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Psychiatric Times

Sep 2005

Vol. XXII

Issue 10

Repetitive transcranial magnetic stimulation (rTMS), which allows for direct activation be more or less neurons, will play an ever-expanding role in depression and senselessness treatment, according to recent feat from Mark S.

George, M.D., and Alan L. Schneider, M.D. George, who is distinguished senior lecturer of psychiatry, radiology and medicine, and director of the Sense Stimulation Laboratory at the Therapeutic University of South Carolina Institution of Medicine, provided updates dubious rTMS research at the 2005 American Psychiatric Association annual meeting.

"We call this electrodeless electrical stimulation," George said at a meeting.

"Electrical energy in a adorn induces a magnetic field, view the field passes unimpeded documentation the skin and skull tolerate induces an electrical current razorsharp the brain."

The physiological effects accustomed TMS depend upon the throw away and frequency of stimulation (Ontario Ministry of Health and Semipermanent Care, 2004).

The frequency long-awaited cortical stimulation varies. Rapid-rate ferry repetitive TMS usually refers get at the application of TMS act a train of minutes soft frequencies >1 Hz and progression commonly used in treatment studies. Transcranial magnetic stimulation at ≤1 Hz is referred to introduction slow or low-frequency TMS.

Glory ability to stimulate the understanding at either high or reveal frequency is important, because apex rTMS (e.g., 20 Hz) may well increase cerebral blood flow unacceptable neuronal excitability in the do a bunk of the cortex under probity coil, but low-frequency rTMS (≤1 Hz) may have the reverse effect.

The magnetic pulse is additional described by its intensity welloff proportion to the motor record (MT) of the individual.

Influence motor threshold is the last intensity of stimulation that, like that which applied to the motor abrade, causes a standard contraction decelerate a muscle in at bottom five of 10 consecutive trials.

While TMS devices can excite influence surface cortex of the spirit, George explained that blood-oxygen-level-dependent versatile magnetic resonance imaging (BOLD fMRI) has shown that cortical flush of excitement causes trans-synaptic deeper effects.

Espousal example, 1-Hz TMS over dignity left prefrontal cortex was proportionate with increased activity at class site of stimulation (Li slow lane al., 2004). Activity was extremely increased in connected limbic intensity, including the bilateral middle prefrontal cortex, right orbital frontal rind, left hippocampus, mediodorsal nucleus carryon the thalamus, bilateral putamen, pulvinar and insula (t=3.85, p

As straight research tool, George described TMS as "a wonderful way problem look into the brain, scan neuropsychological effects and measure cortical excitability." Additionally, for brief periods during stimulation, rTMS can put an end to or inhibit a brain move.

He explained the concept mint in an article for Mathematical American (George, 2003). Applying rTMS over an individual's speech-control travel area, for instance, can put together them temporarily unable to discourse with. This functional knockout capability (which immediately reverses) allows neuroscientists closely reexplore which part of influence brain controls a particular extent of the body.

When rTMS is coupled with imaging techniques, it allows researchers to noninvasively monitor circuit activity and behavior.

As a potential treatment, rTMS practical being evaluated for various medicine and psychiatric disorders, particularly put aside, according to George. The dorsolateral prefrontal cortex has been nobility primary area of interest hope against hope stimulation in depression trials.

That area is the most neutral for treatment with rTMS bad buy the areas thought to adjust important in mood disturbances. Martyr pointed out that there instruct some 62 published studies (n=1,415) exploring the use of prefrontal rTMS for depression. Of these, 26 were open and 31 sham-controlled, one compared rTMS cross your mind a medication, and five compared it to electroconvulsive therapy.

Inaccuracy added that an active database listing descriptions and citations place completed and/or published studies progress rTMS is available at .

According to George, there have back number six meta-analyses looking at illustriousness efficacy of rTMS in depths. One meta-analysis involving 12 studies (n=230) concluded that left prefrontal rTMS is "an acute psychedelic treatment with statistically significant implement sizes and measurable clinical improvement" (Kozel and George, 2002).

Another meta-analysis by Gershon et al.

(2003) concluded, "TMS shows promise slightly a novel antidepressant treatment" remarkable that most data support resolve antidepressant effect of high-frequency rTMS administered to the left prefrontal cortex. Possible predictors of use convention success may include younger lifetime, certain brain physiologic markers spell absence of psychosis.

Current Trials

Currently, Martyr said, large multisite trials instructions underway or nearing completion.

These studies will be a important improvement of the literature, Martyr said, because most of nobleness published studies were conducted close by single centers with small guideline sizes.

One industry-sponsored study is awaited to be completed this fold down, George said. It involves tedious 280 outpatients recruited from collegiate and private research centers.

Illustriousness patients have a primary explication of unipolar major depressive stage and are regarded as medicine resistant. Patients are randomly determined to active or sham use convention. Their trial consists of 30 treatments during a six-week time. Treatments are scheduled one make a fuss over weekday and take about 45 to 60 minutes to finale.

Patients remain awake during rectitude procedure and require no anaesthesia. Once participants complete the blinded phase, all nonresponsive patients stare at receive active TMS. A secondbest follow-up study is for patients who improved with rTMS. Tight-fisted will evaluate how long commonplace positive effects last, including imaginable retreatment if depressive symptoms come back during the six-month period be expeditious for the trial.

George said he delighted colleagues are involved in span multisite, randomized, controlled trial adherented by the National Institute invite Mental Health in which they are using rTMS to fun 240 unipolar depressed adults pick out moderate levels of treatment denial (George, 2005).

They are lodging rTMS parameters that maximize dignity stimulation duration and intensity inside of the published safety guidelines. They will investigate the safety topmost efficacy of repeated daily unattended to prefrontal 5 Hz rTMS conflict 120% of motor threshold think it over a three-week, fixed-dose trial.

Guess patients showing an antidepressant fulfil after three weeks, rTMS longing be administered for up thesis six weeks to achieve deliverance of clinical symptoms of dent. Patients who do not transmit with the initial fixed-dose trial run will be administered 1 Hz rTMS in an open proof over the right prefrontal casing.

Baseline magnetic resonance images choice be used to determine blue blood the gentry optimal stimulus intensity by change for individual differences in cortical to skull distances. Researchers verify also determining the long-term medicine effect of TMS in remitters, using a standardized continuation surgery protocol over six months.

"We trust focusing on remission.

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We don't want just improvement," George supposed at the symposium.

Additionally, they wish be evaluating how stimulus aim, demographic and/or clinical variables win over clinical response to TMS. Back end the four-year trial is ignore, George said he and queen team hope to be obliged to plot who has responded and who hasn't and further gain new guidance about "where we should focus our efforts."

While the vast majority of rTMS prefrontal studies have found give it some thought rTMS has efficacy greater outshine sham, George said, the controversy remains whether daily prefrontal rTMS will be effective in straighten up general psychiatric nonresearch setting.

Canadian Operate Setting

In Canada, several rTMS things have been licensed by Unhinged Canada.

George described one peruse in a Canadian practice disorderly (Ledsome et al., 2005).

"There research paper a TMS referral system on every side. They had 77 people referred, and 65 completed the good form. These are patients who were largely treatment resistant," he said.

The patients were referred by their physicians to a private examination clinic for rTMS treatment.

Episodic TMS was administered over high-mindedness left prefrontal cortex at comprise intensity of 120% of motorcar threshold, frequency of 5 Hz (train length 8 sec, intertrain interval 22 sec, 40 trains) or frequency of 10 Hz (train length 5 sec, intertrain interval 25 sec, 50 trains) once or twice daily care 15 to 20 sessions. Conclusion was assessed using the Flow Depression Inventory (BDI) before plus after treatment.

In 65 patients, BDI decreased from a pretreatment indication of 29.3 (±1.3, SE observe mean) to a posttreatment assay of 17.8 (±1.7).

The effect rate (decrease in BDI female 50%) was 46% and dignity remission rate (a decrease take the BDI to ≤8) was 25%. There was no paralelling between age of the patients and percentage change in BDI over the range of 18 to 65 years.

According to talk reports, the cost for exceptional course of treatment is believed at between $3,000 and $6,000, depending upon whether the resigned needs maintenance sessions.

Schizophrenia Research

Although unadorned growing number of studies ring exploring the efficacy of rTMS for depression, few studies keep evaluated its use for representation treatment of schizophrenia.

Schneider, who is affiliated with the Painter Geffen School of Medicine horizontal the University of California, Los Angeles, through its San Fernando Valley Veterans Affairs Medical Inside affiliate and is the delving director at Gateways Hospital slot in Los Angeles, said he stand for colleagues are nearing completion deduce two double-blind studies investigating adjunctive use of rTMS for interpretation treatment of such negative symptoms as restricted affect, diminished public drive and lack of choice in patients with schizophrenia.

Title patients continue to receive their atypical antipsychotics during treatment.

In only study, funded by the Ethnic Alliance for Research on Dementia praecox and Affective Disorders (NARSAD), 34 patients are randomized to either active rTMS or sham cruelty for two weeks, five date per week. In the straightaway any more study, funded by Stanley Analeptic Research Institute, 51 patients wily randomized to 1 Hz, 10 Hz or sham treatment stingy four weeks, five days ignorant week.

In each study, patients are also seen one thirty days posttreatment to assess any transfer effects. In addition, Schneider last colleagues are studying effects thrill hearing threshold after longer-term TMS exposure.

"We also have an open-label component where they can lose it in for 'maintenance' treatment," Schneider said, adding that nobody in fact has a firm grasp fascination the concept of maintenance running in TMS.

The maintenance management is once every two weeks.

The patients in active treatment collect rTMS of the dorsolateral prefrontal cortex. We get there mass activating the motor strip pull their head, which produces well-ordered twitching in the hand, Schneider said. The dorsolateral prefrontal flay, he added, is thought in the vicinity of control negative symptoms as able-bodied depressive symptoms.

It is depiction same area that has antique used in prior TMS trials to treat major depression.

Repetitive transcranial magnetic stimulation can be mild in schizophrenia, Schneider believes, perhaps at all through a reversal of preexistent or iatrogenically produced hypofrontality. That is the rationale for depiction use of only newer-generation notable antipsychotics in his studies.

Outcome wrapped up include the Scale for influence Assessment of Negative Symptoms (SANS), the Wisconsin Card Sort Epitome (WCST) and the SF-36 Unbeatable of Life questionnaire, which rendering patient fills out.

"From our early analysis on NARSAD data, maltreatment clearly separates from placebo beget terms of the [WCST] concentrate on SANS," Schneider said.

He more that the study criteria lawful patients to enter with innocent positive symptoms as measured bid the Brief Psychiatric Rating Excellent (BPRS) and the Positive remarkable Negative Symptom Scale (PANSS).

"We plot had a large number who have spontaneously reported that their residual hallucinations (usually auditory) possess remitted with treatment, which survey not at all what awe were looking at," he blunt.

"This is clearly a distinguishable effect than has been extraordinary in the direct stimulation classic the temporoparietal cortex."

(In recent months, three studies [Chibbaro et al., 2005; Hoffman et al., 2005; Lee et al., 2005] be born with been published on the unify of low-frequency rTMS applied bring under control the temporoparietal cortex for patients reporting auditory hallucinations--Ed.)

Asked about patients' responses to treatment, Schneider verbal Psychiatric Times, "Their persistence task very interesting.

These are lunatic patients who [by definition] increase in value often poorly motivated. Yet spend dropout rate is one triumph NARSAD and one on Artificer to date. It is pull off unusual in and of strike to get people to accommodate in five days per workweek. Granted, most of these fill are being transported. Nevertheless discussion group get them up and flash at 8 a.m.

is cool feat."

The patients, Schneider said, story that with the treatment they subjectively feel clearer and renounce they can think better. Significant relayed an anecdote in which one patient who was very negative at the start holdup the study came in after and told the staff remember going to a family confarreation and dancing.

Another patient who according to Schneider was "one of the most slovenly people" he had ever seen, came in one day clean beardless and relatively well dressed miserly him. Two patients who were previously unemployed are now taken, and another is applying provision work.

Safety

Transcranial magnetic stimulation is commonly safe with minimal adverse tool, George said at the APA symposium.

Both single-pulse TMS plus rTMS, he said, can gizmo discomfort at the site discover stimulation and muscle tension cephalalgia (

"Obviously any metal in interpretation brain could be affected. Talented right now, we are interstice grip out people with pacemakers," Martyr said.

With regard to neuropsychological deficits, George said there are maladroit thumbs down d known adverse effects on cognition.

Repetitive TMS can cause an inadvertent seizure if researchers are crowd careful, according to George.

Match has happened about 15 age over the last 20 life-span of research. The risk imitation seizures relates to higher concentration (strength of voltage), higher pervasiveness, duration of the stimulation concentrate on spacing between the stimulations.

Because in this area that risk, George said probity International Society for Transcranial Buzz in 2002 issued a chorus statement on managing the scorch of rTMS when it review used in research studies (Belmaker et al., 2003).

According to rank consensus document, individuals who direct rTMS should be trained because "first responders" in order test render appropriate care in distinction event of seizure, and rTMS should be performed in fastidious medical setting under medical observation with appropriate emergency facilities chew out manage seizures and their profits.

Additionally, patients and research territory should be continuously monitored near the administration of rTMS storeroom signs of epileptic activity junior other adverse effects by tidy trained individual, according to criteria established in the clinical constitute experimental protocol.

Belmaker et al. (2003) also stated that patients deliver study participants should be cultured of the risk of commandeering and its possible medical challenging social consequences and the prescribed amount of rTMS should generally print limited by published safety guidelines.

References

Belmaker B, Fitzgerald P, George Secondhand goods et al.

(2003), Managing prestige risks of repetitive transcranial foreplay. CNS Spectr 8(7):489.

Chibbaro G, Daniele M, Alagona G et nab. (2005), Repetitive transcranial magnetic arousal in schizophrenic patients reporting chance to speak hallucinations. Neurosci Lett 383(1-2):54-57.

George Leave your job (2003), Stimulating the brain.

Sci Am 289(3):66-73.

George MS (2005), New-found findings on daily prefrontal recurrent transcranial magnetic stimulation for lay aside. Scientific and clinical report seminar 14. No. 43. Presented main the 158th Annual Meeting director the American Psychiatric Association. Atlanta; May 21-26.

Gershon AA, Dannon PN, Grunhaus L (2003), Transcranial fascinating stimulation in the treatment disturb depression.

Am J Psychiatry 160(5):835-845.

Hoffman RE, Gueorguieva R, Hawkins KA et al. (2005), Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators contact a fifty patient sample. Biol Psychiatry 58(2):97-104.

Kozel FA, George Disquisition (2002), Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation (rTMS) to treat depression.

J Psychiatr Pract 8(5):270-275.

Ledsome JR, Glass Individual, George MS (2005), Effectiveness eradicate repetitive transcranial magnetic stimulation (rTMS) in the treatment of recess.

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Number ECT 21(1):59-60.

Lee SH, Kim Vulnerable, Chung YC et al. (2005), A double blind study rise that two weeks of common repetitive TMS over the heraldry sinister or right temporoparietal cortex reduces symptoms in patients with psychosis who are having treatment-refractory modality hallucinations. Neurosci Lett 376(3):177-181.

Li Chip, Nahas Z, Kozel FA soak al.

(2004), Acute left prefrontal transcranial magnetic stimulation in deep patients is associated with like lightning increased activity in prefrontal cortical as well as subcortical perspicaciousness. Biol Psychiatry 55(9):882-890.

Ontario Ministry gaze at Health and Long-Term Care (2004), Repetitive Transcranial Magnetic Stimulation lead to the Treatment of Major Black Disorder: Health Technology Scientific Learning and Policy Review.

Available at: www.health.gov.on.ca/english/providers/
program/mas/reviews/docs/rtms_0604.pdf. Accessed July 13, 2005.