Deep High-Frequency Repetitive Transcranial Magnetic Stimulation for Smoking Cessation
Condition: Chronic Obstructive Pulmonary Disease; Smoking
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Deep transcranial magnetic stimulation (TMS) is currently being evaluated as a treatment
      option in major depression. It has been shown to be a safe procedure . Deep transcranial
      magnetic stimulation coils are designed to maximize the electrical field deep in the brain by
      the summation of separate fields projected into the skull from several points around its
      periphery. The device is planned to minimize the accumulation of electrical charge on the
      surface of the brain. Such accumulation can give rise to an electrostatic field that might
      reduce the magnitude of the induced electric field both at the surface and inside, thus
      reducing the depth penetration of the induced electric field . Deep transcranial magnetic
      stimulation could be more effective than repetitive transcranial magnetic stimulation due to
      its deeper penetration into brain tissues . The deeper penetration should produce greater
      action on nerve fibers connecting the prefrontal cortex to the limbic system.

      The ability of high-frequency repetitive transcranial magnetic stimulation (rTMS) to alter
      dopaminergic neurotransmission in subcortical structures could explain recent reports, which
      suggest that it has the potential to reduce smoking and nicotine craving. Ecihhammer et al
      demonstrated a reduction in the number of cigarettes smoked and in the desire to smoke after
      a single rTMS treatment (Eichhammer et al., 2003). In addition, Johan et al in a cross-over,
      double-blind, placebo-controlled study demonstrated a reduction in cigarette consumption and
      desire to smoke after a single repetitive transcranial magnetic stimulation treatment (Johann
      et al., 2003). Recently, the investigators have finished a complete study on nicotine
      addiction using repetitive transcranial magnetic stimulation for 10 consecutive days. They
      have found that 10 days of rTMS reduced significantly better from placebo the number of
      cigarettes smoked, nicotine dependence and craving (Amiaz et al 2007, in preparation).
      Interestingly, some of the effects were stronger in the sub-group of patients that were
      presented with smoking-related pictures immediately prior to stimulation onset. Although,
      these results are interesting and exciting, they have two important caveats. First, only
      about 50%-60% of the smokers responded to the repetitive transcranial magnetic stimulation
      treatment. Second, among those responded to the treatment, only 10% had quit totally from
      smoking. Therefore, the potential therapeutic benefit of this treatment is limited. The
      investigators' hypothesis is that deep transcranial magnetic stimulation may be more
      efficient in smoking cessation due to it's deeper penetration and therefore it's capability
      to stimulate deeper fibers of the dopamine-reward-activating system.
    

Detailed description: 
      Research Plan

      I. PARTICIPANTS Male and female cigarette smokers who suffer from COPD. From the general
      population aged 21-70 who wishes to quit smoking and failed to respond to previous
      anti-smoking treatment. They will be recruited by advertisements in the newspapers and
      specific websites. The number of participants in each sub-group (as described in the table
      below) will be 15-17. The investigators will recruit 90-102 subjects over two years.

      II. SCREENING PROCEDURE

      Before stimulation procedures onset, participants will undergo a clinical interview. All
      subject candidates will give written informed consent to take part in the study. Thereafter,
      they will be tested for their baseline pretreatment level of nicotine addiction in a
      screening meeting. This includes a report on the level of consumption (number of cigarettes
      smoked per day and overall duration in years) and a visual analog scale (VAS, see below for
      details). In addition, a urine sample for cotinine levels (nicotine metabolite) will be
      obtained in order to objectively measure levels of nicotine. In addition, several
      self-administered questionnaires will be given to the subjects in order to measure their
      baseline craving and nicotine dependence:

        1. Fagerstrom Test of Nicotine Dependence (FTND) (Heatherton et al., 1991). (Appendix
           no.1a)

        2. Tobacco Craving Questionnaire (TCQ) (Heishman et al., 2003). (Appendix no.1b)

        3. Full demographic questionnaire about medical condition and smoking habits. (Appendix
           no.1c)

      III. MEASURES

      All subjects will undergo various measurements on several visits, as described in table 1-3,
      for nicotine consumption, craving and dependence during the rTMS treatment visits:

        1. VAS: Visual Analogue Scale, on which the subject marks his/her subjective craving on a
           10-cm-long scale in response to the following question: "How much do you crave a
           joint/bong right now?" This "desire to smoke rating" has been shown to be sensitive to
           assess self-reported levels of craving in nicotine smoking (Schuh and Stitzer, 1995;
           King and Meyer, 2000).

        2. Short TCQ: Tobacco Craving Questionnaire, the short version of the TCQ, which has 12
           questions that can be divided into four categories: emotionality, expectancy,
           compulsivity and purposefulness.

        3. FTND: Fagerstrom Test of Nicotine Dependence. Measures the level of nicotine dependence
           (Dijkstra and Tromp, 2002).

        4. Self-report of the number of cigarettes smoked on the previous day.

        5. Urine sample.

        6. BR: desire to smoke and effect on hunger.

        7. Spatial span memory test - in order to evaluate the effect of deep rTMS on spatial
           memory. This test will be conducted in the screening interview and after 10 days of rTMS
           treatment.

      IV. PRESENTATION OF PHOTOGRAPHS

      It has recently been demonstrated that in nicotine-deprived smokers, reward and attention
      circuits are reactivated by mere exposure to smoking-related images, in contrast with neutral
      images (Due et al., 2002). In our experiment, prior to stimulation onset 14 'neutral' or
      'nicotine-related' colored photographs will be presented on a computer screen to the
      participants while there are seated. The 'nicotine-related' photographs will be composed from
      smoking-related scenes, such as lighting up a cigarette, smoking puffs etc. 'Neutral' photos
      will consist of matched pictures without any nicotine related content (e.g. inanimate
      objects, hands, faces etc.). As the investigators have previously shown with the figure-8
      coil experiment, there was a stronger effect of the rTMS treatment in subjects exposed to the
      nicotine photographs. The investigators propose that presentation of the nicotine photographs
      causes the nicotine-related memories to become activated and therefore, labile for
      interference, as previously has been shown (Dudai, 2004 ).

      V. EXPERIMENTAL PROCEDURES

      After screening of the participants while taking into account the inclusion and exclusion
      criteria (described above), they will be divided into experimental groups having similar
      levels of nicotine addiction and demographic background. At selected time afterwards,
      participants will be introduced to the TMS treatment protocol. They will be asked to refrain
      from smoking nicotine for two hours prior to attending the daily treatment session. Prior to
      stimulation onset, the participants will be presented with 'nicotine' photographs.
      Immediately after the offset of the photographs presentation (while memory is reactivated)
      the participants will be applied with real or sham rTMS stimulation. The stimulation site
      will be the PFC using the H-ADD coil.

      Time Table:

      There will be daily treatments for two weeks accompanied with assessment of the level of
      nicotine addiction on selected days using the above-mentioned tools. Thereafter, subjects
      will continue to have maintenance rTMS/sham stimulation treatment: 3 times a week for one
      week, two times a week in the forth and fifth week, once a week in the sixth and seventh week
      (see also table 2). After maintenance, participants will continue with follow up visits that
      will occur once a month for six months (see table 3). This protocol will allow evaluation of
      the short and long-term effects of the rTMS treatment with the possible fluctuations over
      time.

      TMS procedure:

      The investigators will use a Magstim Super Rapid stimulator, which produces a biphasic pulse,
      and our special customized equipment and coils for deep brain stimulation (Zangen, 2005 ).
      The TMS coils, which will be used in this study will be specific versions of the H-coil,
      depending on the region of stimulation. The H-coil versions used in this study, the H-ADD
      coil, have been tested in healthy volunteers and found to be safe and to induce some
      short-lasting (1 hour) cognitive alterations (Levkovitz et al., 2007, accepted). The
      theoretical considerations and design principles of the H-coils are explained in a previous
      study (Roth, 2002 ). In short, the H-ADD coil is designed to generate summation of the
      electric field in a specific brain region by locating coil elements at different locations
      around this region, all of which have a common current component which induce electric field
      in the desired direction .In addition, since a radial component has a dramatic effect on
      electric field magnitude and on the rate of decay of the electric field with distance, the
      overall length of coil elements which are nontangential to the skull should be minimized, and
      these elements as well as coil elements having current component in the opposite direction
      should be located as distant as possible from the brain region to be activated.

      The H-ADD coil is placed on the scalp over the left motor cortex. The center of the coil is
      placed on the scalp with the handle pointing backward and laterally at a 45° angle away from
      the midline. Thus the current induced in the neural tissue is directed approximately
      perpendicular to the line of the central sulcus and therefore optimal for activating the
      corticospinal pathways transsynaptically (Kaneko et al., 1996). With a slightly
      suprathreshold stimulus intensity, the stimulating H-ADD coil is moved over the left
      hemisphere to determine the optimal position for eliciting MEPs of maximal amplitudes (the
      'hot spot'). The optimal position of the coil is then marked relative to the 'hot spot' to
      ensure coil placement throughout the experiment. Resting motor threshold is determined to the
      nearest 1% of the maximum stimulator output and is defined as the minimal stimulus intensity
      required to produce MEPs of >50 µV in ≥5 of 10 consecutive trials at least 5 sec apart. The
      H-ADD coil is held in a stable coil holder ,which can be adjusted at different points
      relative to the 'hot spot' on the scalp.

      Stimulation Protocols:

      The investigators will use either sham or real H-ADD coils, which both produce similar noise
      and share a similar shape (as the investigators have been using in our study on healthy
      volunteers). Stimulation intensity will be 120% relative to the motor threshold in the 'hot
      spot'. PFC location will be determined as follows: 6 cm anterior to the motor 'hot spot' and
      symmetric.

      High frequency stimulation will by applied in order to achieve activation of the stimulated
      brain area and possibly induce LTP like plasticity. The stimulation protocol will be 33
      trains of 10 Hz for 3 seconds, ITI of 20 seconds. The total treatment duration will be 759
      seconds with 990 pulses. . For that purpose the investigators have designed a special cooling
      system for our coils and used them successfully in our healthy volunteers study (Levkovitz et
      al., 2007, accepted).
    

Intervention name(s): High frequency TMS; Sham TMS; Low frequency TMS
Intervention type(s): Device; Device; Device
Intervention description(s): deep TMS HADD coil; sham deep TMS HADD coil; Deep TMS - HADD coil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: COPD