Research Clinics

Repetitive Transcranial Magnetic Stimulation Research Clinic at Yale-New Haven Psychiatric Hospital

• What is Transcranial Magnetic Stimulation, or "TMS?"
• Investigating TMS as an Alternative Treatment for Hallucinated "Voices"

What is Repetitive Transcranial Magnetic Stimulation?

Transcranial magnetic stimulation (TMS) utilizes an electromagnet placed on the scalp that generates magnetic field pulses roughly the strength of an MRI scan. The magnetic pulses pass readily through the skull and stimulate the underlying cerebral cortex. Low frequency (once per second) TMS has been shown to induce sustained reductions in cortical activation in multiple studies. Currently we are conducting studies to determine whether low-frequency TMS can reduce hallucinated voices. Below are descriptions of these studies and information about how to contact us.

Transcranial Magnetic Stimulation as an Investigational Treatment for Hallucinated "Voices"

What are "Voices?"

Auditory hallucinations are experienced by 50-80% of patients with schizophrenia and 10-15% of patients with a mood disorder. These hallucinations, referred to as voices by patients themselves, consist of spoken speech. Sometimes the voices are familiar-persons whom the patient has known. But often the voices are unrecognizable. They comment, cajole, criticize, and in some cases command the patient. Voices are often highly distressing to the patient, especially when verbal content is negative or intrusive. These experiences disrupt one's ability to interact with others, to work, to study-even to sleep. In extreme cases they can produce suicidal behavior. In about 25% of cases, voices respond only partially or not at all to currently available drug therapy. Effective treatment alternatives for these hallucinations would therefore provide a significant benefit to patients and their communities. Some recent studies suggest that voices arise from parts of the brain that are ordinarily involved in perceiving spoken speech. These studies have led us to investigate a new treatment approach. Our strategy is to use low frequency TMS to reduce activation of speech processing brain speech areas in order to curtail hallucinated voices. These studies are described in more detail below.

TMS Studies of Voices

Our first study (completed 2/99) compared effects of active versus sham or "placebo" stimulation in 16 patients with severe, persistent voices. In every patient, "voices" were resistant to medication therapy. In the case of the sham stimulation, the scalp but not the brain was stimulated. The patient was not told which type of stimulation was being given in order to determine whether symptom improvements following magnetic stimulation could be due to a "placebo" response. Patients remained on their medication for the duration of the study. Magnetic stimulation was administered while the patient was awake and was directed above and behind the left ear. A total of 40 minutes of stimulation was given over 4 days. Patients showed improvement following active stimulation that exceeded that observed following the placebo form of stimulation.

A second study assessed effects more stimulation -- a total of 132 minutes of stimulation (compared to 40 minutes) given to the same brain site used in the first study. Stimulation was given over 9 days, and again improvements in AHs following real stimulation greatly exceeded improvements following placebo stimulation. Approximately 53% of patients experienced at least a 50% reduction in their voices compared to 18% of patients receiving the placebo form of stimulation. Duration of improvement ranged from 1 week to over a year. About 50% of patients retained significant improvement for at least three months following the trial.

In our current trial, we use a magnetic resonance imaging (MRI) scan of the brain to locate 2 brain areas that appear to be involved in the production of voices. One area is in a part of the left temporal lobe known as Wernicke’s area, which is ordinarily involved in perceiving spoken speech. The second is a similarly positioned area in the right temporal lobe. The MRI scan is used to position the TMS coil on the scalp above and behind the ears so that it precisely overlies these two brain areas. Our goal is to see if this approach can produce a higher and/or longer rate of response compared to our prior studies.

Roughly 2/3 of the persons in the study start out receiving the real stimulation and 1/3 of patients receive a placebo form of stimulation that feels similar to real stimulation but does not produce the direct brain effects. As in our previous studies, the patient and everyone outside of the TMS team will not know what type of stimulation is being administered during this initial time period. During the first 2 weeks, each of two brain areas located using the FMRI scanning data is tested with five daily 16-minute sessions of TMS. During the third week, additional stimulation is given to the left- or right-sided site that appeared to produce the greatest clinical improvement. No TMS is given on weekends, so this initial phase of the study requires 3 weeks. After this time period, we then tell the patient whether (s)he received the real stimulation or the placebo stimulation. If the patient had received real stimulation, (s)he will be offered a trial of an additional 5 days of real stimulation at the stimulation site producing the greatest improvement during the first three weeks of the trial. If the patient had received placebo stimulation, (s)he will be offered the real stimulation for up to 20 stimulation sessions over four weeks. Thus everyone enrolled in the study has the opportunity of finding out whether TMS is helpful in improving voices.

If a patient finds that TMS is helpful but suffers a return in symptoms, he or she they may enroll in an additional trial where TMS is given after waiting a six month period. We wish to determine if repeated exposure to TMS can again improve voices.

Who is Eligible?

Patient volunteers need to be 18-55 years old, have a diagnosis of schizophrenia, schizoaffective disorder, or affective disorder (depression or bipolar disorder), and experience "voices" at least 3-4 times per day. Individuals with a history of seizures or serious medical conditions may not participate in the study. Patients also cannot abuse drugs or alcohol for at least 30 days prior to study enrollment and during the study itself, and will need to stay on a steady dose of psychiatric medication for that period of time also. We do not require patients to be on psychiatric medication in order to enroll on the study, however. Another requirement is that the patient needs to undergo an MRI scan. This procedure is painless and does not involve injections, but does require lying on a stretcher in a large electromagnet for approximately 75-85 minutes. This may be difficult for people who are claustrophobic. Also people who have metal in their bodies (due, for example, to orthopedic surgery) may not be able to undergo MRI scanning.

Safety Issues Pertaining to TMS

TMS is generally not painful, but can be uncomfortable insofar as a tingling or knocking sensation is produced against the scalp. Scalp muscle contractions sometimes occur during the treatment. There is a very small risk of seizure associated with TMS, but for the frequency of stimulation used in this study (one stimulation per second), the risk is significant only for patients who have a prior history of seizures. We remain concerned regarding any risk to concentration or memory, although the occurrence of concentration and memory problems in our studies has been very rare (occurring in less than 5% of participants). If we encounter such problems the trial is stopped. In those few patients where such difficulties seem to have emerged, these complaints have disappeared in 1-2 days following the halt of the trial. No difficulties in perceiving speech have arisen from TMS in any of our studies to date.

More Facts About the TMS/Hallucination Clinical Trials

Participation in these clinical trials requires approximately 3-7 weeks. Prior to entering the study the patient receives medical, psychiatric and neurological evaluations. Patient volunteers are reimbursed $350 for completing the treatment study and $50 per brain scan. If patients live a considerable distance from New Haven or have severe symptoms, they can be hospitalized at no cost on a research unit at the Connecticut Mental Health Center in order to participate in the study. Otherwise, participation can be on an outpatient basis.

Studies described above are approved by the Yale University School of Medicine Human Investigation Committee (HIC #12679 and 27023). Support this study is provided by the National Institute of Mental Health.

For more information or to make a referral, call or contact Joan Nye, Study Coordinator at 203-737-2762 (joan.nye@yale.edu), or Ralph Hoffman, M.D., principal investigator at 203-688-9734 or ralph.hoffman@yale.edu.

Literature regarding these studies:

Hoffman, R.E., Boutros, N.N., Hu, S., Berman, R,M., Krystal, J.H., Charney, D.S. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet 2000, 355: 1073-1075.

Hoffman, R.E., Hawkins, K.A., Gueorguieva, R. Boutros, N.N., Rachid, F., Carroll, K., Krystal, J.H. transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Archives of General Psychiatry 2003, 60: 49-56.

Hoffman, R.E., Gueorguieva, R., Hawkins, K.A., Varanko, M., Boutros, N.N., Wu, Y.-T., Carroll, K., Krystal, J.H.. Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and predictors in a fifty patient sample. Biological Psychiatry 2005; 58:97-104.

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