BOLD-fMRI response vs. transcranial magnetic stimulation (TMS) pulse-train length: Testing for linearity

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<ul><li><p>Original Research</p><p>BOLD-fMRI Response Vs. Transcranial MagneticStimulation (TMS) Pulse-Train Length: Testing forLinearity</p><p>Daryl E. Bohning, PhD,1* Ananda Shastri, PhD,1 Mikhail P. Lomarev, MD, PhD,1,2Jeffrey P. Lorberbaum, MD,3 Ziad Nahas, MD,3 and Mark S. George, MD1,35</p><p>Purpose: To measure motor and auditory cortex blood ox-ygenation level-dependent (BOLD) functional magnetic res-onance imaging (fMRI) response to impulse-like transcra-nial magnetic stimulation (TMS) pulses as a function oftrain length.</p><p>Materials and Methods: Interleaved with fMRI at 1.5 T,TMS pulses 0.3-msec long were applied at 1 Hz to the motorcortex area for thumb. Six subjects were studied in a TR 1 second session administering trains of 1, 2, 4, 8, and 16pulses, and a TR 3 seconds session administering trainsof 1, 2, 4, 8, 16, and 24 pulses. A simple hemodynamicmodel with finite recovery and saturation was used toquantitatively characterize the BOLD-fMRI response as afunction of train length.</p><p>Results: In both the activations directly induced in motorcortex by TMS and the indirect activations in auditory cor-tex caused by the sound of the TMS coil firing, the BOLD-fMRI responses to multiple pulses were well described by asummation of single-pulse impulse functions.</p><p>Conclusion: Up to 24 discrete pulses, BOLD-fMRI re-sponse to 1 Hz TMS in both motor cortex and auditorycortex were consistent with a linear increase in amplitudeand length with train length, possibly suggesting that stim-uli of 1 to 2 seconds may be too long to represent impulses.</p><p>Key Words: transcranial magnetic stimulation (TMS);fMRI; train length; BOLD response linearity; motor cortexJ. Magn. Reson. Imaging 2003;17:279290. 2003 Wiley-Liss, Inc.</p><p>FUNCTIONAL MAGNETIC RESONANCE imaging (fMRI)using blood oxygenation level-dependent (BOLD) con-trast (13) is well established as a tool for studyingbrain function. Although it is also well known that theBOLD response is highly correlated with blood flow(46), and, in turn with neuronal activity in the brain(7), despite intensive study, the exact relations betweenthe BOLD response and neuronal activity is still notclearly defined. Ideally, one would like to have a quan-titative relation describing the BOLD signal in terms ofthe entire chain of underlying processes that are initi-ated by the discharge of neurons in the cerebral cortexand that make up the brains response to a particularstimulus.</p><p>Originally, because it was the simplest thing to do,because the technology was less sophisticated and be-cause early data were reported to be consistent with alinear response (811), it was first assumed that a lin-ear model described the relation (10,12,13). That is, itwas assumed that the response to a single, very shortstimulus, a so-called impulse response function, couldbe determined, and that the behavior of the system foran arbitrary pattern of stimuli could be described bysuperimposing the individual impulse response func-tions of the series of short stimuli making up the stim-ulus pattern. Mathematically, this is equivalent to say-ing that the output function can be found by convolvingthe stimulus input function with the impulse responsefunction. Alternatively, if the impulse response functionis known, the neuronal activation pattern can be esti-mated from the fMRI response by deconvolving the im-pulse response function (14). Most fMRI analysis tech-niques have been based on the assumption that thesystem is linear (15).</p><p>Even early on, however, Binder, et al (16) reportedthat auditory response was nonlinear at shorter stim-uli, and Boynton, et al (8) noted that visual cortex (V1)responses to the shortest (3 seconds) stimulus tended</p><p>1Department of Radiology, Medical University of South Carolina,Charleston, South Carolina.2The Institute of the Human Brain, St. Petersburg, Russia.3Department of Psychiatry, Medical University of South Carolina,Charleston, South Carolina.4Department of Neurology, Medical University of South Carolina,Charleston, South Carolina.5The Ralph H. Johnson Veterans Hospital, Charleston, South Carolina.Contract grant sponsor: National Alliance for Research in Schizophre-nia and Depression (NARSAD); Contract grant sponsor: Ted and VadaStanley Foundation; Contract grant sponsor: Borderline PersonalityDisorder Research Foundation; Contract grant sponsor: NIMH R21.Presented as a poster at ISMRM 2000.*Address reprint requests to: D.E.B., Radiology Department, MedicalUniversity of South Carolina, 169 Ashley Avenue, Charleston, SouthCarolina 29425. E-mail: bohninde@musc.eduReceived May 9, 2002; Accepted October 30, 2002.DOI 10.1002/jmri.10271Published online in Wiley InterScience (</p><p>JOURNAL OF MAGNETIC RESONANCE IMAGING 17:279290 (2003)</p><p> 2003 Wiley-Liss, Inc. 279</p></li><li><p>to overestimate the response to the longer stimuli. Theyattributed this to neural adaptation. With the increas-ing use of event-related designs (12,13) and carefulscrutiny of the response as a function of stimulusstrength, duration, and interstimulus intervals, evi-dence began accumulating that the response is nonlin-ear, with the most consistent finding being that shortduration stimuli produced responses larger than ex-pected from a linear system (1618). Aside from theimportance this has for fMRI data analysis (14,19,20),this nonlinear behavior has drawn increasing attentionas a means to explore and better define the relationshipbetween neuronal output and the BOLD-fMRI signal,and, ultimately, to find a mathematical relation relatingthe two (5,14,20). For example, this nonlinearity mightbe a result of an overshoot in the neuron activity inresponse to the stimulus onset, response saturation, ornonlinearities within the hemodynamics, such asslower blood volume changes or the nonlinear depen-dence of oxygen extraction on flow, which translate theneuronal activity into the BOLD signal (5,21).</p><p>Common to the majority of these investigations is theuse of very short stimuli, first alone, to define the im-pulse function, and then in series, varying the inter-stimulus intervals and number of stimuli to explore therelationship (14,19,22). The first step being to demon-strate the nonlinearity, and the next step to quantify it.</p><p>Transcranial magnetic stimulation is a technique inwhich a pulsed magnetic field from a small coil is usedto create localized neuron depolarizing currents in thecerebral cortex (23). It has been used to investigatenerve function for over a decade (24), and is finding avariety of applications in neuropsychiatry (25). It is alsopossible to combine transcranial magnetic stimulation(TMS) with fMRI to visualize regional brain activity inresponse to direct non-invasive stimulation (2630). Asa noninvasive way of applying an extremely short (0.20.3 msec) stimulus directly to the cerebral cortex, itprovides a unique means for testing the linearity of theBOLD-fMRI neuronal discharge relationship.</p><p>Because TMS directly induces neuronal depolariza-tion, it is believed that the associated BOLD fMRI re-sponse does not depend on any intervening sensory orcognitive processing, which may itself affect the form ofthe response. Though artificial, it uniquely and nonin-vasively provides what might be called a true impulsefor testing the form of the BOLD-fMRI response and itslinearity with both pulse frequency and train length. Atthe same time, the auditory response caused by theaccompanying short snap of the TMS coil as it is firedprovides a good physiologic reference because it mustbe processed in the same way as other auditory chal-lenges. Figure 1b diagrams a conceptualization distin-guishing the direct and indirect activations, and pro-vides an idea of the relative routes that might beinvolved. The separation into input and output neuronsfollows the suggestion of Logothetis, et al (7) that BOLDactivation may actually reflect more the neural activityrelated to the input and the local processing in anygiven area, rather than the spiking activity commonlythought of as the output of the area. To give an idea ofthe approximate magnitude of the cross-collosal delay,dcc, measurements with an electroencephalogram</p><p>(EEG) (31) immediately after TMS over the motor cortexhave shown the response in the contralateral motorcortex lags that in the ipsilateral motor cortex by 510msec. If the response functions at every step are linear,it would be possible to treat them as a series of convo-lutions and, ultimately, lump them into a single convo-lution with a cumulative delay.</p><p>A cautionary note is important here. A direct neuro-nal discharge stimulated by TMS is artificial and de-pends on the TMS coils field distribution, as well as thenatural neuronal functional organization of the cortex,so the associated BOLD response may well arise from adifferent neuronal discharge pattern than that under-lying strictly physiologic stimulations. Although thismeans that the BOLD response to TMS may not bedirectly comparable to that for physiologic stimula-tions, it also means that that difference might be usedto explore the underlying neuronal discharge.</p><p>Typically applied in trains, electrophysiologic studieswith TMS have reported inhibition when applied at fre-quencies of 1 Hz (32) and facilitation when applied atfrequencies 1 Hz (33). This implies nonlinearity, butwith respect to inter-stimulus interval (ISI) rather thanstimulus train length.</p><p>Though interleaved TMS/fMRI has been successfullyused to detect the BOLD-fMRI response to TMS, theTMS applications were limited to a single pulse (28),fixed length trains of 1821 pulses delivered at 1 Hz(26,29), or a series of 1-second-long, 10-pulse trains(30). None of these studies were able to address thequestion of the linearity of the BOLD response.</p><p>The objective of this work was to use 1-Hz TMS inter-leaved with fMRI to measure the amplitude and dura-tion of the BOLD-fMRI response in motor and auditorycortex as a function of TMS pulse-train length. A fur-ther objective was to fit the unique direct (artificial)motor cortex response induced by TMS, and the indi-rect (physiologic) auditory cortex response accompany-ing it, to a nonlinear hemodynamic model with finiterecover and saturation to determine if the two re-sponses differ, to what degree they show nonlinearity,and if there is any sign of the negative correlation ofTMS response with train length observed with TMS/PET (34) or the inhibition or facilitation observed withelectrophysiologic techniques.</p><p>MATERIALS AND METHODS</p><p>General Experimental Design</p><p>Using interleaved TMS/fMRI (26,27) in a 1.5-T clinicalMRI scanner (EDGE, Rel.9.4, Picker International, Inc.,Highland Heights, OH), BOLD sensitive single-shotecho-planar imaging (EPI)-fMRI images were acquiredcontinuously while individual TMS pulses, at a fre-quency of 1 Hz and 120% of motor threshold (MT), wasapplied over the left motor cortex for the thumb indifferent length trains. The in-magnet stimulation wasperformed using a Dantec MagPro (Dantec MedicalA/S, Skovlunde, Denmark) with special non-ferromag-netic TMS coil of figure-of-eight design. The details ofthe method have been published elsewhere (26,27).TMS stimulation of thumb motor cortex was chosen</p><p>280 Bohning et al.</p></li><li><p>because it allowed independent verification of properfunctional location of the TMS coil in the form of thumbmovement and is the standard area used to obtain MT.</p><p>Six healthy male volunteers (mean age 42.7 10.0years) were studied, in two different scan sessions per-formed several months apart, under a protocol ap-proved by the Medical University of South CarolinasInstitutional Review Board for Human Research.</p><p>In the first scan session, using a TR of 1 second forhigh temporal resolution, pulse trains of 1, 2, 4, 8, and16 pulses were given in pseudo-random order in fiveconsecutive 39-second epochs, with the entire cycle</p><p>being repeated five times for a total scan length of 16.25minutes. In the second scan session, using a TR of 3seconds to allow a longer recovery period and extendedpulse train, pulse trains of 1, 2, 4, 8, 16, and 24 pulses,again in pseudo-random order, were given in six 60-second epochs, with the cycle being repeated four timesfor a total scan length of 24.00 minutes. Coronal sec-tions (102 64 matrix reconstructed to 128 128images, field of view [FOV] 270 mm, TR 1 second,and 72 [or TR 3 seconds and 88], TE 40.0msec, slice thickness 5 mm, slice gap 1.5 mm, withfrequency-selective fat saturation), positioned to bilat-</p><p>Figure 1. a: Z-map for individual showing M1 activations directly induced in the motor cortex by TMS (ipsimotor) and auditoryactivations induced indirectly by its sound. b: Conceptual diagram for TMS action, the n functions representing input andoutput neuron activity in each area; h, the hemodynamic response function; d, the various within-area and between-area delaysin the circuit; and s functions, the BOLD-fMRI signals.</p><p>Linearity of BOLD-fMRI Response to TMS 281</p></li><li><p>erally include motor and auditory cortex, were acquiredevery second (or three seconds).</p><p>In the TR 1 second session, the TMS pulses weregiven 20 msec after the beginning of each volume (eightslices) acquisition. This avoided the radiofrequency (RF)fat saturation and excitation pulses for the acquisitionof the first slice, and gave 105 seconds for the effects ofTMS pulse to dissipate. As will be described in theresults section, this proved inadequate, and resulted insubstantial artifact. In the TR 3 second session, TMSpulses were applied 20 msec after the beginning ofevery fourth slice of the volume (12 slices) acquisition.This again avoided the RF fat saturation and excitationpulse, but this time gave 230 msec for the effects of theTMS pulses to dissipate.</p><p>TMS Coil Placement</p><p>Before the subject was moved into the scanner, the TMScoil, padded with a napkin and with vitamin E capsulesplaced at its ends to help locate it in the structuralimages, was rigidly mounted in the MRI head coil in theapproximate position required to activate the individu-als motor cortex for right thumb. Then, while the TMScoil was intermittently pulsed, initially at high intensity(90% machine output when MT was unknown, lower forsubjects whose approximate MT was known from pre-vious studies), the subjects adjusted their head posi-tion until visible movement of the contralateral (right)hand abductor pollicis brevis (thumb) was consistentlyinduced. Although formal electromyogram (EMG) deter-mination of position and MT were not performed, aclose concordance has been found between EMG-deter-mined MT and visually-determined MT using this Dan-tec system (35). The subjects head was then stabilizedwith foam-padded inflatable restraints. Finally, MT wasdetermined by gradually decreasing stimulation inten-sity until movement (slight thumb twitch) was observedapproximately 50% of the time. The stimulator wasthen set to 120% of the subjects MT. After scannertuning and acquisition of T1-weighted reference images,and before the TMS/fMRI acquisition was started, theTMS coil-to-head relation was rechecked wit...</p></li></ul>


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