This study will examine the effect of transcranial magnetic stimulation (TMS) on short-term
memory in healthy adults. Healthy people use their brains to answer short-term memory
questions in a different way than do patients with schizophrenia. Attention and memory
deficits in schizophrenia patients significantly hamper their recovery and rehabilitation,
yet there are no effective treatments for these impairments. TMS is a method of brain
stimulation that may be able to change the electrical activity of the nerve cells of the
brain and improve certain brain functions. This study will explore the effect of TMS on
memory and perhaps discover brain processes that may be helpful in developing new ways to
Healthy volunteers between 18 and 55 years of age, excluding pregnant women, may be eligible
for this study. Participants undergo the following tests and procedures:
- Medical history, physical examination, blood tests, electrocardiogram (EKG), and urine
pregnancy test for women of childbearing age.
- Magnetic resonance imaging (MRI) and functional MRI (fMRI). These tests are done in
participants who have not had structural and functional MRIs as participants in NIMH's
2-day schizophrenia study within 90 days of entering the current study. MRI is done to
locate the place in the brain to simulate with TMS and fMRI is done to look at brain
activity while the subject solves short-term memory tasks. Both tests are done at the
same session. Before the scan, four vitamin E capsules are taped to the subject's
scalp. After the capsules are in place, the subject lies on a stretcher that is moved
into the scanner - a narrow cylinder with a strong magnetic field. During the scan,
subjects are asked to do some simple tests, such as watching pictures on a screen or
pressing buttons in response to numbers they were shown a few seconds earlier. Scanning
may take up to 2 hours, but usually lasts between 45 and 90 minutes.
- TMS. For this procedure, subjects receive either active TMS or a sham procedure
(placebo) that imitates TMS but does not use real electrical stimulation. For TMS, an
insulated wire coil is placed on the scalp and a brief electrical current is passed
through it. This generates magnetic pulses that travel through the scalp and skull and
cause small electrical currents in the cortex, or outer part of the brain. The
stimulation may cause muscle twitching in the scalp or face and may also cause small
movement of the limbs. During the procedure, electrodes are taped to the scalp to
record the electrical activity of the brain while short-term memory is tested. Two
tests make up a set. There are a total of six test sets; each set takes about 3
minutes. Five periods of electrical stimulation are delivered before each test set.
Each period of stimulation lasts 5 seconds, followed by a 10-second rest period. The
stimulation-rest intervals continue until five periods of TMS have been applied. For
the memory test, subjects press a key on a computer keyboard as quickly and accurately
as possible in a test of their ability to remember a string of numbers, or letters.
- Questionnaires. At the beginning and end of the TMS session, participants fill out
questionnaires that assess their mood, ability to concentrate, and level of anxiety.
Psychiatrists have recognized cognitive dysfunction as the principal impediment to recovery
and psychosocial rehabilitation of patients with schizophrenia since the first edition of
Emil Kraepelin's 1893 masterwork, Dementia Praecox. While currently available
pharmacotherapy may improve psychotic symptoms, there is still no largely effective
treatment for impairments of critical executive functions - attention and working memory -
that are widely considered the functional nexus of this extremely costly illness. Thus, it
appears heuristically reasonable to consider putative modes of treatment that may
specifically target these deficits. For example, abundant evidence supports the assumption
that pre-task alpha band power, measured as mean peak frequency, is inversely associated
with reaction time (RT) - an index of encoding efficiency - in a working memory task.
Additionally, recent evidence suggests pre-task alpha peak frequency predicts outcome on
tests of working memory. Evidence also suggests patient with schizophrenia have low pre-task
alpha peak frequency, and slower RT on working memory paradigms, such as the n-back and
Sternberg compared with healthy controls; taken together, the weight of evidence lends
plausibility to the assumption that an increase in patients' pre-task alpha band power might
be associated with a faster reaction time. Notably in this regard, recent evidence suggests
transcranial magnetic stimulation (TMS) may increase pre-task alpha, and is associated with
a faster RT in healthy subjects. There are as yet no reports of the effect of TMS on alpha
band peak frequency, or reaction time, in patients with schizophrenia. A critical obstacle
to progress in the clinical neuroscience of TMS effects in human subjects until now has been
the absence of a means to determine the optimal subject-specific brain region to target with
TMS. Cortical targets for stimulation are customarily selected on the basis of group mean
data, with the tacit assumption that candidates for TMS all utilize the same distributed
neural circuit to perform a particular cognitive task. This untested assumption is a
conceivable source of the confusing discrepancy of TMS clinical trial outcomes, for example,
in the depression treatment literature. In this regard, a group from our laboratory recently
reported the use of structural equation modeling (SEM) based path analysis to construct
group and subject-specific models of the 2-back working memory task in healthy subjects
studied with PET. The results of this investigation suggest there may be a significant
association between cognitive strategy, circuit path, and memory performance. We found
higher scores were associated with activation of a left hemisphere distributed circuit, and
a verbal cognitive strategy, while lower scoring subjects utilized a right hemisphere
circuit, and a visuo-spatial strategy. Notably, these findings are congruent with those of
previous studies that used different methods of analysis and a similar paradigm. Taken
together, these data suggest that a trial of TMS aimed at improving working memory reaction
time by elevating pre-task alpha power should first identify the predominant nodes of a
subject-specific working memory sub-network as putative sites of stimulation. There are no
reports of such an approach to TMS target selection in either healthy controls, or patients
with schizophrenia. In this proof of concept with healthy subjects protocol, our principle
assumption is alpha frequency TMS directed to a subject-specific predominant node (right or
left DLPFC) of a distributed neural network reduces reaction time on the n-back and
Sternberg working memory paradigms.
1. Male and Female subjects, age 18-55
1. Significant psychiatric, or severe chronic medical illness at the time of the study,
or by history. This criterion includes the absence of substance abuse histories,
learning disabilities or any other DSM-IV AXIS I or II disorder with documented
cognitive impairment. The P.I. or his designate will evaluate medical histories.
Medical conditions that are judged not to interfere with the study may be allowed.
2. Pregnancy, personal or family history of epilepsy, concurrent use of tricyclic
antidepressants, neuroleptic agents, or any licit or illicit drugs that could lower
the seizure threshold, or history of complicated migraine.
3. Persons with surgically or traumatically implanted ferro-magnetic objects in the head
that may pose a physical hazard during magnetic stimulation will also be excluded.
4. Use of psychotropic substances in the last 3 months.
5. Head injury with a period of more than 15 minutes unconsciousness, or head trauma
with any duration loss of consciousness in the last year, or any evidence of
functional impairment due to and persisting after head trauma.
6. Use of caffeine or tobacco in the 2 hours preceding the test.
7. Subjects who have been previously excluded from NIH MRI or TMS protocols for safety
8. Subjects who are found to have eye lesions on exam.
9. First degree relative with a history of cognitive disorder with onset before age 55
by subject report, and by collateral report of at least one other family member, if