. The difference from tDCS, as conveyed in the 
name, is that tACS entails the delivery of alternating current (rather than the 
direct current of tDCS). That is, with tACS the current fluctuates sinusoidally, 
such that during one half of each cycle one electrode serves as anode and the 
other one as cathode, and for the other half of the cycle the pattern reverses. 
Thus, during tACS, the average membrane potential does not deviate from its 
baseline level. Unlike tDCS for which the experimental goal is to tACS is put a 
region of the brain into a prolonged, steady state of increased or decreased 
exciteability, tACS is typically used to influence neuronal oscillations (Herrmann 
et al., 2013).  
 
3.F.4. tRNS is a variant of tDCS, but for which the DC current is held at any 
given level for a relatively brief period of time (typically, on the order of 
seconds), and is randomly stepped between different levels. The mechanisms 
by which tRNS can influence behavior are poorly understood, although the 
principle of stochastic resonance has been proposed. Because we are not 

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proposing to use tCS in tRNS mode, tRNS will not be considered further in this 
protocol. 
 
 
4. 
Potential Adverse Events: 
Please note that each of the entries on this list is “hypothetical”, in the sense 
that the nature of these procedures is such that it is reasonable to be concerned 
that such potential adverse events might be a possibility, and in many cases 
there is a literature exploring such potential events. In the experience of our 
laboratory, however, which extends back to 2007 with EEG (2003-033), to 2003 
with TMS (2003-033 and 2011-0608), and to 2000 with fMRI (2005-503 and 
2012-0652)), no instance of any of these potential adverse events has occurred.  
 
4.A. 
TMS 
 
4.A.1. Seizure Induction 
The major safety concern about TMS is the possibility of eliciting a seizure, 
although TMS has rarely been associated with the induction of seizure, even in 
patients with epilepsy. TMS regimes are subdivided into single-pulse, low 
frequency (<= 1Hz), and high frequency (> 1Hz). Seizure induction, although 
exceedingly rare, is almost exclusively observed after high-frequency TMS well 
above 1Hz and with long stimulation trains (Hallett, Wassermann, Pascual-
Leone, & Valls-Sole, 1999; Wassermann, 1998). A few reports have suggested 
TMS-related seizures occurred after single pulses, but all of these were in 
subjects with epilepsy or other neurological conditions (Classen et al., 1995). No 
seizures have been reported in normal volunteers receiving single pulse TMS, 
nor in patients diagnosed with depression or schizophrenia. Seizures have 
never been reported in subjects receiving 1 Hz TMS. For high frequency studies 
(i.e., repetitive TMS), precise stimulation guidelines have been published that 
specify conservative safe stimulation regimes (Wassermann 1998). More 
recently, these were reaffirmed by the Safety of TMS Consensus Group (Rossi, 
Hallett et al. 2009). In the simultaneous fMRI/TMS study, we will exclusively 
employ single-pulse or low-frequency stimulation regimes (less than or equal to 
a single pulse/sec), which are safe with respect to seizure induction. In the 
repetitive TMS study, the combination of stimulation parameters (i.e., intensity, 
rate, and duration) will fall within the established safety parameters established 
at the International Workshop on the Safety of Repetitive Transcranial Magnetic 
Stimulation (Chen and al. 1997; Wassermann 1998). For repetitive TMS using 
TBS, the risk of seizure is comparable to or less than the other conventional 
high frequency repetitive TMS protocols (Rossi et al 2009, Oberman et al, 
2011). The bulk of the existing literature on the safety of magnetic brain 
stimulation has focused on single pulse TMS, and no adverse effects have been 
reported in the numerous studies in normal and clinical populations. It is 
considered safe with magnetic fields up to 2T, charge density of less than 40 
µC/cm2 per phase, and at repetition rates less than 3 per second (Agnew & 
McCreery, 1987; Gordon et al., 1990). The Magstim magnetic stimulator used in 

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this protocol has a maximal magnetic field strength of 2T (which diminishes to 
0.2 mT 1 meter away from the coil), and the maximum repetition rate is 8 per 
second at full power (30 per second maximum). In reference to single pulse 
stimulation, the FDA has reported that “this type of transcranial magnetic 
stimulator does not now present a potential risk to health, safety, or welfare of 
subjects” (Glass, 1995). Prospective studies designed to systematically evaluate 
health effects have not found changes in EEG, blood pressure, pulse, serum 
cortisol, serum prolactin, cerebral blood flow, memory or cognition (Hamano, 
Kaji, Fukuyama, Sadato, & Kimura, 1993; Levy, Amassian, Schmid, & Jungreis, 
1991; Wassermann et al., 1996), (see Wassermann 1998 for review). Single 
pulse TMS of the motor cortex has been used safely in normal children and 
infants as young as 2 weeks of age (Muller, Homberg, Coppenrath, & Lenard, 
1991; Rossini & Caramia, 1992). Single pulse TMS is now in routine clinical 
diagnostic use in hundreds of neurophysiological laboratories world-wide. 
As the potential for the use of TMS has grown, repetitive TMS is being 
utilized in neuropsychological experiments more often. The major risk that is 
associated with repetitive TMS is seizures. Repetitive TMS has been known to 
elicit seizures in a small number of subjects since its introduction in 1989. In all 
cases, the seizures showed immediate slowing after the TMS was shut off and 
was normalized within 1 to 2 days. However, each of these subjects was 
stimulated with a pulse of extremely high intensity or frequency, or with a very 
low intertrain interval. Subsequent studies have shown that if the stimulation 
intensity, frequency, duration, and total number of pulses delivered per day are 
within the established safety parameters, and there is no history of seizures in 
the subject or his or her family, then repetitive TMS can be safely utilized in 
scientific experiments (Anand and Hotson, 2002; Wasserman, 1998; Rossi et 
al., 2009, Anderson, 2006). Previous studies producing momentary disruption of 
cognitive functions of the cerebral cortex with repetitive TMS have used 
stimulation parameters well within the safety parameters mentioned above 
(Pascual-Leone and Hallett, 1994; Mottaghy, et al. 2002). Testing of subjects 
following repetitive TMS stimulation has shown no neuropsychological deficits 
(Pascual-Leone, et al. 1993).  
 
4.A.2. Headache and mood changes 
The most commonly reported side effect of TMS is headache of muscular 
origin (<5%). Neck pain or scalp pain may also occur. Both typically last up to a 
few hours on the day of stimulation and are usually managed easily with 
standard analgesics (single doses of aspirin or acetaminophen). 1Hz TMS given 
to the prefrontal cortex has been reported to improve mood in patients with 
depression. Mood assessments will be conducted to detect if any mood effects 
are seen in this study. We will inform subjects about possible alterations in 
mood and ask them to report any change immediately.  
 
4.A.3. Magnetic Effects 
Human tissue is virtually nonreactive to magnetic fields (Cadwell, 1991). 
The peak field strength of the device used in this protocol is <2T and the peak 

09/25/23 
 
 
 
13 
magnetic field achieved with the 70 mm figure eight or 90mm circular stimulating 
coil is <1.5T. These figures are within federal guidelines for whole body 
exposure to static magnetic fields during Magnetic Resonance Imaging 
((Schaefer, Bourland et al. 2000); United States Food and Drug Administration, 
Magnetic Resonance Diagnostic Devices Criteria for Significant Risk 
Investigations, at URL http://www.fda.gov/cdrh/ode/magdev.html, 1997). 
According to the World Health Organization task group report, there are no 
adverse effects on human health from short-term exposure to static fields up to 
2T. Exposure to the static field during an MRI is commonly on the order of two 
hours. For comparison, the maximal cumulative exposure time to magnetic 
fields in this protocol is less than 0.032 seconds for single pulse TMS and less 
than 0.048 seconds for repetitive TMS. Subjects with metallic or electronic 
implants will be excluded, due to the risk that magnetic field exposure may affect 
the functioning of such implants. 
 
4.A.4. Effects of Induced Electrical Current 
  The maximal induced electrical current from individual TMS pulses is well 
below levels that would lead to neuropathic effects. The maximum induced 
electrical field and current density per phase are 410V/m and 14 mA/cm2. These 
values are similar to those used with conventional transcranial and direct cortical 
electrical stimulation. The maximal charge density per phase is calculated to be 
≈ 0.94 µC/cm2 (Jalinous, 1991). In animal studies, Agnew and McCreery (1987) 
found no signs of neuronal damage with a higher charge per phase of 10µC/cm2 
when using direct intracranial electrical stimulation at 50 Hz continuously for 24 
hours. The threshold for neuronal injury was a charge density per phase of 40 
µC/ cm2. 
Many histopathological studies in animals have failed to show pathological 
changes in brain after repeated magnetic stimulation (Sgro, Ghatak, Stanton, 
Emerson, & Blair, 1991). The safety of repeated pulses may be proportional to 
the degree to which they exceed motor threshold. Matsumiya (1992) found that 
repeated pulses only produced structural changes when their intensity exceeded 
3.4 times the motor threshold. Neuronal injury occurring at these high intensities 
may well have been secondary to intense head jerking in the unrestrained 
rodents tested. Two epileptic patients have had histochemical evaluation of 
surgically removed temporal lobes following rapid-rate TMS up to 16 Hz, 10 sec 
trains, and up to 1260 total stimuli. No pathological changes attributable to TMS 
were found (Gates, Dhuna, & Pascual-Leone, 1992). 
 
4.A.5. Sound Exposure 
When producing a magnetic pulse train, the stimulating coil produces a 
series of brief clicks. Animal studies have demonstrated that ear plugs prevent 
changes in auditory thresholds despite extensive exposure to long term, 
repeated, high intensity stimulation with associated sound output of up to 157 
dB peak sound-pressure levels (Counter, 1994). No evidence of hearing loss 
has been found in humans exposed to TMS, despite extensive exposure to 
repeated stimulations over several years (Pascual-Leone et al., 1992). Subjects 

09/25/23 
 
 
 
14 
will either wear earplugs (if no EEG recording) or earphones through which a 
white noise will be played throughout each TMS session. This latter procedure 
has been successfully applied in previous studies in order to prevent 
contamination of TMS-evoked EEG potentials by the auditory response to the 
coil’s ‘click’ (Massimini et al 2005, 2010, Rosanova et al 2012, Johnson et al 
2012). 
 
 
 
4.B. 
fMRI 
 
The functional MRI experiments will be conducted using a 3.0 tesla scanner 
(GE Discovery MR750) at the Lane Neuroimaging Laboratory (HERI). This fMRI 
system is FDA approved, and its software incorporates the necessary limitations 
for meeting FDA regulations for safe scanning of patients. The principal 
investigator currently has HS-IRB approval to use these scanners under HS-IRB 
2012-0652.  
Patient screening for MRI contraindications: each subject will be required to 
fill out an MRI screening form that will determine whether the subject has any 
contraindications for MRI. If it is determined that a subject has a specific 
contraindication, such as metal or electronic implants, he/she will be excluded. 
(Note that this does not apply to subjects in “EEG-only” sessions that do not 
involve MRI or fMRI.) 
Patient comfort. Study subjects will be monitored both visually and by 
intercom, so that if the need should arise, they will be moved promptly from the 
magnet. Fans, intercom, cushions, blankets, hearing protection and proper 
lighting are standard comforts for all patients inside the magnet.  
 
4.C. 
EEG 
 
Electroencephalography is a technique commonly used to measure non-
invasively electric brain activity both in research and in the clinic. In this study 
we intend to employ an EEG amplifier specifically designed for TMS 
compatibility. The HS-IRB has previously determined, for the PI’s protocol 2003-
238, and more recently, 2011-0608, that this device can be categorized as “non-
significant risk (NSR)”. This device, produced by Nexstim Ltd. (Helsinki, 
Finland), is the first commercially available TMS-compatible EEG amplifier and 
conforms to applicable safety standards for medical devices IEC60601-1, 
IEC60601-1-4, IEC60601-2-26 (certificates by the regulatory body were 
provided for the approval of HS-IRB protocol 2003-238, and more recently, 
2011-0608). The device is based on a standard electroencephalographer but 
features a proprietary circuitry that allows the rejection of the artifact caused by 
the TMS pulse, thus making possible continuous EEG acquisition during TMS. 
We will also use another EEG system that is compatible with MRI (Brain 
Products GmBH, BrainAmp MR Plus MRI compatible high density EEG system, 
Germany). See http://www.brainproducts.com/productdetails.php?id=6). Finally, 

09/25/23 
 
 
 
15 
for some of the “EEG-only” studies (see section 8.C. below) included in the 
protocol, we will use an EEG system that will be housed in the PI’s laboratory at 
the Brogden Psychology building. Although this system is not intended to be 
used with TMS for this research protocol, the system is TMS-compatible (Brain 
Products (brainproducts.com) actiCHamp Plus 64-channel high density EEG 
System, USA).  
Electroencephalographers are considered non-significant risk devices by 
FDA [21 CFR 812.2(b). An NSR device is defined as a device that does NOT 
present a potential for serious risk to the health, safety, or welfare of a subject 
and is NOT: (1.) an implant; (2.) used in supporting or sustaining human life; (3.) 
of substantial importance in diagnosing, curing, mitigating or treating disease, or 
otherwise prevents impairment of human health; (4.) otherwise a potential for 
serious risk to the health, safety, or welfare of a subjects. The devices have 
previously been found by the HS-IRB to meet criteria from 1 to 4 of the FDA 
information sheets, and the procedure to obtain the EEG is regularly carried out 
by researchers and clinicians throughout the world and there is no history of 
safety problems.  
We foresee no risk from EEG recording. However, some individuals with very 
sensitive skin may experience, on rare occasion, a slight irritation at the site of 
sensor application due to the use of mildly saline conductive gel. Regarding the 
combination of EEG with fMRI, there are no foreseeable additional risks. 
 
4.D. 
Positioning System 
 
The EEG system from Nexstim Ltd. (Helsinki, Finland) also includes a 
frameless positioning device, namely, an optical tracking system that measures 
the 3D position of markers, and thereby determines the real-time position and 
orientation of the tool with markers. The frameless positioning unit helps to 
relate the location of a tool outside the subject's head with respect to the 
subject's structural magnetic resonance images. The product is designed to 
support and guide the positioning of non-invasive magnetic stimulation coil (not 
included) over predefined anatomical structures in scientific and clinical 
procedures. The optical tracking unit applies harmless infrared light to measure 
the location of the tools. The unit is manufactured by Northern Digital Inc, 
Canada, according to the applicable medical safety standards IEC60601-1 and 
UL2601-1. 
Given that the positioning device is entirely passive, and not in touch 
electrically with the subject/patient, the device is harmless. 
 
4.E. 
tCS 
 
tCS is delivered via an electrodes encased in sponge (to prevent direct 
contact with the skin), with the sponge moistened with a conductive medium, 
typically saline or electrode gel. The tDCS parameters employed under this 
protocol will always be within the range used in published work with respect to 
variables that are relevant to safety: current density, current strength (up to 1.75 

09/25/23 
 
 
 
16 
mA), duration (up to 20 minutes) of treatment, and total charge. We will not 
exceed a current of 1.75 mA; using this current and electrodes with a contact 
size of 5x7 cm, we will have a maximum current density at the skin of .05 
mA/cm2, a value well within safety guidelines proposed by Nitsche al. (2003). 
These currents are also well below those induced by transcranial magnetic 
stimulation, which is in the range 14 mA/cm2, and is approved by several current 
HS protocols, including the PI’s 2016-0500. McCreery et al. (1990) have shown 
that current densities below 25 mA/cm2 do not induce brain tissue damage even 
by applying high-frequency stimulation over several hours. For comparison, the 
maximum current we propose to apply is 500 times lower than this. Additionally, 
given the brief duration of the stimulation (up to 20 minutes per session), the 
delivered amount of charge of .06 C/cm2 which is 3600 times less than the 
minimum amount of charge associated with tissue damage (216 C/cm2, Yuen et 
al., 1981).  
Stimulation will be conducted by the principal investigator or a trained 
research assistant. Research assistants conducting the study will always 
undergo a formal training session in the use of the device by the principal 
investigator. The training session will include hands-on practice soaking the 
electrode pads in saline solution. The principal investigator will create 
documentation for each individual research assistant that will administer tDCS 
which specifies that they have completed this device training. 
Experiments involving the administration of tDCS will have the same 
essential design; we will seek evidence of tDCS on behavioral tasks that have 
minimal risk. To this end, subjects will typically be tested during or after tDCS; 
effects of tDCS (either disruption or enhancement) will be sought by comparing 
performance between stimulation conditions and at different times (i.e. during 
vs. post-stimulation). The identical procedure will be used within a single study 
to allow for comparison between conditions, however the procedure may 
change between studies. For example, in a case of an task that lasts for longer 
than 15-20 minutes (the typical length of tDCS stimulation), the most powerful 
way to measure effects of stimulation is to assess performance during the initial 
part of the experiment that includes stimulation and compare it to performance 
in the latter part of the experiment (post-stimulation). By computing the 
interaction (i.e., slope difference) for performance during stimulation and post-
stimulation as a function of stimulation condition (sham, cathodal, anodal), we 
can effectively measure the effect of different stimulation conditions. 
The experiments will also include a sham stimulation condition. In this 
condition, a 1-1.75 mA current will be delivered for approximately 10 seconds at 
the beginning of the sham condition before being extinguished over the course 
of 5 seconds. This brief current may cause a slight tingling or itching sensation 
at the initiation of treatment. With this brief current at the initiation of the sham 
treatment, many investigators have found that subjects could not distinguish 
between real and sham treatment (Gandiga et al, 2006). 
 
5. 
Study Design:  
 

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17 
All studies will be performed at HERI, which houses both the Lane Family 
Neuroimaging Laboratory (a 3T MRI scanner) and the electrophysiology 
laboratories of Dr. Tononi and Dr Postle which house the EEG and TMS 
equipment. Note that only people listed as Key Personnel for this study are 
involved in any of the research procedures, and only those listed as Key 
Personnel have access to the study data and are involved in the analysis of 
study data. They will enroll young adults (between the ages of 18-35) free from 
any neurological or psychiatric diagnosis.  
 
6. 
Study Duration:  
 
 
Below, the study duration is denoted for each sub-study:  
 
A. Sub-study L.3 (TMS/EEG_1D): One 1 hr MRI visit for localization. 
Two-three 4-hr TMS/EEG sessions. 
B. Sub-study M.1 (TMS/EEG_motion): One 1 hr MRI visit for localization. 
Two 4 hr TMS/EEG sessions.  
C. Sub-study M.2 (TMS/EEG_motion_color): 1 hr MRI visit for 
localization. Two 4 hr TMS/EEG sessions.  
D. Sub-study T.1 (UMI1): three sessions (a training session in fMRI 
scanner, TMS/fMRI session targeting IPS, TMS/fMRI session 
targeting LASSO-identified cortex, each up to 2 hr in length. 
E. Sub-study T.2 (UMI2): three sessions (a training session in fMRI 
scanner, TMS/fMRI session targeting IPS, TMS/fMRI session 
targeting LASSO-identified cortex, each up to 2 hr in length. 
F. Sub-study U (EEG Training): One visit 3.75  hr for EEG session, 5 
hours per week for 2 weeks of training on the material, and a 
subsequent 3.75 hr visit for a final EEG session.  
G. Sub-study O (Biacom EEG):  One 2 hr visit for EEG session. 
H. Sub-study V (FREQMOD): One 1.5-hr visit for EEG session  
I. Sub-study W: One 1.5-hr visit for tCS session 
J. Sub-study X: One 2.5-hr visit for tACS session 
K. Sub-study Y (2Back EEG): One 2-hr visit for EEG session 
L. Sub-study Z: (SPACEORDEREEG): One 3-4-hr visit for EEG session 
M. Sub-study AA: (SPACETIME EEG): One 3-4-hr visit for EEG session 
N. Sub-study AB: (LTM EEG): One 1-hr for behavioral session; Two 3-4 
hr visits for EEG sessions 
O. Sub-study AC: (DACOM): One 3-4-hr visit for EEG session 
P. Sub-study AD: (MFE): One 3-4 hr visit for EEG session 
Q. Sub-study AE: (HAMS): One 4 hour visit for EEG session 
R. Sub-study AF: (PIII): One 4-hour visit for EEG session 
 
 
 
 
7. 
Subject Population:  

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18 
 
Below, the subject population is denoted for each sub-study:  
 
 
A. Sub-study L.3 (TMS/EEG_1D): 24 subjects 
 
B. Sub-study M.1 (TMS/EEG_motion): 24 subjects 
 
C. Sub-study M.2 (TMS/EEG_motion_color): 24 subjects 
 
D. Sub-study T.1 (UMI1): 24 subjects  
 
E. Sub-study T.2 (UMI2): 24 subjects 
 
F. Sub-study U (EEG Training): 24 subjects 
 
G. Sub-study O (Biacom EEG): 24 subjects 
 
H. Sub-study V (FREQMOD): 24 subjects 
 
I. Sub-study W: 24 subjects 
 
J. Sub-study X: 24 subjects 
 
K. Sub-study Y: 42 subjects 
 
L. Sub-study Z: 24 subjects 
 
M. Sub-study AA: 30 subjects 
 
N. Sub-study AB: 24 subjects 
 
 
O. Sub-study AC: 24 subjects 
 
 
P. Sub-study AD: 30 subjects 
 
    Q. Sub-study AE: 25 subjects 
 
 
R. Sub-study AF: 20 subjects 
 
 
*Note: 17 subjects from M.1 and 2 subjects from M.2 had been 
completed under 2011-0608. Therefore, total subject population for this protocol, 
2016-0500, is 479.  
 
 

09/25/23 
 
 
 
19 
The subject population will consist of young adults who have no 
psychiatric diagnosis. As we propose new sub-studies during the life of this new 
protocol, we will adjust the total number of subjects. Subjects who have a status 
relationship with the principal investigator may also be involved. These fall into 
two categories. One is post-doctoral and graduate students directly involved in 
the project and who will be authors of the publications reporting the results of 
the experiments. They may participate in situations in which they may find 
participation an important way for them to fine-tune the procedures and 
eventually interpret the results. The second category is individuals affiliated with 
the lab but not directly working on this study, who may wish to volunteer in a 
“moonlighting” capacity; that is, to earn money by being a research participant. 
Explicit policy of the laboratory forbids direct recruitment of status-relationship 
subjects falling under either category. We do not, however, forbid voluntary, self-
initiated participation. In all cases, regardless of the circumstances of 
recruitment, participation as a subject will be entirely voluntary. One’s choice 
with regard to participation in this study will in no way affect one’s grades, 
evaluation, or position at the University of Wisconsin.  
The subject population for each of the proposed repetitive TMS 
experiments will consist of 24 young adults. Our experience with several studies 
performed under protocol H-2003-033 and 2011-0608 has been that an initial 
recruitment of 24 subjects is necessary to yield a final N of 16. The reasons for 
this are varied; in some subjects, abnormalities from the MRI scan precludes 
further involvement, others meet exclusion criteria, as determined by the 
psychiatric interview; still others simply fail to participate in all stages of the 
experiment (common attrition). Our goal is to have 16 subjects in the final N of 
most sub-studies. In some cases, we may require more based on relevant 
literature or findings from pilot studies. This will permit us to directly compare the 
results from these sub-studies with those of Hamidi et al. (2009), the study from 
the PI’s group that first characterized the individual differences in the effects of 
repetitive TMS on the EEG and on behavior. Because of its precedence, this 
experiment serves as the normative dataset against which the results of all the 
sub-studies proposed here will be compared.  
We have not yet carried out a study with tCS, but our working 
assumption, based on careful reading of the literature and consultation with 
colleagues, is that the reasoning that we have applied to the design of TMS 
studies will also apply to tCS studies. 
 
 
8. 
Procedures 
8.A. Simultaneous TMS-fMRI study (involves sub-studies T.1 and T.2): 
 
8.A.1. MRI Scan 
In order to determine the stimulation sites, a T1-weighted 3D volumetric 
scan will be obtained from each subject prior to repetitive TMS administration. 
This will provide a structural map of each subject’s brain. The map will enable a 

09/25/23 
 
 
 
20 
3-dimensional reproduction of each subject’s brain, which will be utilized for 
exact positioning of the TMS coil. 
The procedures of the anatomical MRI will be the same as those 
approved for this PI in HS-IRB #2007-0075 and #2012-0652. There will be no 
TMS stimulation during this stage of the study. 
 
8.A.2. TMS Motor Threshold (MT) 
All TMS will be performed using a Magstim Super Rapid2 Magnetic 
stimulator (Magstim Company Limited, Spring Gardens, Whitland, Wales, UK, 
http://www.jalimedical.com/rapid2.pdf) with two special nonferromagnetic TMS 
coils with a figure-8 design. For simultaneous fMRI/TMS stimulations, two 10 m 
shielded cables will connect the coil to the stimulator console positioned outside 
the scanner door. 
The delivery of TMS pulses will be controlled by the fMRI console using a 
TTL pulse to trigger the Magstim stimulator via its external trigger interface. The 
pulses will be delivered 100 msec after an image acquisition, once every 20 sec; 
see below.  
Single TMS pulses will be used to determine MT in each subject. MT is 
defined as the minimum magnetic flux needed to elicit a threshold EMG 
response (50 µV in peak to peak amplitude) in a target muscle in 5 out of 10 
trials using single pulse TMS administered to the contralateral primary motor 
cortex. MT is the standard in the field for determining the intensity of TMS 
(George et al., 1999). An authoritative set of safety guidelines for determining 
motor threshold is universally observed by researchers and clinicians who 
employ TMS – “Risk and safety of repetitive transcranial magnetic stimulation: 
report and suggested guidelines from the International Workshop on the Safety 
of Repetitive Transcranial Magnetic Stimulation, June 5-6, 1996” (Wassermann 
1998). These guidelines specify the combined maximum levels of three 
stimulation parameters – intensity, rate, and duration – that have been 
demonstrated to be safe with human subjects. The guidelines published in 
(Wassermann 1998) (and subsequently reaffirmed in Rossi et al., 2009) indicate 
that an intensity of maximum stimulator output at a rate of 1 Hz for a duration of 
5 sec falls within the safe range. Therefore, our method of beginning the MT 
determination procedure at 75% of stimulator output, possibly increasing 
intensity to as much as 100% of stimulator output, and delivering single TMS 
pulses at a rate no higher than .1 Hz (1 every 10 sec), falls within established 
norms for safe usage of TMS.  
A “safety certified” member of the research team will be in the room with 
subjects during all TMS procedures. To qualify as safety certified, a member of 
the research team must undergo the following safety training: 1. Adult CPR and 
First Aid (American Red Cross OR American Heart Association Certified 
Courses and Instructor; 8 hour training). The CPR course teaches the skills of 
CPR, relief of an obstructed airway for victims of all ages, and rescue breathing 
including bag valve mask and barrier device. First aid will include emergency 
management of common acute medical situations. Both courses are intended 
for people who provide health care to patients in a wide variety of settings. 

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21 
Written and skill testing is required. 2. Seizure identification and emergency 
management. (Epilepsy Foundation of South Central Wisconsin; 1.5 hour 
training.) The course will include education in seizure types and their typical 
presentations (aided by video clips); emergency management of seizures, and 
seizure first aid. This training will be completed with staff instructors from the 
Epilepsy Foundation. 
These training certifications will be documented, and remain current while 
the personnel are involved with any of our studies. A full list of safety certified 
personnel will be a part of the “Key Personnel” list included in each Continuing 
Review report. Additionally, all additions to this list will be submitted to the HS-
IRB via a Change of Protocol application.  
In the event of a seizure or any other medical emergency during a research 
session, the policy will be the same as the UW Psychiatric Clinic, which 
operates in the same facility as our laboratory spaces. The policy states that the 
first response is to call 911 and administer appropriate first aid. This procedure 
is based upon recommendations from the Epilepsy Foundation of South Central 
Wisconsin and the American Red Cross. Following this, if no physician is in the 
room, a pre-designated physician who is in the building will be contacted. 
Additionally, each of the research areas where human subjects are cared 
for will have postings of emergency procedures for seizures, as well as well-
marked postings of emergency response numbers (e.g. 911). Additionally, a 
phone list for key personnel by cell phone will be available in these spaces. 
 
8.A.3. Scanning 
 
MRI studies will be performed on the 3 tesla MRI scanner (GE SIGNA, 
Milwaukee, WI) located in the Lane Family Neuroimaging Laboratory. 
 
8.A.3.a. Positioning of the TMS coil 
TMS coils will be mounted in the MR head coil (either a single coil or one coil on 
the right side and one on the left) with vitamin E capsules placed at the ends 
and center of each TMS coil to help locate its position in the structural images. 
Subjects will wear earplugs, and vision will be unconstrained. While lying on the 
gantry outside the scanner bore, the subjects will insert their heads into the MR 
head coil. Several vitamin E tablets will be affixed to the surface of each TMS 
coil to visualize placement within the MRI scanner. Vitamin E tablets are visible 
in MR images. Prior to scanning, the positions on the head surface for the initial 
coil placement will be estimated for the stimulated anatomic regions using the 
positioning apparatus and procedure described in section 4.D (“4. Potential 
Adverse Events, D. Positioning System”) and the capsules will be fixed to the 
head surface. The subject will be positioned in the scanner and a high resolution 
3D T1-weighted SPGR sequence will be run (the TMS device will be off) with a 
1x1x2 mm voxel size (260x260x120 mm FOV with a 256x128x60 acquisition 
matrix). The acquisition time for the T1-weighted sequence is 3 minutes (using a 
21 msec TR). The locations of the vitamin E tablets will be compared relative to 

09/25/23 
 
 
 
22 
the desired anatomic regions desired for TMS stimulation. The amount of shift in 
the spatial position of the coil on the head surface will be estimated to center the 
coil over the desired anatomy. The subject will be moved out of the scanner 
bore, the TMS coil repositioned, the subject placed back in the scanner and the 
3D T1-weighted scan will be repeated to ensure that the new coil position is 
correct. If a second position adjustment is deemed necessary, the subject will be 
moved out again, coil will be repositioned, followed by a third 3D T1-weighted 
image set.  
 
8.A.3.b. Behavioral tasks for current, ongoing sub-studies  
 
 
4. Sub-study T.1. TMS-fMRI of the category-level 
representation of the UMI.  
Sub-study T.1. will largely replicate the behavioral task of sub-
study L.1. (two-item dual-retrocue task), using simultaneous 
fMRI rather than EEG. fMRI will provide higher spatial 
sensitivity and allow us to additionally use iterative LASSO 
(regularized regression for identifying voxels representing 
stimulus specific information) to identify parietal areas for TMS 
targeting. The study will be comprised of three sessions (a 
training session, TMS/fMRI session targeting IPS, TMS/fMRI 
session targeting LASSO-identified cortex).  
 
5.  Sub-study T.2. 
 
Sub-study T.2 will largely replicate the behavioral tasks of sub-
study L.2. Training data will be generated from a scanning 
session during which 420 unique directions of motion and 420 
unique colors are presented for 4 sec, each flashing at 1 Hz, 
with 8 stimulus-presentation epochs occurring serially to 
constitute a mini-block, and a 4-sec period at the end of each 
mini-block during which subjects indicate the number of 
speed/luminance changes they detected. During each mini-
block, one randomly determined 4-sec epoch will be blank. (5 
scans * 12-miniblock/scan * 84 stimuli/mini-block = 420 
stimuli.) The 420 stimuli will be drawn at random, without 
replacement, from a set that is equally spaced around the 
360° range of the stimulus space. The training session will 
comprise 10 7.2-min scans, with color and motion scans 
alternating during the course of the roughly 1 hr 20 min of EPI 
data acquisition. The experimental task will feature two 
conditions: two-stimulus trials and one-stimulus trials. On two 
stimulus trials, the targets will be a set of moving white dots, or 
a set of stationary colored dots. Subjects will then be cued as 
to whether direction or color will be probed. Subjects will then 
indicate whether or not a probe stimulus exactly matches the 

09/25/23 
 
 
 
23 
cued dimension of the target. On one-stimulus trials, the 
targets will be the same, but the probe will be a single 
stimulus, presented centrally, comprised of dots appearing in 
one of the three colors and moving in one of the three 
directions. Subjects indicate whether the probe stimulus 
matches with regard to just the dimension specified by the 
target. The rationale is to quantify (with Forward Encoding 
Model fits) the dynamics of the “reactivation” effect found in 
sub-study L.1., and to measure TMS-evoked effective 
connectivity within the voxels that contribute to the 
representation of the UMI (using iterative LASSO as in sub-
study T.1.), and between these voxels those that may 
maintain a top-down “pointer” to them.  
 
 
 
8.A.3.c. Dosing of TMS 
It has been demonstrated that TMS motor threshold in part depends on the 
distance from the coil to the underlying cortex, suggesting that dosing TMS 
should take into account the distance from scalp to cortex over the specific area 
to be stimulated (McConnell et al., 2001; Stokes et al., 2007). To achieve this, 
the distance from the scalp to the cortical target will be calculated with the 
frameless stereotaxic system that we use to guide the targeting of TMS 
(NexStim NBS), and any difference between this distance and the scalp-to-
cortex distance for the location used to calculate MT will be corrected with the 
formula described by Stokes et al. (2007).  
 
8.A.3.d. Experimental design 
 
4.   Sub-study T.1. 
The design: 3 (stimulus category: direction; face; word) x 2 
(cueing: stay/switch) behavioral task. The IPS and the 
LASSO-identified targets will be in opposite hemispheres, 
and the latter will always be at least 5 mm distant from the 
nearest lip of the IPS. 108 trials per session yield 36 trials 
during which the critical stimulus category is a UMI. Single 
pulses of TMS, delivered at 110% of resting motor threshold 
intensity will be delivered on each trial during either the delay. 
Therefore, based on Guller et al. (2012), two scanning 
sessions will be required to generate a sufficient number of 
trials for each stimulation site.  
 
5.   Sub-study T.2.  
The design: The experiment will use the behavioral design of 
3 (stimulus category: direction; face; word) x 2 (cueing: 
stay/switch).  Iterative LASSO; FEM; and TMS-fMRI will be 

09/25/23 
 
 
 
24 
involved. The rationale is to quantify (with FEM fits) the 
dynamics of the “reactivation” and to measure TMS-evoked 
effective connectivity within the voxels that contribute to the 
representation of the UMI (Interative LASSO), and between 
the voxels that maintain a top-down pointer to them.   
 
 
 
8.A.3.e. TMS and fMRI acquisition 
Functional imaging with TMS will be performed using an event related 
experimental design. The functional MRI pulse sequence is a standard pulse 
sequence that comes installed on the GE Discovery MR750 system, and is 
currently used by the PI of the present protocol for his on-going fMRI studies (PI: 
Postle; HS-IRB 2012-0652). EPI imaging parameters will be: TR = 2 seconds, 
TE = 30 msec, 64x64 acquisition matrix, 200x200 mm FOV, sagittal acquisition, 
36 slices (4 mm thick with 0.5 mm gap) over the entire brain will be prescribed. 
During the acquisition period, subjects will watch a featureless black screen.  
 
Neither single pulse TMS (i.e., less than or equal to 1 Hz), as employed in 
the simultaneous fMRI/TMS study) nor repetitive TMS require IDE approval 
because of the low risk associated with these techniques, as evidenced by their 
history of several years of incident free use in research by multiple centers 
around the world (e.g., Ashbridge, Walsh, & Cowey, 1997; Beckers & Hombert, 
1991; Brandt, Ploner, Meyer, Leistner, & Villringer, 1998; Chen & al., 1997; 
Duzel, Hufnagel, Helmstaedter, & Elger, 1996; Epstein, 1998; Grafman & 
Wasserman, 1999; Hufnagel, Claus, Brunhoelzl, & Sudhop, 1993; Jahanshahi et 
al., 1998; Mottagh, Gangitano, Sparing, Krause, & Pascual-Leone, 2002; Muri, 
Vermersch, Rivaud, Gaymard, & Pierrot-Deseilligny, 1996; Oyachi & Ohtsuka, 
1995; Pascual-Leone, Bartres-Faz, & Keenan, 1999; Pascual-Leone et al., 
2000; Ro, Cheifet, Ingle, Shoup, & Rafal, 1998; Walsh & Cowey, 2000; 
Wassermann, 1998).  
 
8.B. Repetitive TMS and Single Pulse TMS study: involves sub-studies 
L.3, M.1, M.2  
 
8.B.1. MRI Scan 
In order to determine the stimulation sites, a T1-weighted 3D volumetric scan 
will be obtained from each subject prior to repetitive TMS administration. This 
will provide a structural map of each subject’s brain. The map will enable a 3-
dimensional reproduction of each subject’s brain, which will be utilized for exact 
positioning of the TMS coil. 
The procedures of the anatomical MRI will be the same as those 
approved for this PI in current HS-IRB 2012-0652. There will be no TMS 
stimulation during MRI scanning.  
 
 

09/25/23 
 
 
 
25 
8.B.2. Determining individual alpha frequency (IAF) with EEG. 
Each individual’s EEG cycles at a slightly different rate, the so-called IAF. To 
measure this, a 60-electrode cap will be applied and connected to the TMS-
compatible EEG amplifiers. The subject will then sit comfortably with her/his 
eyes open and closed for six alternating blocks of 30 sec each. (This is the 
typical procedure for measuring the alpha band component of the EEG signal, 
because alpha is strongest when the subject is resting and not engaged in task 
performance.) The resultant EEG data will be band-pass filtered to isolate 
components oscillating from 8-13 Hz, then submitted to a fast fourier transform 
(FFT) to determine at what frequency, within this range, the power is greatest. 
The frequency with the greatest power in the spectrum is the IAF. 
 
8.B.3. TMS Motor Threshold (MT) 
This will be identical to the procedure described for the simultaneous TMS-
fMRI study under section 8.A.2., above.  
 
8.B.4. Scanning  
 
 
8.B.4.a. Behavioral Tasks 
 
4. Sub-study M.1. Comparing the effects of repetitive TMS 
delivered at multiple frequencies (MRI-guided) on visual 
short-term memory for the direction of motion.  
Briefly, subjects will be asked to remember for short periods of 
time the direction of a group of dots moving (serial 
presentation). At the end of the delay period, a dial appears, 
and subjects will rotate the dial such that its line matches as 
closely as possible the direction of motion they had to 
remember. During the first session, subjects will be scanned in 
the fMRI while performing the task in order to identify the 
targets for subsequent rTMS. On a second day, behavioral 
tasks will be performed while recording EEG. Delay period 
rTMS will occur on two-thirds of the trials (10Hz, p=.5; or 20Hz, 
p=.5) with the remaining trials having no TMS. Stimulation will 
be applied on the middle temporal cortex (MT+) and 
intraparietal sulcus (IPS) on separate days. 10Hz is the 
frequency at which rTMS has been delivered on all of our 
previous studies and it is also the natural frequency of the 
posterior areas (including MT+) whereas 20Hz is the natural 
frequency of parietal areas (including IPS) as reported by 
Rosanova M, Casali A, Bellina V, Resta F, Mariotti M, 
Massimini M (2009) Natural frequencies of human 
corticothalamic circuits. J Neurosci.17;29(24):7679-85 
 
5. Sub-study M.2. Comparing the effects of repetitive TMS 
delivered at multiple frequencies (MRI-guided) on visual 

09/25/23 
 
 
 
26 
short term memory across stimulus dimensions.  
This study will replicate sub-study M.1. with the exception that 
subjects will be remembering both directions of motion and 
colors. Depending on which item is tested, the probe will either 
be identical to sub-study M.1. (motion) otherwise the dial will be 
a color wheel that subjects adjust to match the cued target. 
 
 
 
 
8.B.4.b. Positioning of the TMS coil 
 
TMS will be performed in a clinic setting at the Wisconsin Psychiatric Institute 
and Clinic (WisPIC). For each subject, a digital 3D reconstruction of the 
subject’s brain will be produced from the MRI data. After the subject is 
comfortably seated in a chair, s/he is fitted with a headband that contains 
fiducial markers that can be detected with an infrared camera. After these 
markers are calibrated with the 3D reconstruction of the brain scan, this 3D 
image moves on a computer screen, in real time, in precisely the same way as 
the subject’s head (and, therefore, as her/his brain). The TMS coil is also 
detected by the infrared camera. When it is positioned over the subject’s skull, a 
representation of the TMS coil and its zone of maximal stimulation can be 
viewed in relation to the brain. In this way, precise positioning of the TMS coil 
with respect to the brain can be achieved, and we will target specifically the 
regions described above. The TMS coil will be held by an articulating stabilizing 
arm that will hold the TMS coil rigidly in position when its stimulating position 
has been achieved. Note that this is the apparatus and procedure described in 
Section 4. D. (“4. Potential Adverse Events, D. Positioning System”). 
 
 
8.B.4.c. Dosing of TMS 
 
In several previous studies performed under protocols H-2003-033 and 
2011-0608, the PI’s group has delivered trains of repetitive TMS at a rate of 10 
Hz, with stimulator intensity 10 % above-motor threshold (Feredoes, Tononi et 
al. 2006; Postle, Ferrarelli et al. 2006; Feredoes, Tononi et al. 2007; Hamidi, 
Tononi et al. 2008; Hamidi, Tononi et al. 2009; Feredoes and Postle 2010). 
These stimulation parameters, together with a 5 sec inter-trial interval, fell within 
the safety guidelines for repetitive TMS (Wasserman, 1998; Rossi et al., 2009). 
Although we will stick to these parameters for some of the proposed studies, 
recent results obtained with these parameters (Hamidi et al., 2009) have created 
scientific reasons to vary these stimulation parameters systematically, as 
described above in Sections 8.B.4.a.1 and 8.B.4.a.2. Specifically, some of the 
proposed studies entail repetitive TMS at the frequency of sustained delay-
period oscillatory power, which ranges across subjects from 10 Hz through 20 
Hz, or at the natural frequency of the superior parietal lobule, which ranges 
across subjects from 18 Hz – 24 Hz. Following the published repetitive TMS 

09/25/23 
 
 
 
27 
safety guidelines of Wasserman (1998), which were recently confirmed in a 10-
year follow-up by the Safety of TMS Consensus Group (Rossi et al., 2009), 
repetitive TMS trains of between 10 Hz and 20 Hz, delivered at 110% of motor 
threshold, are considered safe if delivered for a duration not exceeding 1.2 sec 
(i.e., a total ≤ 24 pulses), and repetitive TMS trains of up to 25 Hz, delivered at 
110% of motor threshold, are considered safe if delivered for a duration not 
exceeding 0.7 sec (i.e., a total ≤ 17 pulses). Note that these parameters also 
include an inter-train interval ≥ 5 sec. Thus, proposed studies featuring repetitive 
TMS delivered at a frequency greater than 10 Hz but ≤ 20 Hz will feature 1.2 
sec-long stimulation trains, and studies featuring repetitive TMS delivered at a 
frequency of between 20 and 25 Hz will feature 0.7 sec-long stimulation trains. 
Another procedure that we would like to implement in our research skill is TBS 
which is another form of repetitive TMS that has been recently shown to be 
suitable for fMRI studies. 
 
1. Sub-study L.3 
Single-pulse TMS will be delivered at 90-110 V/m during the 
delay period between 2 and 3 seconds after the cue on each 
TMS present trial. Over the course of a 2 hour session, 
participants will receive a total of 540 pulses. 
 
2. Sub-study M.1 
Repetitive TMS will be delivered in 500 msec-long trains of 10 
Hz (5 pulses/train) and 20Hz (10 pulses/train) at 90% of 
phosphene threshold, at the beginning of the delay period. 
There will be a minimum of 9-second interval between all 
trains. 
3. Sub-study M.2 
Repetitive TMS will be delivered in 500 msec-long trains of 10 
Hz (5 pulses/train) and 20Hz (10 pulses/train) at 90% of 
phosphene threshold, at the beginning of the delay period. 
There will be a minimum of 9-second interval between all 
trains. 
 
 
 
8.B.4.d. Experimental Design 
 
 
 
1. Sub-study M.1. 
Repetitive TMS trains at 10 Hz and 20Hz will be applied for 500 
msec and delivered at 90% of phosphene threshold intensity 
during the delay period to MT+ and to IPS in separate 
sessions. There will be a 9 second interval between all trains. 

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28 
Subjects will perform eighteen blocks (consisting of 34 trials) 
per stimulation site. (Total of 612 trials per stimulation site with 
408 featuring repetitive TMS, 1/2 of these at 10Hz and 1/2 of  
these at 20Hz). The number of pulses that could be delivered 
on one stimulation site is maximum 3,060. 
 
2. Sub-study M.2. 
The design will replicate M.1. with the exception that subjects 
will be asked to remember both directions of motion and colors. 
 
  
 
 
 
TMS will be performed with a Magstim Super Rapid2 Magnetic stimulator 
(Magstim Company Limited, Spring Gardens, Whitland, Wales, UK) equipped 
with a circular and a figure-8 coil. Triggering of the pulses will be initiated by the 
computer program presenting the stimuli to the subject. This program can be 
interrupted by the experimenter at any time. Neither single pulse TMS nor 
repetitive TMS (as proposed for the require IDE approval because of the low risk 
associated with these techniques, as evidenced by their history of several years 
of incident free use in research by multiple centers around the world (e.g., 
Ashbridge et al., 1997; Beckers & Hombert, 1991; Brandt et al., 1998; Chen & 
al., 1997; Duzel et al., 1996; Epstein, 1998; Grafman & Wasserman, 1999; 
Hufnagel et al., 1993; Jahanshahi et al., 1998; Mottaghy et al., 2002; Muri et al., 
1996; Oyachi & Ohtsuka, 1995; Pascual-Leone et al., 1999; Pascual-Leone et 
al., 2000; Ro et al., 1998; Walsh & Cowey, 2000; Wassermann, 1998). 
 
8.C. 
EEG-only: includes sub-studies O, U, V, Y, Z, AA, AB, AC, AD, 
AE, & AF 
 
A separate set of EEG only experiments will build upon the questions and 
findings from previous sub-studies approved under this protocol and others from 
the PI (2012-0652), using new behavioral tasks that better assess questions 
answered using electroencephalography without fMRI or TMS. The procedure 
for these sub studies will be similar to those of Repetitive TMS studies (8.B.) 
except that there will be no initial fMRI session, and once subjects are fitted with 
an EEG cap, they will perform the behavioral tasks without the use of TMS 
procedures. 
 
8.C.1.A. Behavioral tasks 
 
1. Sub-study O: Comparing biased-competition versus 
passive-decay models with EEG 
This sub-study will replicate the procedure of approved sub-
study J.2. the PIs fMRI IRB (2012-0652) using the same 

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29 
behavioral task. The experimental task will begin with the 
presentation of a search target, drawn from the set of three 
stimulus types. After a delay, a “search array” comprising the 
target plus a second stimulus is presented. Both stimuli in the 
search array flicker, and each changes state a randomly 
determined 0-3 times during each trial. Subjects count the 
number of changes in the target image, ignoring changes in the 
nontarget image, and, at the offset of the array, report the 
number of target changes. MVPA will be performed on EEG 
data in an attempt to classify neural activity associated with the 
three stimulus categories and evaluate biased competition as a 
mechanism for changes in the decode-ability of these patterns. 
 
2. Sub-study U: Pre and post-training session EEG 
recordings 
This sub-study performs pre and post-training sessions where 
subjects perform a number of tasks designed to measure 
various aspects of working memory and attention. The sub-
study compares performance on these tasks after two different 
sets of training regimens to the performance before training.  
Electroencephalography (EEG) is used to record for the 
entirety of these sessions using the EGI Geodesic GES System 
400 Sensor nets and the accompanying NetStation 4 software 
for data collection. Each of the two sessions, pre and post-
training, last approximately 3.75 hours, with 2.25 hours of that 
spent engaging in the tasks and breaks given approximately 
every 9 minutes. Each session consists of seven different tasks 
testing differing aspects of working memory and attention. The 
tasks descriptions are below.  
 
#1. Digit Span: On each trial, a variable number of digits are 
presented one after another in the center of the screen. The 
subject’s job is to remember all the digits in the order they were 
presented. Between 1 and 12 digits are presented, and the 
subject is prompted to write down the digits he/she sees in 
order on the sheet, with an emphasis on accuracy.  
 
#2. N-Back: On each trial, the subject hears a letter and sees a 
bluesquare somewhere on the screen. On the one-back trials, 
the subject presses the “A” key only if the spoken letter is the 
same as the one on the previous trial. Additionally, the subject 
presses the “L” key only if the square is in the same position as 
on the previous trial.  The subject only has a few seconds to 
respond, and the emphasis is on accuracy. After a variable 
number of trials, the subject is asked to report whether the 

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30 
letter and/or square are the same as those presented two trials 
back (2-back).  This applies for 3-back trials, 4-back trials etc.   
 
#3. ANT: At the beginning of each trial, the subject sees a 
cross in the center of the screen.  The subject focuses on the 
cross. After a period of time, either a single blue arrow head or 
a group of blue arrow heads appear either above or below the 
cross. In the single arrow condition, the subject hits the left 
arrow key as quickly as possible if the arrow is pointing to the 
left, and the subject hits the right arrow key as quickly as 
possible if the arrow is pointing to the right.  In the group arrow 
condition, the subject hits the left arrow key as quickly as 
possible if the center arrow is pointing to the left. The subject 
hits the right arrow key as quickly as possible if the center 
arrow key is pointing to the right. In addition to the arrows, 
there are either one or two blue asterisks that appear near the 
cross right before the onset of the arrows.  In the single asterisk 
condition, the arrow target eventually appears in the same 
position as the asterisk.  In the double asterisk condition, the 
arrow target appears either above or below the cross. The cues 
help the subject to respond more quickly.  
 
#4. PIMP: At the beginning of each trial, there is a white cross 
in the center of the screen. Four circles appear in the corners 
of the screen. Each circle will contain a number of moving dots.  
The focus is only on the red/blue circles.  After a brief duration, 
the four circles disappear, and a single white circle with moving 
dots will appear in the center of the screen.  If the dots in the 
white circle are moving in the same direction as the dots in one 
of the target circles (red/blue), the subject should hit the “1” 
key. If the white dots are moving in a different direction than the 
ones from the target, the subject should hit the “2” key. There 
are six blocks, each lasting about 8 minutes.  
 
#5. OSPAN: At the beginning of each trial, there is a math 
problem on the screen. The task is to indicate whether or not 
the answer to the math problem is correct. If the answer is 
correct, the subject should hit the left arrow key.  If the answer 
is incorrect, the subject should hit the right arrow key. Shortly 
after, the math problem is replaced with a letter. The subject 
should remember this letter. The subject receives anywhere 
between 1 and 7 of these math problems and letter 
combinations in a row. After a variable number of math 
problems, the subject must write down all of the letters that 
he/she recalls seeing in the previous trials in the order they 
were presented.  

09/25/23 
 
 
 
31 
 
#6. Filtering: On each trial, the subject sees a display of 
colored lines. The display appears, disappears, and reappears. 
The task is to determine whether the red lines changed position 
from the first to the second display, focusing only on the red 
lines.  A change in the red line position is indicated by clicking 
the right arrow key. No change in the red line position is 
indicated by the left arrow key.  
 
#7. RAPM Pre (post version for post-test): A series of patterns  
on the screen appear, but a piece of the pattern is missing. The 
subject’s task is to select the piece that he/she thinks best fits 
the pattern by pressing the corresponding number on the 
keyboard. The subject has 20 minutes to complete as many 
patterns as possible.  
 
3. Sub-study V: (FREQMOD) Speed of alpha oscillations and 
temporal resolution of perception measured with EEG 
This sub-study addresses the question of whether there is a 
correlation between the speed of individuals’ alpha oscillations 
(measured with EEG) and the temporal resolution of their 
perception. EEG data is recorded from a 60-channel cap 
connected to an Eximia 60-channel amplifier (Nextim, Helsinki, 
Finland) while subjects complete a two-flash fusion task.  The task 
aims to determine the minimum time between two successive light 
flashes needed to perceive two, as opposed to one, distinct 
flashes.  Subjects are seated 70 cm away from the monitor with a 
100 Hz screen-refresh rate.  Each trial begins with a central 
fixation cross (.98 degrees of visual angle) that reduces luminance 
to prepare subjects for the stimuli.  The duration of the warning 
period is drawn from a uniform distribution between 1000 and 
1500 ms. The fixation cross is present throughout the trial and the 
screen background is black. Grey disk stimuli are presented left or 
right of the fixation  with equal probability and are always in the 
same location within a trial.  Half of the trials are two-flash trials in 
which the first disk stimulus was present for 40 ms, followed by a 
blank screen of 10, 20, 30, 40 or 50 ms duration, followed by a 40 
ms disk. The other half involves one-flash trials for which a single 
disk is presented. Subjects indicate whether they saw one or two 
flashes with a key press on a computer keyboard. The experiment 
takes 1.5 hours in total.  
 
4. Sub-study Y: (2Back EEG) Tracking unattended memory 
representation in a 2-back task with EEG 
This sub-study addresses the question of whether neural activity 
(measured with EEG) can be decoded to reveal the orientation of 

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32 
objects that were briefly seen moments ago. EEG data is recorded 
from a 60-channel cap connected to an Eximia 60-channel 
amplifier (Nextim, Helsinki, Finland) while subjects complete a two-
back orientation recognition task. Each block consists of serial 
presentation of orientation grating stimuli (set of 6 possible 
orientations), with subjects indicating at each presented stimulus, 
starting at number 3, whether it matches that shown two stimuli 
ago. The goal will be to decode, using multivariate pattern voxel 
analysis (MVPA) and inverted encoding models (IEM), the neural 
activity associated with each of the 6 orientations, and to identify 
differences in activation when the memory report is accurate 
versus inaccurate. The experiment will take 2 hours in total.  
 
5. Sub-study Z: (SPACEORDEREEG)  
The aim of the study is to investigate the oscillatory and 
representational dynamics of contextual information in visual 
working memory. EEG data is recorded from a 60-channel cap 
connected to an Eximia 60-channel amplifier (Nextim, Helsinki, 
Finland) while subjects complete a working memory orientation 
recognition task. Each block consists of serial presentation of 
orientation grating stimuli with subjects indicating their memory for 
those stimuli. The experiment will take 3-4 hours in total.  
 
6. Sub-study AA: (SPACETIME EEG)  
The aim of the study is to investigate how spatial and temporal 
expectation of forthcoming visual stimuli modulate both behaviour 
and brain oscillations. EEG data is recorded from a 60-channel 
cap connected to an Eximia 60-channel amplifier (Nextim, Helsinki, 
Finland) while subjects complete a working memory orientation 
recognition task. Each block consists of serial presentation of 
orientation grating stimuli with subjects indicating their memory for 
those stimuli. The experiment will take 3-4 hours in total.  
 
7. Sub-study AB: (LTM EEG)  
The aim of the study is to shed light on the working memory-long 
term memory transfer mechanisms.  EEG data is recorded from a 
60-channel cap connected to an Eximia 60-channel amplifier 
(Nextim, Helsinki, Finland) while subjects complete a working 
memory orientation recognition task. Each block consists of 
presentation of dot-motion stimuli with subjects indicating their 
memory for those stimuli. The EEG portion of the experiment will 
take 6-8 hours in total, split over two sessions, with an additional 
1-hour behavioral session.  
 
8. Sub-study AC: (DACOM) 

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33 
The purpose of the study is to 1) investigate the trial-to-trial 
adaptive control of working memory in handling distraction from 
the discrimination stimuli, and 2) examine the neural correlates of 
the control processes in working memory, specifically testing the 
temporal and spatial characteristics of the control signal. EEG data 
are recorded from a Brain Products (brainproducts.com) 
actiCHamp Plus 64-channel high density EEG System while 
subjects complete a working memory dual-task paradigm. Each 
block consists of presentation of oriented Gabor patches, with an 
endogenous spatial cue indicating which of the two to memorize, 
and then they remember that orientation throughout the task, and 
recall the remembered orientation at the end of the trial. During the 
delay of the working memory task, another Gabor patch with 
varying levels of contrast will appear and participants will perform a 
psychophysical discrimination task on its orientation and report 
whether it is clockwise or counterclockwise compared to a vertical 
orientation. The experiment will take 3-4 hours in total. 
 
9. Sub-study AD: (MFE) 
The purpose of the study is to 1) find a neural marker of binding 
multiple features into VWM, and 2) investigate whether position 
information is an especially important feature for VWM binding. 
EEG data are recorded from a Brain Products (brainproducts.com) 
actiCHamp Plus 64-channel high density EEG System while 
subjects complete a typical visual working memory (VWM) task. 
Before memory array display, at the beginning of each trial, an 
arrow will be presented for 200 msec as a cue to notice either the 
left or right side of the memory array to be memorized. Four 
colored bars will be presented as the memory array then. The 
session will be separated into three block conditions to require 
participants to remember either Color and Orientation, Color and 
Position, or only Color in each block, respectively. At the end of 
each trial, one of the required features will be tested. All three 
blocks will be conducted with a counterbalanced order across 
participants. The experiment will take 3-4 hours in total. 
 
10. Sub-study AE: (HAMS) 
The purpose of this study is to find the neural mechanism whereby 
the irrelevant information is removed from working memory. EEG 
data are recorded from a Brain Products (brainproducts.com) 
actiCHamp Plus 64-channel high density EEG System while 
subjects complete a typical visual working memory (VWM) task. 
The participant will be required to make memory-based judgments 
of images in two tasks. The first task will include the presentation 
of three to-be-remembered oriented line patches with a memory 
judgment about one of the memory items after a brief delay period. 

09/25/23 
 
 
 
34 
Patches may be presented sequentially or simultaneously, at the 
same location on the screen or at different locations across two 
conditions, and cued to be retained or dropped after a short delay 
in order to report the remembered orientation by adjusting a 180-
degree dial. The second task will include the presentation of one 
patch and subjects will be asked to report the orientation of it after 
a delay. The experiment will take 4 hours total. 
 
11. Sub-study AF: (PIII) 
The purpose of the study is to investigate the ways in which 
prioritization of information in working memory protects its 
representation from interference to support more accurate 
behavior based on those memories. This study will test this directly 
both at the behavioral and neural levels. EEG data are recorded 
from a Brain Products (brainproducts.com) actiCHamp Plus 64-
channel high density EEG System while subjects complete a 
typical visual working memory (VWM) task. The participant will be 
required to make memory-based judgments of images in two 
tasks. The first task will be a double-serial retrocue (DSR) task 
much like those typically used in the protocol's studies. The DSR 
task will involve the sequential presentation of two oriented 
patches. After a brief delay, a retrocue in the form of a digit ('1' or 
'2') will indicate which memory of the two oriented patches will be 
tested. After a longer delay of 4s, a test stimulus ('recall') will 
appear on the screen, which includes a line whose orientation can 
be adjusted by a trackball mouse to match the remembered 
orientation. To remind participants which item they are to recall, 
the retrocue digit will also re-appear on the recall display. After the 
participant makes their adjustment response, feedback will be 
provided by changing the color of the central fixation marker to 
green, yellow, or red, corresponding to small, mid, or large errors, 
respectively. Then, a second retrocue will appear that may be the 
same digit (50% of trials) or the other digit (50% of trials), followed 
by a shorter delay of 1s, and a second recall interval and feedback 
response. The second task will be comprised of 'neutral cue' trials 
that will serve as a control condition to understand the effects on 
performance of the meaningful retrocues. This task will be similar 
to the first portion of the DSR task with the sequential presentation 
of two oriented patches followed by a delay period. During the 
retrocue period, a '0' digit will appear to equate the task dynamics 
with the DSR task, but to be uninformative about which item will be 
tested. After the longer delay of 4s, the recall display will appear 
with a '1' or '2' digit indicating which item will be tested and the 
participant will make their adjustment as in the DSR task and 
receive feedback. At this point, the trial will end. The experiment 
will take 4 hours total. 

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35 
 
 
 
 
8.D. 
tCS: includes sub-studies W and X 
 
The sub-studies employing tCS are designed to address questions raised by the 
results of previous EEG studies in the lab, for example, Samaha et al., in press) 
and sub-study V, published as (Samaha and Postle, 2015). 
 
8.D.1.A. Behavioral tasks 
 
1. Sub-study W: tACS study of the speed of alpha 
oscillations and temporal resolution of perception 
measured with EEG 
This sub-study will replicate the procedure of approved sub-
study V, using the same behavioral task. Subjects are seated 
70 cm away from the monitor with a 100 Hz screen-refresh 
rate.  Each trial begins with a central fixation cross (.98 degrees 
of visual angle) that reduces luminance to prepare subjects for 
the stimuli.  The duration of the warning period is drawn from a 
uniform distribution between 1000 and 1500 ms. The fixation 
cross is present throughout the trial and the screen background 
is black. Grey disk stimuli are presented left or right of the 
fixation with equal probability and are always in the same 
location within a trial.  Half of the trials are two-flash trials in 
which the first disk stimulus was present for 40 ms, followed by 
a blank screen of 10, 20, 30, 40 or 50 ms duration, followed by 
a 40 ms disk. The other half involves one-flash trials for which a 
single disk is presented. Subjects indicate whether they saw 
one or two flashes with a key press on a computer keyboard. 
The experiment takes 1.5 hours in total. 
 
2. Sub-study X: tCS of 2-choice orientation discrimination 
with confidence ratings. 
On each trial a black and white grating stimulus will appear at 
the center of a computer screen for a short period (33 ms). The 
stimulus will either be tilted to the left or to the right of vertical 
by 45 degrees. The subject’s task is to decide whether the 
grating was tilted to the left or right. Following this response, 
they will rate their confidence in their decision on a 1-4 scale 
using the computer keys. The experimental manipulation is 
whether tCS or sham tCS is applied over occipital-parietal 
cortex. Subjects will complete the task under both conditions, 
the order of which will be counter balanced. EEG will also be 
recorded from 6 occipital-parietal electrode sites. Prior to this 
main task a short (3 min) staircasing procedure will be run in 

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36 
order to titrate the contrast of the grating stimulus to achieve 
task performance of ~75% accuracy. Total task time will be 1 
1/2 hrs, which, with an estimated 30 minutes of setup, will 
result in ~2 Hrs of total experiment time.  
 
 
 
9. 
Inclusion and Exclusion Criteria: 
 
9.A. Inclusion Criteria: 
 
1. 
Age of ≥ 18; 
2.     Right-handed;  
3. 
Be in good health- determined by the investigator on basis of 
medical history, physical and neurological exam; for “EEG-only” 
sessions no physical or neurological exams will be performed;  
4. 
Female subjects must attest to the fact that they are not pregnant 
on the day of the TMS procedures (by signing the relevant section 
of the consent form. This does not apply to “EEG-only” sessions; 
6. 
Able to understand and speak English; 
7. 
Able to provide written consent prior to admission. 
 
 
9.B. Exclusion Criteria. 
(Note: these are screened for by key personnel performing telephone 
screening and on-site screening (on day of the experimental session). 
 
1. 
History of epilepsy, stroke, brain surgery, cranial metal implants, 
structural brain lesion, devices that may be affected by TMS 
(pacemaker, medication pump, cochlear implant, implanted brain 
stimulator) (physician evaluation and medical history); 
2. 
Women who are breast-feeding (self-report)*; 
3. 
History of head trauma with loss of consciousness for greater than 
5 minutes; 
4.  
Any history of seizures; 
5. 
Any family history of seizures*; 
6.      Diabetes requiring insulin treatment*; 
7.      A serious heart disorder or subjects who have had a heart attack 
within the last 3 months;  
8.      Subjects who meet DSM-IV criteria for alcohol /drug abuse 
problems within the last six months;  
9.  
Any current Axis I or II diagnoses or past Axis I diagnoses;  
10.    Required use of medication that affects CNS function;  
11.    A subject with metallic implants, such as prostheses, shrapnel or 
aneurysm clip-S, or persons with electronic implants, such as 
cardiac pacemakers. The magnetic field generated by the MR 

09/25/23 
 
 
 
37 
machine can cause a displacement or malfunctioning of these 
devices*;  
12.    The female subject who is pregnant or planning to become 
pregnant;  
13.    The subject has had a diagnosis of cancer in the past 3 years 
and/or has active neoplastic disease;  
14.    The investigator anticipates that the subject will be unable to 
comply with the protocol. 
15.    Prohibited Concomitant Treatment: Any investigational medication; 
antipsychotic, antidepressant; or ECT; Other psychotropic 
medications including sedative hypnotics (excluding chloral 
hydrate zaleplon); sumatriptan (and similar agents); anxiolytics and 
herbals (e.g., St. John’s Wort, Kava Kava); an introduction or 
change in intensity of psychotherapy; any non- 
psychopharmacologic drug with psychotropic effects (e.g., 
antihistamines, beta blockers).  
17. Colorblindness 
18. Poor or Uncorrected vision 
19. History of fainting/syncope 
 
* Denotes criterion that does not apply to “EEG-only” sessions. 
 
In all instances in which a subject has been excluded from participation, we will 
discard all data from that subject relating to the reason for exclusion. 
 
10. 
Study Evaluations.  
 
10.A. Pre-Study Screening: 
 
The Informed Consent will be reviewed and signed prior to any study 
procedures being completed. Individuals currently taking a psychoactive 
medication, will not be allowed to enter this study. The following procedures will 
be completed: MRI Screening Form and Health Screening Form.  Information 
obtained from those who fail to pass the screening will not be retained. 
Following these assessments, the subject will be scheduled for the experiment 
at HERI. A technician will conduct a follow-up interview to inquire about the 
subjects’ comments and concerns about the experimental procedure.  
 
 
10.B. Efficacy Evaluations:  
 
N/A 
 
10.C. Safety Evaluations:  
 

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10.C.1. Safety will be monitored by reports of adverse events, vital 
sign measurements and lab evaluations. HERI is staffed by 
medical personnel and equipped with supplies for neurological 
monitoring (EEG), respiratory assistance (Ambu bag, oxygen tank 
and mask), and management of seizure (intravenous line 
materials, injectable anticonvulsant medication). A physician on 
call will be available at all times during testing. To prevent the risk 
of metallic objects being propelled by the magnetic field induced 
by the TMS device, metallic objects will be removed from the close 
vicinity of the device (< 10cm), as recommended by the 
manufacturer. This will include removing jewelry. Watches and 
magnetic sensitive devices (credit cards) will be kept at least 50 
cm away from the coil.  
The safety procedures in this protocol were drawn from the IFCN 
committee recommendations and studies of the safety of TMS 
(Wassermann 1998) and from a study of “tolerability and safety of 
high daily doses of repetitive transcranial magnetic stimulation in 
healthy young men” (Anderson, 2006). Subjects will be screened 
for any history of seizure in themselves or family members 
(including febrile seizure), medications or conditions known to 
decrease seizure threshold (ETOH), implanted metallic objects or 
devices (e.g. pacemaker, TENS, cochlear implant, surgical clips), 
and any neurological or medical conditions. 
 
10.C.2. Data Safety and Monitoring Plan 
• Seizure induction is the type of adverse event that is 
explicitly captured under the monitoring plan; however, 
unanticipated adverse events that pose a serious physical risk to 
subjects are also included. Each safety certified member of the study team 
is responsible for alerting the PI (Postle) as soon as possible after the 
occurrence of a serious  
• Adverse event. 
• With regard to the “frequency of assessments/analysis of 
data or events captured by the monitoring plan,” this procedure is 
in place for each experimental session. 
• The time frame for reporting an adverse event is as soon as 
possible once the safety and care of the subject has been 
addressed. 
• The stop rule will be triggered by a single incidence of a 
serious adverse event.  
• Unanticipated problems or adverse events will be reported 
to the HS-IRB per the IRB’s posted reporting policy.  
• Adherence to the IRB-approved protocol is monitored 
weekly by the PI, via 1-on-1 meetings that he holds with each 
safety certified member of the study team who is actively running a 
sub-study. 
 

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39 
10.D. Imaging: Adventitious Findings 
 
A radiologist reviews all scans. Scans from all subjects are 
reviewed, although, if a study involves a series of scans within a 6-
month period, only the 1st scan from a subject requires review. Dr. 
Howard Rowley has typically served as the radiologist overseeing 
the reading of scans for MRI studies. Clinically significant results 
will be reported to subjects no later than 37 calendar days from the 
day the imaging was completed (30 days for the reading of the 
image and 7 days are allowed from the date the image was read to 
contact the research participant). Subjects are given the option to 
have their physician informed of clinically significant findings as 
well. 
 
 
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Appendix A: Seizure Identification and Emergency Management 
 
Seizure Identification 
There are many different types of seizures. People may experience just one 
type or more than one. The kind of seizure a person has depends on which part 
and how much of the brain is affected by the electrical disturbance that 
produces seizures. Experts divide seizures into generalized seizures (absence, 
atonic, tonic-clonic, myoclonic), partial (simple and complex) seizures, 
nonepileptic seizures and status epilepticus. 
  
Generalized – Generalized seizures affect both cerebral hemispheres from 
the beginning of the seizure. They produce loss of consciousness, either briefly 
or for a longer period of time, and are sub-categorized into several major types: 
generalized tonic clonic; myoclonic; absence; and atonic. 
  
Partial – In partial seizures the electrical disturbance is limited to a specific 
area of one cerebral hemisphere. Partial seizures are subdivided into simple 
partial seizures (in which consciousness is retained); and complex partial 
seizures (in which consciousness is impaired or lost). Partial seizures may 
spread to cause a generalized seizure, in which case the classification category 
is partial seizures secondarily generalized. 
  
Partial seizures are the most common type of seizure experienced by 
people with epilepsy. Virtually any movement, sensory, or emotional symptom 
can occur as part of a partial seizure, including complex visual or auditory 
hallucinations. 
• 
Simple - People who have simple partial seizures do not lose 
consciousness during the seizure. However, some people, although fully 
aware of what's going on, find they can't speak or move until the seizure 
is over. They remain awake and aware throughout. Sometimes they can 
talk quite normally to other people during the seizure. And they can 
usually remember exactly what happened to them while it was going on. 
However, simple partial seizures can affect movement, emotion, 
sensations, and feelings in unusual and sometimes even frightening 
ways. 
• 
Complex - Complex partial seizures affect a larger area of the brain than 
simple partial seizures and they affect consciousness. During a complex 
partial seizure, a person cannot interact normally with other people, is not 
in control of his or her movements, speech or actions; cannot control 
what he or she is doing; and does not remember afterwards what 
happened during the seizure.  
• 
Non-epileptic – Non-epileptic seizures are episodes that briefly change a 
person's behavior and often look like epileptic seizures. The person 
having non-epileptic seizures may have internal sensations that resemble 
those felt during an epileptic seizure. The difference in these two kinds of 
episodes is often hard to recognize by just watching the event, even by 

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trained medical personnel. But there is an important difference. Epileptic 
seizures are caused by abnormal electrical changes in the brain and, in 
particular, in its outer layer, called the cortex. Non-epileptic seizures are 
not caused by electrical disruptions in the brain. 
  
Status Epilepticus 
Most seizures end after a few moments or a few minutes. If seizures are 
prolonged, or occur in a series, there is an increased risk of status epilepticus. 
The term literally means a continuous state of seizure and is considered a 
medical emergency. Status Epilepticus is defined as 30 minutes of uninterrupted 
seizure activity. An estimated 42,000 deaths and thousands more instances of 
brain damage per year follow episodes of status. Status epilepticus is most 
common in the very young and the very old, with the lowest incidence at ages 
15-40. 
 
Seizure Management 
 
Convulsive Seizure  
 
For individuals that experience generalized seizures, the following first aid 
should be provided in order to assure safety for all individuals involved and 
nearby.  
• 
Keep calm and reassure onlookers. 
• 
Don't hold the person down or try to stop his movements. 
• 
Time the seizure with your watch. 
• 
Clear the area around the person of anything hard or sharp. 
• 
Loosen ties or anything around the neck that may make breathing 
difficult. 
• 
Put something flat and soft, like a folded jacket, under the head. 
• 
Turn him or her gently onto one side. This will help keep the airway clear. 
Do not try to force the mouth open with any hard implement or with 
fingers. It is not true that a person having a seizure can swallow his 
tongue. Efforts to hold the tongue down can injure teeth or jaw. 
• 
Don't attempt artificial respiration except in the unlikely event that a 
person does not start breathing again after the seizure has stopped. 
• 
Stay with the person until the seizure ends naturally. 
• 
Be friendly and reassuring as consciousness returns. 
• 
Contact on-call physician. 
• 
If, at the discretion of the physician, the subject does not require 
admission to a hospital, accompany him/her to his/her home to insure 
that he/she arrives safely. 
 
Non Convulsive 
 
For individuals that experience non-convulsive, the following first aid should be 
provided in order to assure safety for all individuals involved and nearby.  

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• 
Watch the person carefully and explain to others what is happening. 
Often people who don't recognize this kind of behavior as a seizure think 
that the dazed person is drunk or on drugs. 
• 
Speak quietly and calmly in a friendly way. 
• 
Guide the person gently away from any danger, such as a steep flight of 
steps, a busy highway, or a hot stove. Don't grab hold, however, unless 
some immediate danger threatens. People having this kind of seizure are 
on "automatic pilot" so far as their movements are concerned. Instinct 
may make them struggle or lash out at the person who is trying to hold 
them. 
• 
Stay with the person until full consciousness returns. 
• 
Contact on-call physician. 
• 
If, at the discretion of the physician, the subject does not require 
admission to a hospital, accompany him/her to his/her home to insure 
that he/she arrives safely. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix B: Completed Studies Category A  
 
1. Sub-study A: The role of parietal regions as sources of attentional 
control for spatial attention and spatial working memory. 
The purpose of this study is to test the hypothesis that single pulses of TMS 
delivered to the superior parietal lobule (SPL) and intraparietal sulcus (IPS), 
areas implicated in the control of attention, will alter posterior task-related 
activity in a similar way for spatial delayed recognition as they do for spatial 
attention. More specifically, we predict that when subjects are attending to a 
location of space to, for example, the left of central fixation, the response 
evoked by a single pulse of TMS will be greater in magnitude in visual regions in 
the right hemisphere than in the left. The same pattern is predicted when 
subjects are remembering the locations of stimuli that had been presented to the 
left of fixation at the beginning of a delayed-recognition (i.e., “working memory”) 
task. Study A will combine a delayed-recognition task with a variant that requires 
spatial attention rather than spatial working memory. In the delayed-recognition 
task subjects will be presented with four dark-gray shapes appearing serially in 
four different locations on the (lighter gray) screen. The center of the screen is 
marked with a cross on which the subjects must keep their eyes throughout the 
trial. The stimuli are followed by a 8 second delay period, during which, on half 
of the trials, TMS is delivered. Finally, a white circle appears on the screen, and 
subjects indicate with a button press whether or not this probe appears in the 
same location as had one of the four shapes. In the spatial attention task, the 
fixation cross will rotate so as to point, throughout the delay period, to the 
location on the screen to which the subject should attend in order to detect a 
briefly presented, faint target that will appear with an unpredictable latency. The 
single pulse of TMS will be delivered with the same timing during both the 
working memory task and the attention task. During the inter-trial interval (ITI), 
the subject will perform a visuomotor tracking task that requires moving a cursor 
so that it stays on top of a moving target stimulus. The subject moves the cursor 
by pressing directional keys on a keypad. Performance is measured as the error 
between the position of the target and position of the cursor, as well as of the 
velocity of the cursor (e.g., if it stops moving). 
Experimental Design: The design, 3 (task: attention; delayed recognition; no 
task) x 2 (visual field) x 2 (TMS: present, absent) factorial (modified to exclude 
empty and nonsensical cells), yields blocks/scans of 18 trials each. Single 
pulses of TMS, delivered at 110% of resting motor threshold intensity will be 
delivered to the right SPL, right IPS, and right postcentral gyrus (PoCG, a 
control area selected because it is not involved in the cognitive constructs under 
investigation). Stimulation will be blocked by region, with the order 
counterbalanced across subjects, with 3 consecutive blocks per region. (Total of 
162 trials, 81 featuring TMS; therefore, total of 81 pulses delivered per 
experiment. Because trials are randomized with respect to whether or not a 
TMS pulse is delivered, the minimum time between pulses will be 18 sec (when 
pulses are delivered on two consecutive trials).) 
 

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2. Sub-study B.  
Is the source of object-based attentional control the same for nonmemory 
attention tasks as for working memory tasks?  
The attention task will present a flickering (750 msec on, 250 msec off) shape of 
approximately 1 degree of visual angle at central fixation, and the subject’s task 
is to indicate with a button press each time a feature of the shape changes. 
Shapes will be drawn from a set of polygons that have been normatively 
determined to be difficult to verbalize, and have been used in several of the PI’s 
studies of object working memory. There are 4 variants of each shape, each of 
which differs by just one salient feature, and changes among the 4 will occur 
unpredictably an average of 3 times (range = 1 – 5) per trial. The delayed-
recognition task will draw from the same pool of stimuli as the attention task, 
with invalid probes drawn from one of the 3 variants of the target shape from 
that trial. The regions to be targeted will be the frontal eye fields (FEF), a region 
previously targeted in two studies conducted under protocol H-2003-033, and 
the region from sub-study A that provide the most robust results, plus the leg 
area of somatosensory cortex in the postcentral gyrus (PoCG), an area used as 
a stimulation control area in many of the studies completed under protocol H-
2003-033. During the inter-trial interval (ITI), the subject will perform a 
visuomotor tracking task that requires moving a cursor so that it stays on top of 
a moving target stimulus. The subject moves the cursor by pressing directional 
keys on a keypad. Performance is measured as the error between the position 
of the target and position of the cursor, as well as of the velocity of the cursor 
(e.g., if it stops moving). 
Experimental Design: The design, 3 (task: attention; delayed recognition; no 
task) x 2 (visual field) x 2 (TMS: present, absent) factorial (modified to exclude 
empty and nonsensical cells), yields blocks/scans of 18 trials each. Single 
pulses of TMS, delivered at 110% of resting motor threshold intensity will be 
delivered to the right FEF, right SPL or IPS, and right PoCG. Stimulation will be 
blocked by region, with the order counterbalanced across subjects, with 3 
consecutive blocks per region. (Total of 162 trials, 81 featuring TMS; therefore, 
total of 81 pulses delivered per experiment. Because trials are randomized with 
respect to whether or not a TMS pulse is delivered, the minimum time between 
pulses will be 18 sec (when pulses are delivered on two consecutive trials).) 
 
 
3. Sub-study C.  
Further investigation of the mechanisms of object-based attentional control and 
its relation to object working memory. 
The logic will be to cross two stimulus types – faces and houses – with two task 
types – attention and working memory. Tokens of the two stimulus types will 
always be presented superimposed at central fixation, a procedure that has 
been used to demonstrate that object-based attention can selectively bias 
activity in regions associated with processing either stimulus type, depending on 
task instructions. The responses evoked by TMS pulses during task 
performance will ascertain whether the targeted regions are a source of object-

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56 
based attentional selection by indicating whether TMS pulses have differential 
effects on face-selective vs. house-selective cortex as a function of task 
instructions. The regions to be targeted will be the same as those from Study B. 
During the inter-trial interval (ITI), the subject will perform a visuomotor tracking 
task that requires moving a cursor so that it stays on top of a moving target 
stimulus. The subject moves the cursor by pressing directional keys on a 
keypad. Performance is measured as the error between the position of the 
target and position of the cursor, as well as of the velocity of the cursor (e.g., if it 
stops moving). 
Experimental Design: The design, 3 (task: attention; delayed recognition; no 
task) x 2 (visual field) x 2 (TMS: present, absent) factorial (modified to exclude 
empty and nonsensical cells), yields blocks/scans of 18 trials each. Single 
pulses of TMS, delivered at 110% of resting motor threshold intensity will be 
delivered to the three from sub-study B. Stimulation will be blocked by region, 
with the order counterbalanced across subjects, with 3 consecutive blocks per 
region. (Total of 162 trials, 81 featuring TMS; therefore, total of 81 pulses 
delivered per experiment. Because trials are randomized with respect to 
whether or not a TMS pulse is delivered, the minimum time between pulses will 
be 18 sec (when pulses are delivered on two consecutive trials).)  
 
4. Sub-study D. Comparing the effects on spatial working memory of 
repetitive TMS delivered at multiple frequencies (MRI-guided) 
This study modifies the procedure of the working memory task from sub-study A 
by shortening the delay period to 3 sec, simultaneously recording the EEG, 
including three EEG sessions, and varying the frequency at with repetitive TMS 
is delivered, so as to compare the effects of repetitive TMS delivered at 10 Hz, 
IAF+1Hz, and the frequency of sustained delay-period oscillatory power in the 
10 - 20 Hz range. In this sub-study subjects will be presented with four dark-gray 
shapes appearing serially in four different locations on the (lighter gray) screen. 
The center of the screen is marked with a cross on which the subjects must 
keep their eyes throughout the trial. The stimuli are followed by a 3 second 
delay period, during which, on half of the trials, repetitive TMS is delivered. 
Finally, a white circle appears on the screen, and subjects indicate with a button 
press whether or not this probe appears in the same location as had one of the 
four shapes. The three frequencies are of interest for varying reasons: 10 Hz is 
the frequency at which repetitive TMS has been delivered on all of our previous 
studies of spatial working memory, and comparison of results with the other two 
frequencies vs. the “gold standard” of 10 Hz will thus be very informative. IAF+1 
Hz is the frequency at which Klimesch et al. (2003) have reported facilitatory 
effects of repetitive TMS, and offers a parameter by which repetitive TMS 
frequency can be tailored to the physiology of individual subjects. Sustained 
delay-period oscillatory power has been observed in many published EEG 
studies, including Hamidi, M., Slagter, H.A., Tononi, G., and Postle, B.R. (2009). 
Repetitive transcranial magnetic stimulation affects behavior by biasing 
endogenous cortical oscillations. Frontiers in Integrative Neuroscience, 3:14. 
doi:10.3389/neuro.07.014.2009. PMC2707056. Thus, it offers a second task-

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related parameter by which repetitive TMS frequency can be tailored to the 
physiology of individual subjects. As indicated above, the sub-study will include 
three EEG sessions. The first will be the brief “eyes open/eyes closed” session 
to determine IAF, the second will entail repetitive TMS at 10 Hz and at IAF +1, 
the third, repetitive TMS at 10 Hz and at the frequency of sustained delay-period 
oscillatory power. The reason for using 10 Hz during two sessions is that 
although previous studies have revealed individual differences in the effects of 
repetitive TMS on both behavior and task-related EEG (Hamidi et al., 2009; 
Sub-study L), we do not yet know whether these patterns of individual 
differences are stable over time. That is, if 10 Hz repetitive TMS produces an 
increase in alpha-band power and a decrease in accuracy for subject #1, and a 
decrease in alpha-band power and an increase in accuracy for subject #2 
(mirroring what we saw in Hamidi et al (2009)), will these same two subjects 
show similar effects if they perform the same experiment on a different day? In 
other words, what is the test-retest reliability of our procedure? The third session 
will occur on a different day than the second. 
Experimental Design: Repetitive TMS will be delivered in 1.2 sec-long trains of 
10 Hz, IAF +1, and sustained delay-period oscillatory power, at 110% of the 
resting motor threshold intensity, at the beginning of the delay period. There will 
be a 5 second interval between all trials. 
 
 
5. Sub-study E. The effects on spatial working memory of repetitive TMS 
delivered at a region’s natural frequency (MRI-guided) 
The natural frequency of a corticothalamic circuit is the frequency with which a 
brain region oscillates when stimulated by a pulse of TMS (analogous to the 
“ringing” that results from striking a bell, Rosanova et al., 2009). For the superior 
parietal lobule (SPL) this corresponds to 20 Hz. The SPL has been the target of 
most of our previous repetitive TMS studies of spatial working memory, and 10 
Hz repetitive TMS of the SPL has produced interesting behavioral and EEG 
results (i.e., Hamidi et al., 2008; 2009). The purpose of this sub-study is to 
compare the results of repetitive TMS of SPL at 10 Hz with those of repetitive 
TMS of SPL at this region’s natural frequency, which can vary between 18 – 24 
Hz depending on the individual. At issue is whether the natural frequency 
reflects a functional property of a region, or whether it is merely a byproduct of a 
region’s corticothalamic architecture that does not influence that region’s 
function. The procedure for Sub-study E will replicate that of Sub-study D, with 
the exceptions that there will be two sessions (instead of 3; Session 1 will entail 
IAF estimation and natural frequency estimation, and Session 2 will entail task 
performance), and repetitive TMS will be delivered concurrent with behavioral 
task performance at IAF +1 and at the subject’s natural frequency.  
Experimental Design: Depending on the natural frequency of SPL for a given 
subject, all repetitive TMS trains will be delivered for either 1.2 sec (if natural 
frequency ≤ 20 Hz) or 0.7 sec (if natural frequency > 20 Hz and ≤ 25 Hz), at 
frequencies of IAF+1Hz and of the subject’s natural frequency, at 110% of the 

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resting motor threshold intensity, at the beginning of the 3 sec-long delay period. 
There will be a 5 second interval between all trials. 
 
 
6. Sub-study F. The effects of cognitive training on sustained delay-period 
brain activity. 
Analyses of data from two previous studies performed by the PI’s group under 
protocol H-2003-033 indicate that there are considerable individual differences 
in the patterns of sustained delay-period oscillations as measured by EEG. The 
nature of these differences is intriguing, because they are present despite the 
fact that all subjects are performing the same task, and are generally doing so at 
the same level of proficiency. They raise such question as: Do these differences 
underlie individual differences in behavior? Do they reflect differences in the 
cognitive processes engaged by different individuals, or, instead, perhaps 
differences in trait-like physiological profiles that do not relate directly to task 
performance? Answers to these questions will contribute importantly to 
understanding which elements of sustained delay-period oscillations are critical 
for working memory-task performance. The strategy for addressing these 
questions, to be implemented in this sub-study, will be twofold: a) administer 
several psychometric tests that measure important cognitive and affective traits, 
and evaluate which covary with sustained delay-period oscillations; and b) 
assess the effects on sustained delay-period oscillations of a 5 week-long 
course of cognitive training on a working memory task. Previous work indicates 
that such training can produce improvement on working memory-task 
performance that generalizes to other cognitive domains (e.g., Olesen et al., 
2004). Our question will be which, if any, aspects of sustained delay-period 
oscillations are also sensitive to cognitive training. Thus, there are three 
categories of behavioral task in this sub-study: the EEG and TMS-EEG tasks 
during which sustained delay-period oscillations are measured, the 
psychometric tasks, and the training task.  
a) EEG and TMS-EEG. The EEG recording session 
will proceed in four blocks, each comprising 150 
trials. For Block 1, subjects will perform a spatial 
delayed-recognition task (similar to those 
conducted under H-2003-033), in which either 2 or 
4 squares are presented serially in to-be-
remembered locations in a pre-cued quadrant of 
the screen, followed by a delay period of 3750 
msec, followed by the onset of a circle that either 
does or does not (with equal probability) appear in 
one of the cued locations. For the three 
subsequent blocks the task will be repeated, but in 
Block 2, two pulses of TMS will be delivered 
during the delay period (this TMS procedure will 
be identical to the one previously approved by the 
HS-IRB under protocol fH-2003-033); in Block 3, 

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irrelevant (i.e., not to be remembered) squares will 
be presented in an uncued quadrant of the screen 
at the same time as the to-be-remembered 
squares; and in Block 4, irrelevant (i.e., not to be 
remembered) squares will be presented during the 
delay period of the trial. 
b) Psychometric tasks. Each of these has been 
selected to estimate a psychological construct 
believed to related to working memory-task 
performance. 
i) Change Detection. This task is frequently used to 
estimate “visual short-term memory [VSTM] 
capacity” (e.g., Vogel & Machizawa, 2005). After a 
200 ms fixation plus a cue to covertly attend to 
either the left or right visual hemifield, a target 
memory array of randomly colored squares is 
presented for 100 ms with set sizes of 3, 4, 6, or 8 
items. Subjects remember the target colors in the 
cued hemifield and ignore the other field. 
Following probe array, subjects indicate match 
versus non-match with button press.  
ii) Precision Task (Bays & Husain, 2008) - This task 
will assess the precision with which an item’s 
orientation is remembered. An array of colored 
bars is presented in one hemifield for 1000 ms 
during which the subject covertly attends to the 
array while maintaining fixation. Following a 500 
ms delay, a probe appears in the same or different 
orientation as one of the stimulus bars. Probe 
duration is 250 ms following which the subject 
must indicate whether or not there was an 
orientation change. 
iii) Operation Span task: This is a standard test to 
assess “working memory capacity” (Turner & 
Engle, 1989) Serial presentation of stimuli (letters) 
is interleaved with arithmetic problems that 
subjects must solve as they are presented. The 
task ends unpredictably, after varying numbers of 
letters are presented, with a cue requiring recall of 
the order of the letters 
iv) Sustained attention task. (Demeter et al., 2008). 
Subjects fixate on the center of the screen and 
report if they perceived the stimulus after probe 
tone. On 50% of trials the stimulus, a small gray 
box, will flash at fixation. A distractor condition 

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adds a flashing background to the baseline task 
making the target less distinguishable. 
v) Guided search: This task probes ability to control 
attention via internal representations (e.g., Gold et 
al., 2007). Subjects see a template shape (a 
bracket oriented up, down, left, or right). Next, an 
array of similar items (distractors) and one 
template match are presented. Subjects search 
the array for a match and indicate if a match 
exists. The task is “guided” via internal 
representation of the target. RT and accuracy will 
be measured. Difficulty is varied by the set size 
(4,8,12, or 16 distractors).  
vi) Stroop Task (Stroop, 1935): This is a classic test 
assessing selective attention, cognitive flexibility, 
and processing speed. Subjects name the color in 
which words are presented, with difficulty 
increased when, e.g., the word “red” is presented 
in blue ink. 
vii) Attention Control Scale: This 20-question 
inventory quantifies self-reported ability to control 
attention through assessment of attention focusing 
and flexibility (for example multitasking; Derryberry 
and Reed, 2002; Derryberry and Rothbard). 
Typical items include “When concentrating I ignore 
feelings of hunger and thirst”. Subjects report how 
often they agree with the statement on a 4-point 
scale. The inventory is self-paced. 
viii)Raven’s Advanced Progressive Matrices (Raven 
et al., 2003): This is a nonverbal test to assess the 
construct of “general fluid intelligence” (gF). Each 
matrix problem is a set of eight pictures, arranged 
in a 3 x 3 grid with the last picture missing. The 
order and design of the given pictures follows a 
rule. Subjects deduce the rule and choose the last 
image from a set of 8 options. The test consists of 
a set of 36 problems in increasing order of 
difficulty, administered via paper and pencil. 
Subjects solve as many matrix problems as 
possible within 40 minutes. 
ix) Spielberger State-Trait Anxiety Inventory (STAI-
X2, Spielberger et al., 1983) is a common 
measure of trait-like individual differences in non-
clinical anxiety (i.e., it is not designed to assess 
clinical anxiety disorder). This 20-question 
inventory determines if a person has anxiety as a 

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trait (versus a state - STAI-X1). Typical items 
include “I feel secure” and “I wish I could be as 
happy as others seem to be” where the subject 
rates how often the statement is applicable. 
x) BIS/BAS (Behavioral inhibition system/ activation 
system) - This widely employed 24-item 
questionnaire assesses behavioral inhibition and 
activation (Carver & White, 1994). The BIS is 
postulated to regulate aversive motivational 
behavior towards environmental factors such as 
punishment and inhibits movement towards a 
goal. Typical BIS questionnaire items include 
“Criticism or scolding hurts me quite a bit”. The 
BAS system is postulated to control appetitive 
behavior regulated by dopamine systems. Typical 
BAS questionnaire items include “I go out of my 
way to get things I want”. The subject indicates 
how much they agree or disagree with the 
statement.  
xi) Bartlett Impulsivity Scale (BIS-11, Patton et al., 
1995). This is a 30-item inventory to assess 
impulsive traits. Impulsiveness is broken down into 
first order factors including attention, motor, self-
control, cognitive complexity, perseverance, and 
cognitive instability. Representative items include 
“I am a careful thinker”. Items are scored on a 4 
point scale where 1=rarely to 4=always. Scale 
reliability has been confirmed, and the inventory 
has been reassessed to accommodate updated 
findings in the field. 
xii) Personality Research Form E: This 20-question 
inventory is widely used for assessing personality 
traits including impulsivity, aggression, autonomy, 
and nurturance (Jackson, 1974). 
c) Training Task. The training task will be an 
adaptive spatial n-back task (Olesen et al., 2004), 
in which subjects view a 4 x 4 grid, stimuli are 
presented serially in different cells (duration = 500 
msec, interstimulus interval = 2500 msec, 1 trial is 
3000 ms) and subjects indicate for each whether 
the current stimulus appears in the same location 
as had the stimulus n items previously. (E.g., in 
the 1-back condition, subjects compare the current 
item to the previous one, in the 2-back condition, 
they compare the current item to the item-before-
last, etc.) The task is adaptive in that the n varies 

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as a function of performance, according to the 
following algorithm: there are 20 trials per block, 
performance > 90% will increase the n-level, 
performance on 3 consecutive blocks that are < 
50% will decrease the n-level. Each day, the 
sessions start at n = 2. Subjects will perform this 
task for 40 min per day, M-F, for 5 consecutive 
weeks. Subjects can take a break every 10 blocks. 
Training will be performed in the PI’s laboratory at 
the Brogden Psychology building.  
Experimental Design: 2 pulses of TMS will be 
delivered at 110% of MT during the delay period. 
The timing of the first pulse will be jittered relative 
to the onset of the delay period, and averaging a 
latency of 750 msec (+/- 250) for the first pulse 
and 2000 msec for the second pulse relative to the 
onset of the delay period. The interval between 
pulses will be jittered, and will average 1250 msec. 
 
7.Sub-study G. The effect of repetitive TMS using theta burst stimulation 
on spatial working memory as measured by fMRI-EEG. Behavioral tasks will 
be performed during fMRI scanning and will be similar to those approved as 
sub-study G under the PI’s protocol HS-IRB #2012-0652. Briefly, subjects will be 
asked to remember for short periods of time (8 seconds) the direction of a group 
of dots moving. On any given trial, one, two, or three of the dot patterns can be 
moving. At the end of the delay period, a dial appears, and subjects will rotate 
the dial such that its line matches as closely as possible the direction of motion 
of the color-matching dot pattern. During the first day’s scanning session, 
subjects will perform 180 trials across six runs. On a second and third day, there 
will be a break after the first three runs and repetitive TMS using TBS will occur, 
before running the last three runs. A short perceptual task will also be added on 
each day to control for potential perception modification in the encoding phase 
and it will be done before the main task.  
 
The aim of this study is to explore the neural mechanisms 
underlying findings from previous fMRI studies by the PI’s 
group. In Riggall and Postle (2012), we showed that the 
contents of a single item held in visual short term memory 
(STM) can be decoded from sensory visual cortex, despite 
the fact that these areas do not exhibit elevated, sustained 
activity. In Emrich SM, Riggall AC, Larocque JJ and Postle 
BR (2013), we confirmed these results, and also discovered 
showed that the neural representations changes as a function 
of load, in manner that corresponded to load-dependent 
declines in mnemonic resolution. Thus, the aim of this sub-
study is to better understand how these visual 

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63 
representations and related brain circuits are disrupted as a 
result of TBS of a given brain area (i.e., middle temporal 
visual cortex – MT and inferior parietal sulcus - IPS). More 
specifically, we would like to investigate how item-specific and 
load-specific visual STM representations are affected by the 
perturbation of different brain areas involved in working 
memory. Lee and D’Esposito (2012) stimulated the prefrontal 
cortex (PFC) with TBS before a working memory task, and 
showed that PFC disruption decreased the tuning of 
extrastriate cortex responses, coinciding with decrements in 
working memory performance. They also found that activity in 
the homologous PFC region in the nonstimulated hemisphere 
predicted performance following disruption (i.e., participants 
with greater homologous PFC activity and greater 
connectivity between this region and extrastriate cortex were 
the most resistant to PFC disruption). What if we directly 
stimulate the sensory cortex which holds the visual 
representation of the visual STM (versus the parietal lobe)? 
Our main hypothesizes would be that after TBS of occipital 
cortex (i.e., MT area known to be involved in motion), there 
will be a decrement in behavioral responses and a decreased 
memory representation in the visual cortex, which might most 
strongly affect the high memory load trials. After TBS of 
parietal cortex (i.e., IPS known to be involved with the load), 
we might expect to also have a decrease of behavioral 
responses (probably with high load) but the representation of 
the information per se in the visual cortices should stay the 
same, confirming a role for attentional control, but not 
stimulus representation, per se, in this region. 
 
Experimental Design: TBS is an innovative non-invasive 
repetitive TMS technique that has been recently shown to 
have several advantages over the conventional repetitive 
TMS. First, the conventional repetitive TMS can induce 
performance-enhancing or performance-impairing effects for 
any given individual, which creates variability in the data. 
Second, at present, conventional repetitive TMS cannot be 
used during fMRI scanning due to a number of practical 
considerations. In particular, the heating of the TMS coil, 
which builds up over repeated high-frequency trains, would 
pose a complication. Outside of the fMRI lab, an air-cooled 
system counteracts this, but this apparatus does not fit inside 
the bore of the magnet. Thus, a repetitive TMS protocol inside 
the scanner would need to incorporate periodic lengthy 
pauses to allow the cooling down of the coil. Third, applying 
conventional repetitive TMS before fMRI scanning, in a 

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64 
manner comparable to what we are proposing to do with TBS, 
the effects would be short lasting (usually 15 minutes or less) 
and often weak and highly variable (Gangitano et al., 2002). 
TBS is therefore ideally suited for studying the effects of 
repetitive TMS with fMRI because of its rapid and safe 
administration as well as its robust and less variable 
responses across populations of subjects. We propose to use 
a continuous TBS protocol that consists of 50 Hz trains of 
three TMS pulses repeated every 200 ms continuously over a 
period of 40 seconds (600 pulses total). Continuous TBS has 
been shown to depress activity in the stimulated brain region 
for up to 60 minutes following stimulation (Huang et al., 2005, 
2009). The TBS procedure will be the same as in previously 
published studies (Huang et al., 2005, 2009; Lee and 
D’Esposito, 2012; Andoh and Zatorre, 2012; Morgan et al, 
2013) and will follow the established safety guidelines (Rossi 
et al, 2009; Oberman et al, 2011). The risk of adverse events 
during TBS is comparable to or less than the other 
conventional high frequency repetitive TMS protocols (Rossi 
et al 2009, Oberman et al, 2011). 
 
8.Sub-study H. Comparing the effect of repetitive TMS on items inside and 
outside of the focus of attention. This study replicates procedures from 
Zokaei et al. (2013) where 4 pulses of 20Hz rTMS at 60% of stimulator output 
was shown to abolish any recency effect from serial presentation and even 
improve performance on non-privileged items. In addition, these parameters are 
applied to dual retrocueing paradigms previously used by Dr. Postle’s group. 
Experiment 1 will replicate the Zokaei et al. (2013) design. Experiment 2 will use 
the same task with modified timing. Experiment 3 will test the attentional 
retrocueing paradigm. Experiment 1 will measure only the behavioral effects of 
rTMS, while both experiments 2 and 3 will be carried out while simultaneously 
collecting EEG data. All subjects will undergo a functional localizer in the MRI 
(fMRI) during the 1st session (behavioral neurological testing and MRI) to identify 
optimal motion sensitive target locations in MT+. In all studies we will be 
including an active control where the same TMS parameters are applied to 
primary somatosensory cortex. 
Experimental Design: 4 pulses of 20Hz rTMS (150ms train) will be delivered at 
110% of adjusted motor threshold (Stokes et al., 2005) to motion sensitive areas 
of MT+ (identified by functional localizer task) or primary somatosensory cortex 
(S1). The task structure is such that there is never less than 5000ms between 
trains. 
 
 
 
Experiment 1: Subjects will view 2 random dot 
kinematograms (RDKs) presented serially (300ms 

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65 
each) at fixation (one red, one green). The center 
of the screen is marked by a white cross on which 
subjects must maintain fixation throughout the trial. 
The stimuli are each followed by a mask and then a 
delay. On half of the trials, TMS is applied delay 
following either the 1st or 2nd RDK and mask. The 
second delay is followed by a response probe 
consisting of a circular aperture and a radial line 
(either red or green) indicating which stimulus to 
respond to. The subjects are instructed to adjust 
the line until it points in the same direction as the 
motion in the indicated RDK stimulus.  
 
Experiment 2: This task will be identical to 
Experiment 1 with the exception that the timing will 
be changed to allow for spectral-power EEG 
analyses. 
 
Experiment 3 (2 sessions): Subjects will view 2 
random dot kinematograms (RDKs) presented 
serially (300ms each) at fixation (one red, one 
green). The center of the screen is marked by a 
white cross on which subjects must maintain 
fixation throughout the trial. The stimuli are each 
followed by a mask and then a delay. The fixation 
cross will then either turn red or green indicating a 
retrocue as to which stimulus will be probed 
Retrocues are always 100% informative. TMS is 
then applied during the delay period following the 
first retrocue on half of the trials. A subset of trials 
will then probe the cued stimulus (this condition 
serves to force participants to utilize the 1st retrocue 
and not simply rely on the 2nd retrocue for probe 
information). The probes will be identical to those 
from experiment 1. A second retrocue then appears 
(on half the trials, the same stimulus will be cued 
again), followed by a final delay and the probe. 
 
9.Sub-study I. Testing the effects of TMS on connectivity between delay-
active frontal and parietal regions with posterior visual regions involved in 
stimulus-specific storage. Participants will perform a delayed-recall task for 
visual motion and color (motion and color on separate blocks of trials). Each trial 
will begin with the presentation of an endogenous cue arrow (1 s), indicating the 
visual hemifield to be attended to during the trial. Following the cue, three sets 
of dots will be presented sequentially (500 ms each, 250 ms ISI) on each side of 
the screen, with either 1 or all 3 sets on each side moving/colored. Following a 

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66 
delay period (2 s), participants will be required to recall the color or direction 
of motion of one of the stimuli from the attended side, indicated by a numeral 
representing the sequential position of the dot pattern to recall in the center of 
the screen. Participants will recall this direction/color by rotating (with a 
trackball) an indicate bar within a circular aperture/color wheel until it points 
towards the remembered color or direction. During the delay period (randomly 
750ms-1250ms into) single pulse TMS will be delivered to one of three sites 
identified using fMRI localizer scans collected earlier: 1: Area MT+ (identified 
with a moving vs. static dot pattern localizer task), 2: interparietal sulcus (IPS) 
(identified from areas showing a parametric increase in activity during the delay 
period between loads one and three and 3: dorsolateral prefrontal cortex 
(dlPFC) (identified similarly to IPS). 
Experimental Design: Single-pulse TMS, at 100 V/m as calculated by NBS, will 
be delivered once per trial during the delay period.  There will be a minimum of 
7.5 seconds between TMS pulses.  Subjects will complete a total of 576 trials, 
for a total of 576 pulses delivered during the experiment. 
 
10. Sub-study K. Oscillatory dynamics of near-threshold TMS-induced 
percepts. This study examines the neural dynamics associated with conscious 
perception of TMS-induced percepts called phosphenes.  While recording EEG 
and finding near-threshold stimulation intensities whereby participants report 
experiencing phosphenes on roughly 50% of trials, we aim to exam the pre-
stimulus EEG activity that is predictive of whether a participant experiences a 
phosphene on that trial or not.  We also aim to examine the neural activity 
occurring after the TMS pulse that distinguishes trials where phosphenes were 
reported from those when they were not.  Participants will first complete a 
structural MRI scan for later use in TMS targeting.  Participants will then receive 
TMS to their primary visual cortex as well as posterior parietal cortex, where 
phosphenes have been reported in the past.  For each stimulation site, and after 
each pulse is delivered, participants will respond verbally if a percept was 
present or not.  The TMS stimulation intensity will be gradually increased until a 
threshold is found for each participant where 5 out of 10 stimulations result in a 
phosphene.  Since a minority of the population do not see phosphenes, we will 
exclude participants who have not reported percepts after 100 stimulations at 
90% of the maximum stimulator output.  This threshold will be used for the 
remainder of the behavioral task.  Participants will then be seated in front of a 
computer screen and, while recording EEG, will be asked to maintain fixation on 
a crosshair in the center of the black screen.  TMS pulses will be delivered at 
pseudo-random intervals, followed by a 1 second black screen.  Using a 
computer mouse, participants will then report on a sliding scale (1-100) their 
confidence that a percept was present. 
Experimental Design: A total of 800 TMS pulses will be delivered: 400 at 
primary visual cortex and 400 at posterior parietal cortex, all using the intensity 
defined during the thresholding procedure. There will be between 3.5 to 6.5 
seconds between the application of each TMS pulse. The MRI scan and TMS-
EEG session will take place on different days. 
 

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11.Sub-study N. Examining the role of DLPFC in promoting visual-stimulus 
awareness and emotional regulation using TMS (MRI-guided). In a within-
subjects design, following the delivery of TMS to either the dorsolateral 
prefrontal cortex (DLPFC) or a control region, postcentral gyrus (PoCG), 
behavioral tasks will be performed during an EEG session and will be similar to 
those approved in protocols HS-IRB #2011-0542 and SE-IRB # 2012-0100 
(Lapate et al., 2014). Behavioral tasks will comprise two tasks: the emotional 
misattribution paradigm, and a visual awareness task. Briefly, in the emotional 
misattribution paradigm, participants will be shown valenced facial expressions, 
which will be followed by neutral stimuli (neutral faces, abstract images) shortly 
thereafter (1000-5000ms). Participants will then be asked to indicate with a 
button press their preference ratings for the novel neutral stimuli. EEG data will 
be continuously recorded. In addition, pupil diameter and skin conductance 
responses may be collected to obtain information about the magnitude of 
emotional change evoked throughout the session. Following this task, 
participants’ visual awareness of the valenced facial expressions will be 
assessed using two 2-alternative forced choice paradigms (2AFC) where 
individuals will be asked to report on stimulus properties (e.g., face orientation; 
facial expression), as well as subjective visibility (i.e., clarity of the visual 
experience) using the Perceptual Awareness Scale (PAS). These 2 tasks 
combined will comprise no more than 288 trials and will take no longer than 40 
minutes to complete, totaling a session (per TMS target; DLPFC and PoCG) of 
less than 1 hour. Participants will also be asked to complete questionnaires 
assessing their mood. We will pilot two previously approved TMS protocols 
(sub-studies A and G), offline theta-burst repetitive (tb) TMS, and online single 
pulse to determine which method is best suited for DLPFC inhibition in the 
context of this experiment. Both online and offline TMS modes of stimulation fall 
under the safe use guidelines of TMS that our lab has followed on all previous 
sub-studies (for TBS risk/benefit differences/similarities, see sub-studies A & G). 
In the session with single-pulse TMS to DLPFC vs. PoCG, the single TMS pulse 
will be delivered immediately prior to the presentation of the valenced facial 
expressions.  
The two aims of this study are (1) to directly probe whether DLPFC plays a 
causal role in preventing emotional misattribution when individuals are aware of 
emotional stimuli and (2) to examine whether the hypothesized DLPFC role in 
preventing emotional misattribution is mediated via its effect on subjective visual 
awareness of the emotional stimuli. Conscious (e.g., visual) awareness of an 
emotional stimulus has been reported to modulate behavior following emotional 
processing, with greater emotional misattribution following unaware relative to 
aware emotional-stimulus processing, which is typically seen as valence-
congruent shifts in evaluative ratings (e.g., likeability) of novel neutral stimuli (Li, 
Moallem, Paller, & Gottfried, 2007; Murphy & Zajonc, 1993; Rotteveel, de Groot, 
Geutskens, & Phaf, 2001). The neural bases of this effect have begun to be 
explored (Lapate et al, submitted) and are consistent with the role DLPFC is 
known to play in emotional regulation (Delgado, Nearing, Ledoux, & Phelps, 
2008; Erk et al., 2010; Lee, Heller, van Reekum, Nelson, & Davidson, 2012) and 

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68 
behavioral regulation (Figner et al., 2010; Hare, Camerer, & Rangel, 2009; 
Knoch, Schneider, Schunk, Hohmann, & Fehr, 2009; Steinbeis, Bernhardt, & 
Singer, 2012). Critically, DLPFC engagement during visual-stimulus processing 
is a neural correlate of subjective visual awareness (Lau & Passingham, 2006), 
i.e., being associated with the internal representation of the stimulus that 
facilitates conscious access to it. Accordingly, depression of DLPFC via tbTMS 
impairs subjective access to visual stimuli, namely, simple geometric shapes 
(Rounis, Maniscalco, Rothwell, Passingham, & Lau, 2010). Given the evidence 
for the role of DLPFC function for promoting subjective awareness of visual 
stimuli, and goal-oriented (rather than stimulus-driven) behavior, it is 
hypothesized that inhibitory TMS stimulation over DLPFC (vs. control area, 
PoCG) will produce increased emotional misattribution. Further, subjective 
awareness of the visual stimuli is postulated to be reduced via DLPFC inhibition 
and to function as a plausible mediator of the DLPFC inhibition effect on 
emotional misattribution. The current study aims to test these two hypotheses by 
inhibiting DLPFC via TMS as participants undergo the emotional misattribution 
and awareness tasks. 
 
Experimental Design: Theta-burst TMS (tbTMS) 
As in Study G, we propose to use a continuous TBS protocol that consists of 50 Hz 
trains of three TMS pulses repeated every 200 ms continuously over a period of 40 
seconds (600 pulses total). Continuous TBS has been shown to depress activity in the 
stimulated brain region for up to 60 minutes following stimulation (Huang et al., 2005, 
2009). The TBS procedure will be the same as in previously published studies (Huang et 
al., 2005, 2009; Lee and D’Esposito, 2012; Andoh and Zatorre, 2012; Morgan et al, 
2013) and will follow the established safety guidelines (Rossi et al, 2009; Oberman et al, 
2011). The risk of adverse events during TBS is comparable to or less than the other 
conventional high frequency repetitive TMS protocols (Rossi et al 2009, Oberman et al, 
2011). Single-pulse TMS As in Study A, Single-pulse TMS, at 100 V/m as calculated by 
NBS, will be delivered once per trial, immediately prior to the presentation of the 
valenced facial expressions. There will be a minimum of 6 seconds between TMS 
pulses. When combining the emotional misattribution and awareness tasks for each 
PoCG and DLPFC sites, subjects will complete a total of 576 trials, for a maximum total 
of 576 pulses delivered during the experiment.  
Questionnaires: 
Subjects will fill out several well-validated questionnaires to evaluate mood and 
assess potential TMS- induced mood chances, which will be completed during 
their visits at the Waisman and HERI Laboratory. They will take approximately 
15 minutes to complete, and will include the following measures: 
1. Positive and Negative Affect Scales-State & -Trait 
(PANAS; Watson, Clark, & Tellegen, 1988) 
2. The Implicit Positive and Negative Affect Test (IPANAT; 
Quirin et al., 2009) 
3. Spielberger State Anxiety Inventory X-1 & Spielberger Trait 
Anxiety Inventory X-2 (STAIX; Martuza & Kalistrom, 1974) 
4. The Toronto Alexithymia Scale (TAS; Parker et al., 2003) 

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5. The Mindfulness Attention Awareness Scale (by Davidson) 
6. Inhibitory Control Scale from the Adult Temperament 
Questionnaire (Evans & Rothbart, 2007) 
7. Emotion Regulation Questionnaire (Gross & John, 2003) 
 
 
12.Sub-study P: Temporal Expectations as measured with EEG 
This sub-study will build on the findings of sub-study K. Behavioral task will be 
completed while EEG is recorded from an EGI system 256 electrode cap. The 
task was about 1 hour, plus 1 hour of EEG setup. Subjects have to decide 
whether a briefly presented oriented grating is tilted to the left or the right and 
then rate their subjective visibility of that grating.  On each trial, a color cue 
appears before the grating that indicated when the grating would appear relative 
to the cue.  Some cues are predictive, in that the grating always appears after 
the same delay following the cue.  Some cues are unpredictive, because they 
do not predict when the stimulus would appear. Subjects are instructed to use 
the cue to anticipate when the stimulus would appear.  This is done while EEG 
data is recorded.   
 
13.Sub-study Q: Speed of alpha oscillations and temporal resolution of 
perception measured with EEG 
This sub-study addresses the question of whether there is a correlation between 
the speed of individuals’ alpha oscillations (measured with EEG) and the 
temporal resolution of their perception. EEG data is recorded from a 60-channel 
cap connected to an Eximia 60-channel amplifier (Nextim, Helsinki, Finland) 
while subjects complete a two-flash fusion task.  The task aims to determine the 
minimum time between two successive light flashes needed to perceive two, as 
opposed to one, distinct flashes.  Subjects are seated 70 cm away from the 
monitor with a 100 Hz screen-refresh rate.  Each trial begins with a central 
fixation cross (.98 degrees of visual angle) that reduces luminance to prepare 
subjects for the stimuli.  The duration of the warning period is drawn from a 
uniform distribution between 1000 and 1500 ms. The fixation cross is present 
throughout the trial and the screen background is black. Grey disk stimuli are 
presented left or right of the fixation  with equal probability and are always in the 
same location within a trial.  Half of the trials are two-flash trials in which the first 
disk stimulus was present for 40 ms, followed by a blank screen of 10, 20, 30, 
40 or 50 ms duration, followed by a 40 ms disk. The other half involves one-
flash trials for which a single disk is presented. Subjects indicate whether they 
saw one or two flashes with a key press on a computer keyboard. The 
experiment takes 1.5 hours in total.  
 
14. Sub-study R: Investigation of visual perception 
In this experiment (lasting approximately 2 hours total), EEG and fMRI signal will 
be simultaneously recorded while subjects perform a visual detection task. A 
stimulus will be presented, and subjects will be asked whether it was a face or a 

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house; then, they will be asked how visible the stimulus was on a pseudo-
continuous scale. 
 
 
 
15.Sub-study L.1 Comparing the effects of single pulse TMS to attended 
and unattended items in short-term memory (MRI-guided).  
In this sub-study subjects will be presented with two stimuli (a face, a word, or a 
patch of coherently dots moving in a random direction). The center of the screen 
is marked with a cross on which the subjects must keep their eyes throughout 
the trial. The stimuli are followed by a 5 second delay period and then a cue 
(arrows) indicating which item (top or bottom) is to be remembered for an 
upcoming memory probe. A single pulse of TMS is applied 2.5 seconds after the 
cue; the memory probe is presented 2 seconds after the TMS pulse. Then 
another cue is presented to indicate which item is to be remembered for a 
second memory probe presented after another 4.5-second delay. Subjects 
indicate with a button press whether or not the memory probe matches the cued 
item. The difference in the TMS evoked response on the EEG during the delay 
period when subjects are remembering attended (cued) versus unattended 
(uncued) items in short-term memory is of interest. Therefore, in each of the 
three EEG sessions, TMS is targeted to an area identified as important for 
representing each category of stimulus (face, word, motion) during a short-term 
memory delay period, providing observations of the TMS evoked response 
when the targeted category is in each of three states: attended, unattended, or 
absent on that trial.  Single pulse TMS will be delivered at 90-110 V/m 2.5 
seconds after the cue on each trial. Single pulse TMS delivered at 90-110 V/m 
will be applied during the delay period to a face selective, word selective, or 
motion selective region of interest. There will be a 3 second interval between all 
trials. Subjects will perform eight blocks (consisting of 24 trials) per stimulation 
site. (Total of 192 trials.) 
 
16.Sub-study L.2. Comparing behavioral effects of single pulse TMS on 
reactivation of representations for unattended memory items.  
Sub-study L.2 will replicate the procedures of L.1., except that on half of the 
trials the uncued item will be tested (25% of total trials for the first probe and 
25% of total trials for the second probe). For this sub-study, subjects will have 
only the anatomical fMRI and no task will be completed in the scanner. No EEG 
will be recorded during this task. Single pulse TMS will be delivered at 90-110 
V/m after the cue on each trial. Single pulse TMS delivered at 90-110 V/m will 
be applied during the delay period to the Precuneus (a portion of the superior 
parietal lobule). There will be a 2 second interval between all trials. Subjects will 
perform ten blocks (consisting of 36 trials) per stimulation site. (Total of 360 
trials.) Half of the total trials (180) will probe the uncued item. Half of these 
‘catch’ trials will occur on the first and the other on the second probe. Probe 1 
‘catch’ trials will end after the first probe. 
 

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Sub-study J. Behavioral and EEG effects of Area MT Stimulation on 
Transparent Motion Memory and Perception. This sub-study will test the 
hypothesis that cortical area MT in humans is crucial for representing multiple 
directions of simultaneously moving stimuli both during the stimulus presentation 
period and during the Working Memory (WM) delay period that follows the visual 
stimuli. Human subjects will first view visual stimuli composed of random dots 
moving simultaneously in two directions, which gives rise to the percept of two 
superimposed surfaces moving transparently in different directions. The angle of 
separation between these moving dot surfaces is systematically varied from 0-
60 degrees in order to probe the nature of the percept. This stimulus aperture 
will be presented in the left visual hemi-field at an eccentricity of 5.5 degrees 
away from the center of fixation, corresponding to the site used in the MRI 
localizer task for identifying area MT in each subject. After a 1 second delay 
period following this initial presentation (the “sample”), the subject will be cued 
as to which set of moving dots they should respond to. The subjects will then be 
presented with a circle, at the center of which is the mouse cursor (“probe”). 
They will make an outwardly radial mouse movement towards the outer edge of 
the circle in the direction they perceived the cued stimulus to have been 
traveling (“response”). When the probe is presented following a delay, 
information about motion needs to be stored in visual WM for subsequent output 
as a mouse movement. We will deliver repetitive Transcranial Magnetic 
Stimulation (rTMS) to cortical area MT of human subjects either during the 
visual stimulation period or the WM delay period, with simultaneous recoding of 
EEG. In addition to the blocks of trials performed with MT stimulation, we will 
perform a smaller number of trial blocks with area S1 stimulation as a control. 
We will measure behavioral performance in terms of the error between the 
response and sample directions and compare these measures under both TMS-
on and TMS-off conditions. Many of the results obtained here will help guide the 
study design for future experiments probing this same question in monkeys as 
part of a collaboration with Xin Huang. Repetitive TMS trains at 10 Hz delivered 
at 110% of the resting motor threshold intensity, will be applied for 1.0 sec either 
during the delay period or during the stimulus presentation to area MT/V5 plus 
to a postcentral gyrus control site (S1). There will be a 2 second interval 
between all trials, meaning subjects will not experience successive trains of 
rTMS with an interval shorter than 6 seconds. Subjects will perform 7 blocks 
(consisting of 30 trials) at the MT/V5 stimulation site and 3 blocks of 30 trials at 
the postcentral gyrus control stimulation site. This gives a total of 300 trials, 200 
featuring repetitive TMS (for each block, 1/3 of trials have rTMS during the delay 
period, 1/3 have rTMS duing the stimulus presentation period and 1/3 of trials 
have no rTMS; all are randomly distributed throughout a block). The total 
number of pulses that will be delivered in this experiment is 2000. Repetitive 
TMS will be delivered in 1.0 sec-long trains of 10 Hz at 110% of the resting 
motor threshold intensity, at either the beginning of the delay period or at the 
start of stimulus presentation. There will be a 2 second interval between all 
trials, meaning that the shortest possible time between successive trains of 

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rTMS is 6 seconds (corresponding to a “delay period stimulation” trial being 
followed by a “stimulus period stimulation” trial). 
 
 
Sub-study S: Decoding memory for visual motion.  
This sub-study attempts to decode a subject’s memory for visual motion. The 
study duration is one fMRI scan which takes approximately 2.75 hours. During 
the scan, the subject performs two tasks.  For the first task, the subject fixates 
on a central dot that changes between blue and red. While the central dot is 
blue, the subject is instructed to hold down the button, and when the central dot 
is red, the subject is instructed to release the button. During this task, there is a 
patch of dots in the subject’s peripheral vision. The dots alternate between 
moving or remaining stationary. The subject is instructed to pay attention to the 
patch of dots without averting his/her gaze away from the central colored dot.  
After three rounds of this task, the second task begins. For the second task, the 
subject fixates on a central white cross that brightens just before the trial starts. 
Shortly after, the dots appear to be moving in one direction. The goal of the task 
is for the subject to remember the direction of the moving dots by mentally 
visualizing the moving dots even after they are no longer on the screen. A few 
seconds later, a wheel with a central radial spoke appears on the screen.  To 
indicate the direction of motion of the moving dots from the subject’s memory, 
the subject aligns the spoke with the direction the dots were traveling and click 
the left trackball button. After the response, the central cross changes color to 
indicate the accuracy of the response.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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