Transcranial Magnetic Stimulation

Transcranial magnetic stimulation is a technology that has been developed to nonin-vasively activate nerve cells through the scalp (Barker et al., 1985). For example, if a single TMS pulse is applied over the "thumb area" of the motor cortex, it will induce a movement in the contralateral thumb. A unique aspect of TMS is its relative safety, ease of application, and the awake and interactive state of the subject being stimulated (Nahas et al., 2000a). The major side effect is unwarranted seizures, which have been absent since the adoption in 1998 of the International Workshop in the safety of repetitive pulse of TMS (rTMS) guidelines (Wassermann, 1998). TMS has been used as a neuroscience tool to study brain localization, brain connectivity, and cortical excitability in relation to other parameters such as peripheral electromyogram (EMG), electroencephalogram (EEG), blood flow, neurotransmitters, or the modulating effects of central nervous system (CNS) drugs (Epstein et al., 1996; Edgley et al., 1990; Amassian, 1993; Grafman et al., 1999; George et al., 1996b; Pascual-Leone et al., 1996; Martin et al., 1997; Nedjat et al., 1998; Mosimann et al., 2000). TMS has also found use as a neuro-physiologic diagnostic tool and as a potential therapy for neuropsychiatric conditions. Here, we will focus on TMS as a somatic intervention for therapeutic purposes. Investigators are now using rTMS over the prefrontal regions to treat depression and are exploring other neuropsychiatry applications (George et al., 1999a).

Transcranial magnetic stimulation is not a new idea. In 1896, the French engineer Arsenne d'Arsonval applied TMS over the retina and induced phosphenes. In 1910. Pollacsek and Beer filed a patent in Vienna to use magnetic stimulation for the treatment of depression. However, it wasn't until the 1990s that the technology became sufficiently developed to allow induced electromagnetic fields that caused cortical neuron depolarization. TMS relies on Faraday's law of electromagnetic induction (Bohning, 1999). The TMS capacitor discharges high-amplitude electric current in the TMS coil and in turn generates a magnetic field, up to 20,000 times that of the earth, which passes unimpeded and very focally through the scalp. The magnetic field then induces a secondary electric field in the brain. In effect, the magnetic field gets converted to the electrochemical energy that directly depolarizes superficial neurons (at a maximum depth of 2 mm) and indirectly influences pathways to which these neurons connect.

Thus, TMS can affect cells at some distance from the stimulation site through transynaptic connections, as demonstrated with functional imaging studies (Paus et al., 1997; Kimbrell et al., 1997; Bohning et al., 1998). Because the induced electric field is parallel to the scalp, myelinated axons with a bend at the junction between gray and white matter are the primary candidates for depolarization with TMS.

Currently, TMS coils follow one of 2 basic designs (Bohning, 1999). They can be either round and generate a diffuse ring of magnetic field or a Figure 8 coil in which the summation of the 2 round coils is greatest at the center. This latter design allows a more focal stimulation. Single TMS pulses can produce isolated excitatory and inhibitory events in nerve pathways such as the corticospinal system. Since TMS applied to the motor cortex can readily induce a contralateral thumb movement, the intensity needed to generate 5 movements out of 10 trials is defined as motor threshold (MT). TMS pulses can also be delivered in pairs, a few milliseconds apart (paired-pulse TMS), to probe cortical excitability by examining the influence of a first pulse onto the effect of a second pulse on motor evoked potentials (MEPs) (Ziemann et al., 2000). Finally, trains of repetitive TMS (or rTMS) are postulated to modulate the neuronal activity both distally and at the site of stimulation. TMS thus offers the advantage of noninvasively modulating a neuronal network without the limitations of drug interactions and side effects seen with psychotropic drugs nor the need for general anesthesia necessary in ECT and MST (George et al., 1996a).

In the early 1990s the first applications of rTMS to treat depression emerged independently in the United States, Austria, and Israel. The nearly simultaneous publications that resulted form these efforts reported the initial attempts at treating depression using nonfocal stimulation with a round TMS coil held over the vertex (Hoflich et al., 1993; Grisaru et al., 1994; Kolbinger et al., 1995). Results were promising but inconclusive. Based on functional imaging evidence that showed a predominance of hypofrontality in depression, as well as data that prefrontal changes in rCBF predicted ECT response, George and Wassermann proposed that dorsolateral prefrontal cortex (DLPFC) stimulation might have a more powerful antidepressant effect (George et al., 1994). It was their impression in pilot work that a session of left DLPFC TMS temporarily improved mood in depressed subjects, whereas right DLPFC made them dysphoric. They published their first attempt using an open design in 1995 (George et al., 1995). All of the TMS studies since then have followed that lead, utilizing prefrontal stimulation [both left (Pascual-Leone et al., 1994; Berman et al., 2000; Padberg et al., 1998; Loo et al., 1999; George et al., 2000, Nahas et al. 2003). and right (Klein et al., 1999)].

The method for prefrontal localization in the George et al. (1995) article was defined as 5 cm forward and in a parasagittal plane from the optimal spot for producing contralateral thumb movement. This later became the standard applied rule although more recently the stereotactic navigation system demonstrated the limitation of this general rule in targeting Brodmann area 9 or 46 in most subjects (Herwig et al., 2002). If focality and targeted stimulation of these two areas are necessary for the antidepressant effect of rTMS, then this rule may account for the limited response rates seen so far in some clinical trials.

Recently, there have been four independent meta-analyses with different statistical methods investigating the acute antidepressant effect of rTMS (Fig. 17.1). Three found a moderate effect and clear significance from sham treatment (Burt et al., 2002; McNamara et al., 2001; Holtzheimer et al., 2001), whereas one using the Cochrane

. Garcia-Toro et al (2001a)

Avery et al (1999)

George et al (2000) GRAND MEAN

Padberg et al (1999)

_ Kimbrell et al (1999) _ Manes et al (2001) Lisanby et al (2001)

Eschweiler et al (2000)

. Garcia-Toro et al (2001b)

0.50

1.75

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Figure 17.1. Forrest plot of Hedges' d effect size and 95% confidence intervals for left prefrontal rTMS treatment of depression. The 12 double-blind sham-controlled treatment trials of left prefrontal repetitive transcranial magnetic stimulation are graphed. The vertical line indicates the study's Hedges' d treatment effect size. The horizontal lines indicate the 95% confidence intervals of the treatment effect using nonparametrical variances. The grand mean effect is clearly significant with the confidence interval not including zero.

method concluded otherwise (Martin et al., 2002), even though researchers noticed positive effects after 2 weeks of fast left and slow right prefrontal TMS. Kozel and George (2002) identified and limited their meta-analysis to rTMS of left prefrontal cortex, first arms of randomization in sham-controlled studies of 2 weeks duration, and concluded that left prefrontal rTMS has an acute antidepressant treatment with clinically significant effects.

The large variance in placebo response across the sham-controlled TMS studies (the large variance in sham treatments was not explained at any point earlier) may be due to different cohorts across studies, only the subject (not the investigator) being blind to the treatment cell or variability in sham techniques. Concerning sham technique, some researchers hold the coil at a 45° or 90° angle with one lateral or anterior edge of the coil touching the scalp. This directs most of the magnetic field away from the brain, but it may still induce electric fields and possibly stimulate brain tissue (Lisanby et al., 1998; Loo et al., 2000). This shortcoming of current TMS research is being addressed with more sophisticated sham coils and more elaborate study designs in which TMS administrators remain masked to the randomization along with the patient. To date, four studies have shown no significant difference between TMS and sham treatment, two of these were designed with TMS as an add-on to a serotonin reuptake inhibitor treatment (Loo et al., 1999; Manes et al., 2001; Lisanby et al., 2001a; Garcia-Toro et al., 2001).

Because both TMS and ECT utilize electricity to induce electric currents in the brain, it has been tempting to compare them. There are now three published reports (Grunhaus et al., 2000, Janicak et al., 2002, Pridmore et al., 2000) that show equal efficacy for these techniques in the nonpsychotic depressed population. It is worthwhile to mention that these studies have mostly used TMS in longer trials (up to 20 days) than previously cited studies (maximum 10 days of treatment). This may well account for the higher response rate along with the possibility of a more homogenously studied population. Grunhaus et al. (2000) found that up to 4 weeks of daily fast left DLPFC rTMS among nonpsychotic patients was equivalent in efficacy to ECT, though ECT showed a better effect among psychotically depressed patients. The TMS cohort showed a 26 percent relapse rate, similar to ECT, in a naturalistic follow-up at 6 months (Dannon et al., 2002). (Note: Our group is, in fact, investigating TMS as maintenance treatment with either once per week session or 5 successive daily sessions per month.) In an investigation of combined treatments, Pridmore et al. (2000) studied 22 outpatients with either left unilateral ECT for 2 weeks or one ECT per week followed by 4 days of left prefrontal rTMS. At the end of 2 weeks, the two cohorts showed equal efficacy, with an average 75 percent drop in Hamilton Depression Rating Scale (HDRS). In this design, it appears that TMS may not interfere with ECT mechanisms and may be complimentary. Janicak et al. (2002) randomized 22 depressed adults to receive either 12 bilateral ECT treatments or 20 TMS sessions over 4 weeks, after which nonrespon-ders were given the option to crossover to the other condition. Both groups showed equal efficacy (average drop of HAM-D was 65 percent), number of responders (about 67 percent of subjects with improvement greater then 50 percent), and time of antide-pressant onset (between the second and third week). Reported subjective cognitive impairment was greater for the ECT groups than TMS.

These clinical studies administered stimulation intensity in the range of 80 to 110 percent of MT (the amount of TMS to generate thumb movement). As a group, they suggest that higher intensity stimulation may be more effective in treating depression, perhaps through maximizing energy delivery to the cortex. Blood flow changes induced by different TMS intensities over the prefrontal cortex in healthy subjects, using TMS interleaved with functional MRI (fMRI) support this notion (Nahas et al., 2000b). Left prefrontal stimulation at 100 percent and 120 percent MT produced a greater blood flow response under the coil than did 80 percent MT. At 120 percent MT, left prefrontal stimulation induces increased activity in ipsilateral insula. Bohning et al. (1998) showed similar findings over motor cortex with greater brain activity at 110 percent MT than 80 percent MT (Fig. 17.2).

A closer look at the data in depression trials suggests that a greater number of stimulation sessions is also indicative of greater response. All the ECT versus TMS studies have administered treatments for a period of greater than 2 weeks. Therefore,

Figure 17.2. Probing of prefrontal/limbic connection using interleaved TMS/fMRI in five healthy adults. 1 Hz left prefrontal TMS (green bar) at 120% MT causes changes in left dorsolateral prefrontal cortex (site of stimulation), right orbitofrontal, bilateral auditory cortex, and right anterior temporal pole. See ftp site for color image.

Figure 17.2. Probing of prefrontal/limbic connection using interleaved TMS/fMRI in five healthy adults. 1 Hz left prefrontal TMS (green bar) at 120% MT causes changes in left dorsolateral prefrontal cortex (site of stimulation), right orbitofrontal, bilateral auditory cortex, and right anterior temporal pole. See ftp site for color image.

the next generation of TMS studies is looking at maximizing both intensity and duration of treatment in order to increase effect size and enhance the clinical applicability of antidepressant effects. Additionally, our group has also shown that a greater distance from the skull to prefrontal cortex requires a higher stimulation intensity to produce an effect. Skull to prefrontal cortex distance increases with age at a greater ratio than distance to motor cortex so that using the MT to calculate prefrontal stimulation intensity, as is commonly done, may be faulty especially in the elderly (McConnell et al., 2001). Given the initial poor response in depressed elderly treated with TMS and the knowledge that the magnetic fields drop off logarithmically, Daryl Bohning in our group developed a formula to adjust the intensity of prefrontal delivered stimulation based on the motor threshold, distance from scalp to prefrontal cortex, and distance from scalp to motor cortex (Bohning, 1999)1 By applying this customized delivery based on individual MRI scans, we have shown an improved depression response rate in the elderly.

The antidepressant mechanisms of action of TMS are still unknown. Nonfo-cal rTMS has been reported to induce ECT-like changes in rat brain monoamines, beta-adrenergic receptor-binding down-regulation, and astroglial gene expression up-regulation (Fleischmann et al., 1996; Ben-Sachar et al., 1997; Fujiki et al., 1997). More recently, Post and Keck (2001) have completed a series of studies using focal TMS in rat models. They modeled the TMS fields coupled to brain morphology to simulate comparable conditions in which focal TMS is applied in humans. They largely replicated earlier nonfocal TMS animal studies. There is now accumulating evidence that TMS also exerts a neuroprotective antioxidative effect and increases the intrahip-pocampal expression of brain-derived neurotrophic factor (BDNF) and cholecystokinin (CCK) (Post et al., 1999).

In humans, prefrontal rTMS can influence sleep by increasing rapid eyes movement (REM) latency and prolonging the non-REM-REM cycle (Cohrs et al., 1998). Left DLPFC TMS has been shown to increase peripheral thyroid stimulation hormone (TSH) levels in depressed subjects (Szuba et al., 1999; George et al., 1996b), as shown in mood induction studies, and healthy young adults, as shown in sleep studies (Cohrs et al., 1998). This finding raises the intriguing possibility that TMS may cause mood or antidepressant changes through effects of circulating hormones and the HPA axis. Functional neuroimaging studies before and after several left prefrontal TMS sessions administered to depressed subjects support the notion that left prefrontal stimulation shows local and distant effects, such as in the limbic system (mainly, the cingulate and amygdala) (Teneback et al., 1999; Nahas et al., 2001b; Paus, 2001).

To date, the one strong prognosticator of poor response is the degree of treatment resistance. Other potential prognosticators of response rate are late-onset depression

'Delivered intensity (percent MT) = MP(-0.36 x dPC))/(exp(-0.36 x dMC)) where dPC is the measured MRI distance (in millimeters) from the scalp to the prefrontal cortex, and dMC is the distance for motor cortex. This formula is based on Daryl Bohning's previous measurements of TMS magnetic fields with MRI phase maps. It assumes that the effective stimulation intensity is proportional to the magnetic field measured at the center of the coil and has the same rate of exponential decrease with distance (Bohning personall communication).

or vascular depression, baseline metabolic activity of prefrontal cortex (Speer et al., 1999), and lower or higher degree of cortical excitability (Maeda et al., 2002).

Although a number of clinical rTMS studies in depressed subjects have been published in the last 2 years with a modest but consistent effect size, fewer focused on schizophrenia. Geller et al. (1997) were perhaps the first to use TMS of the prefrontal cortex to study mood changes in schizophrenic patients and suggested that it could modulate schizophrenic symptoms. Slow and fast prefrontal rTMS has been tested for treatment of positive, negative, and/or mood symptoms with mixed results (Rollnik et al., 2000; Nahas et al., 1999). Hoffman et al. (2000) hypothesized that unlike the excitatory effect of fast stimulation, slow frequency rTMS would have inhibitory effects on brain activity. They demonstrated that slow temporal rTMS for 4 days significantly decreased auditory hallucinations compared to sham. These results were replicated in a group of nine subjects (d'Alfonso et al., 2002), although other labs have tried and have not been able to replicate these findings (K. Ebmeir, personal communication, Philadelphia, 5/22/02).

Obsessive-compulsive disorder (OCD) (Baxter, 1990) and Parkinson's disease have fairly well defined functional neurocircuitry. Yet, so far, TMS therapeutic investigations have yielded very limited and preliminary results (Greenberg et al., 1997). Potential uses of TMS to study and treat posttraumatic stress disorder (PTSD) and Tourette's disorder also warrant further research. All clinical investigations will benefit from improved sham applications to both investigator and study subject (Kosel et al., 2002).

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