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<ul><li><p>University of Toronto Medical Journal158</p><p>An Introduction to TranscranialMagnetic Stimulation and Its Use in the Investigation and Treatment of Depression</p><p>Dan Mozeg, BSc., (0T0), and Edred Flak, MD, FRCP(C)</p><p>Neuropsychiatry</p><p>Mon</p><p>ique</p><p> LeB</p><p>lanc</p><p>Abstract Research during the past decade and a half has led to thedevelopment of Transcranial Magnetic Stimulation(TMS). In this procedure a pulsed magnetic field gener-ated extracranially induces focal intracranial electrical dis-charges. TMS has been used in the investigation of neu-rological and neuropsychiatric disorders, and morerecently has emerged as a tool in the study and treatmentof depressed mood in the context of Major DepressiveDisorder and Bipolar Disorder. Although data are limit-ed and preliminary, early results are promising withregards to the efficacy of TMS in alleviating depressedmood. The antidepressant effect, however, is currentlyshort-lived, lasting hours to weeks. TMS appears to besafe, with only minor side effects in both healthy andneurologically impaired individuals. However, a possibleincreased predisposition to generalized seizures may existamong those with multiple sclerosis, stroke, and epilepsy,both during and following the procedure. Ongoingresearch into optimization of hardware specifications,treatment protocols, and side-effects, may allow TMS toemerge as an alternative to psychoactive medications andelectroconvulsive therapy in treating primary psychiatricdisorders where depressed mood is prominent, as well assecondary and reactive depression arising in the contextof medical conditions and surgical procedures.</p><p>Transcranial Magnetic Stimulation An IntroductionFollowing the discovery of the unified and interchangeablenature of electric and magnetic forces, it became evidentthat electric currents generate magnetic fields while chang-ing magnetic fields generate electric currents. By this time it</p></li><li><p>had already been well established by Galvanis and Voltasclassic experiments that electric currents were capable ofstimulating neuronal tissues. The combination of these twoconcepts the unity of electric and magnetic forces, and theresponsiveness of neurons to electrical stimulation is nowbeing harnessed to study and manipulate the central nervoussystem (CNS) from both neurologic and psychiatric per-spectives. A technique called Transcranial MagneticStimulation (TMS) uses an externally generated changingmagnetic field to induce electric current intracranially. Thisis in contrast to the application of an electric current that isgenerated externally and transmitted to the brain throughthe skull (for example in electroconvulsive therapy). Whenelectricity is forced to pass through the skull, the currentused must be relatively large as the skull is a powerful insu-lator with an electrical resistance 8 to 15 times greater thanthat of soft tisues.2 Furthermore, externally generated elec-tric currents cannot be focally directed as the skull dissipatesthe electricity globally leading to massive depolarization ofcortical and subcortical structures.2 Such difficulties are min-imized upon exposure of the skull to TMS, where thechanging external magnetic field undergoes minimal attenu-ation in the skull tissues while inducing smaller, focallydirected electric currents within the brain.1,2</p><p>Barker et. al. first described in 1985 the use of a pulsed (i.e.changing) magnetic field focused over specific regions ofthe cerebral cortex to induce muscle action potentials.3,4 Theuse of pulsed magnetic fields to induce electrical activity inperipheral nerves had been described much earlier, in the1960s.1 The mathematical framework describing howpulsed magnetic fields may be used to generate electricalcurrents in the human brain was subsequently described byBarker in 1987.1 The technique requires a hand-held coilshaped as a circular disc (or more recently as a figure-8),with an inner diameter of approximately 60 millimeters(mm) and an outer diameter of approximately 130mm. Thecoil is held near the patients head, and is connected to apower-source which generates an electric current that isswitched on and off repeatedly producing a changing mag-netic field in the vicinity of the coil. The frequency at whichthe current (and hence magnetic field) is pulsed varies fromas low as 1-5 Hz to as high as 25-30 Hz. The higher fre-quency technique has been found to be particularly effectivein psychiatry and has been termed Rapid Rate TranscranialMagnetic Stimulation (rTMS).1,5,6 rTMS is believed to beunique in that rapid pulsation can induce electrical currentswithin neurons while they are in the refractory period,although how this relates to an altered clinical manifestationis unclear. The magnetic field, passing largely unimpededthrough the skull, induces a current within the brain tissue.1</p><p>Depending on the region of the brain over which the coilis physically placed, specific circumscribed areas can bestimulated. This avoids generalized seizure-like dischargeand global stimulation of cortical and subcortical structures.</p><p>TMS has been used for multiple purposes in the field ofneurology including establishing hemispheric language dom-inance, localization of epileptogenic foci, and the study ofmotor pathways originating at the cerebral cortex and rele-vant motor pathway physiology.1,2,6,7 It has also been utilizedin neuropsychiatry in the mapping of attention, memory,movement, speech, and vision.8 Clinically, TMS has beencombined with electromyographic studies (EMG) to deter-mine impairment in CNS conduction pathways by measur-ing differences in the rates of muscle activation upon elec-tromagnetic stimulation at the cerebral cortex in comparisonwith similar stimulation at spinal nerve roots.1,9,10 Thisassessment is useful in the diagnosis and prognostication ofdemyelinating diseases such as multiple sclerosis. Morerecent efforts have focused on the use of TMS in the symp-tomatic improvement of Parkinsons disease.9,11,12</p><p>Being a relatively new technique, optimization of parameterssuch as frequency of pulsing of the magnetic field, size ofthe coil utilized, strength of the magnetic field generated,and duration of induction of electrical current has yet to beestablished.13,14 Furthermore, it is likely that such parameterswill vary substantially depending on the specific neurologi-cal or psychiatric applications.</p><p>Use of TMS in the Treatment of Primary MoodDisordersSeveral serendipitous findings in the course of neurologicaland psychoneurological testing have suggested that TMSmay be useful in the study and treatment of primary psy-chiatric mood disorders. Grisaru et. al. noted an improve-ment in the mood of two Parkinsonian patients followingTMS while measuring nerve conduction times, while studiesof hemispheric language dominance using rTMS have foundaffective reactions in a considerable number of patients fol-lowing dominant frontal cortex stimulation.7,15,16 Given thatTMS is focally applied, however, the question arose as towhich specific regions of the brain should be stimulated.Dysfunction in the frontal lobes, particularly involving theleft prefrontal cortex, has been implicated in the develop-ment of major depressive episodes.13,17,20 Furthermore, stud-ies of patients with strokes causing damage in the left pre-frontal cortex have suggested an increased risk ofdeveloping depression, while studies of patients with multi-ple sclerosis have shown a greater number of plaques in theleft frontal lobe of those who have comorbid depression incomparison to patients with similarly severe multiple scle-rosis but no depression.17,20 Findings from functional neu-roimaging studies, Computed Tomography, and MagneticResonance Imaging have also described abnormalities in theleft prefrontal cortex in both primary and secondary depres-sion.17,19 The observation that TMS may affect mood states,and the implication of the frontal lobes in the pathogenesisof depression have led investigators to examine the efficacyof TMS applied to regions of the frontal cortex in studying</p><p>volume 76, number 3, May 1999 159</p></li><li><p>University of Toronto Medical Journal160</p><p>apparent mood changes were evoked by rTMS applied toany scalp position when compared to baseline. However,left prefrontal TMS did result in a significant increase in thesadness rating on the visual analogue scale, and a signifi-cant decrease in the happiness rating when compared tothe right- and mid-prefrontal regions.</p><p>George et. al. also demonstrated a lateralization in theirstudy of 10 healthy volunteers, although left prefrontal stim-ulation was again found to be associated with a worseningof mood.21 After applying rTMS to the right, left, and mid-frontal corteces, as well as to the occipital and cerebellarregions, left prefrontal stimulation was found to be associ-ated with an increase in self-rated feelings of sadness, whileright prefrontal stimulation was found to be associated withan increase in self-rated feelings of happiness.21 The resultsof these two studies are inconsistent with the previouslydescribed studies which showed improvement in moodwhen the left prefrontal cortex was stimulated. The differ-ence may stem from variability in the physical parametersand settings of the TMS equipment, and the protocol used.Furthermore, these two latter studies assessed healthypatients over the course of hours while the previouslydescribed two studies assessed pathologically depressedpatients over the course of several weeks. This raises thepossibility that TMS may impact differently on healthy indi-viduals as compared to those who are depressed. It is worthnoting that all studies implicate the frontal lobes as impor-tant in the maintenance of mood states and point to a lat-eralization of mood within them.</p><p>Assessment of the value of TMS in the management ofmood disorders has also been attempted within the contextof laboratory models. Fleischmann et. al. in 1995 describedthe effects of TMS on rat brains in behavioural models ofdepression.18 Their findings suggested that TMS had neuro-logical and behavioural effects similar to those induced byelectroconvulsive shocks.</p><p>Safety of TMSBarker et. al., describing TMS in its early days, believed thistechnique to be relatively safe.1 They calculated the amountof thermal energy deposited in tissues as a result of the pro-cedure to be very small. They described the peak magneticfield used in the procedure as being similar in magnitude tothe static fields used in magnetic resonance imaging scan-ners, and noted that no adverse effects had yet been attrib-uted to such magnetic fields. Consistent with this view is thereport by Pascual-Leone et. al., whereby none of the seven-teen patients in their study reported adverse effects otherthan minor headaches which were relieved with mild anal-gesics.13 Bridgers and Delaney assessed 30 healthy adults forcognitive and motor performance following TMS.22 No sta-tistically significant declines in story recall, word association,visual recall, or grip strength were observed. A study of 9normal volunteers by Pascual-Leone et. al. found that</p><p>and treating depression arising in the context of MajorDepressive Disorder (MDD) and Bipolar Disorder(BD).13,17,18</p><p>George et. al. in 1995 reported an open study of six patientswith treatment resistant depression, who were subjected torTMS of the left prefrontal cortex over the course of oneweek.17 All patients had primary mood disorders, five beingBD type II and one suffering from MDD. All were in themidst of a major depressive episode. For the group as awhole a significant improvement in mood was noted, witha decrease in the mean Hamilton Depression Rating Scalescore from 23.8 to 17.5 on the 17-item scale.</p><p>Pascual-Leone et. al., in 1996, described a multiple cross-over, randomized, placebo-controlled trial studying rTMSstimulation of the left dorsolateral prefrontal cortex in drugresistant depression.13 Seventeen patients with MDD, multi-ple relapses of major depressive episodes, and psychotic fea-tures were studied. The patients received 5 courses of TMS,each lasting five days. These included real left frontolateralTMS, real right frontolateral TMS, placebo TMS of thesetwo regions, and real TMS of the mid-frontal region. Boththe Hamilton Depression Rating Scale and the BeckDepression Inventory were used to assess depressed moodat baseline and following treatment. Nine of the patientswere found to experience improvement in mood only fol-lowing administration of real left frontolateral TMS, whilethree patients reported improvement in mood followingboth administration of left frontolateral and mid-frontalTMS. Two patients reported subjective improvement inmood following only real left and real right frontolateralTMS. In all patients the lowest Beck and Hamilton scores(i.e. least depressed mood) followed administration of leftfrontolateral TMS, and represented a statistically significantimprovement over baseline. TMS stimulation of all otherareas of the brain demonstrated no statistically significantimprovement (and at times an increase) in Hamilton andBeck scores versus baseline. The average duration for whichpatients reported a significant improvement in mood fol-lowing left frontolateral TMS was limited to 2 weeks fol-lowing cessation of stimulation of this area.</p><p>Pascual-Leone et. al. studied 10 healthy volunteers andassessed subjective perception of five emotional domains onvisual analogue scales.20 These domains included happi-ness, anxiety, tiredness, pain and discomfort, andsadness. TMS was applied over the course of 3.5 hours,with 5 minute sessions and 30 minute intervals between ses-sions. After each session participants were required to fill inthe five analogue scales, noting the intensity of each of theabove emotions. The TMS sessions involved right pre-frontal, left prefrontal, and mid-frontal regions, applied invarying order to correct for possible sequential effects ofthe treatment. The authors concluded that no clinically</p></li><li><p>rTMS was not associated with significant changes in neu-rological examination findings, cognitive performance,EEG, electrocardiogram, or levels of anterior pituitaryhormones.23 However, the highest intensity stimulus ofTMS did produce a focal seizure in one patient, which sec-ondarily became generalized. Chokroverty et. al. concludedthat TMS was not associated with any apparent deleteriouseffects in the short term and in long term follow-up of 16to 24 months, after assessing EEG data, psychometric testresults, anterior pituitary hormone levels, and onset offatigue in normal subjects undergoing this procedure.24</p><p>Transient decline in delayed recall was noted, resolving 2weeks after the procedure.</p><p>Several authors raised the possibility of seizure inductionduring or following TMS in healthy subjects and in thosewith neurological conditions such as epilepsy andstroke.2,25,26,27,30 The majority of reports, however, have beenanecdotal. Others contend that TMS is a safe procedure inboth healthy and neurologically impaired persons. Kand...</p></li></ul>

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