Deep Low-Frequency Repetitive Transcranial Magnetic Stimulation for Cessation of Pathological Gambling
Deep Low-Frequency Repetitive Transcranial Magnetic Stimulation for Cessation of Pathological Gambling
Pathological gambling (PG) is characterized by a persistent pattern of continued gambling
 behavior despite its adverse consequences. PG is a chronic, progressive, male-dominated
 disorder, which has a prevalence of 1% to 3.4% among US adults. Deep transcranial magnetic
 stimulation (TMS) is a novel neuro-stimulation method capable of inhibiting neuronal activity
 when given in low frequency. The hypothesis of this study is that , Pathological gambling
 will be ameliorated if low frequency magnetic field using Brainsway H1 coil will be applied
 to the left dorso-lateral prefrontal cortex of these patients.
Deep Low-Frequency Repetitive Transcranial Magnetic Stimulation for cessation of pathological
 gambling

 Introduction:

 Pathological gambling (PG) is characterized by a persistent pattern of continued gambling
 behavior despite its adverse consequences. PG is a chronic, progressive, male-dominated
 disorder, which has a prevalence of 1% to 3.4% among US adults. Typically, the patient's life
 becomes dominated by the gambling behavior leading to overwhelming financial burdens, an
 inability to maintain a career, and to the eventual disintegration of family relationships.
 The enormous personal and social consequences of this disorder include a high rate of suicide
 attempts, legal problems, and criminal behavior [R1].

 Several theoretical models of drug addiction have suggested that addiction is related to
 abnormal activity in the ventromedial prefrontal cortex system, which is necessary for
 inhibiting both the craving for immediate reward and excitement-seeking behavior [ref2].
 Neuropsychological studies of pathological gamblers [ref 3to9 ref2 ref10] have demonstrated
 that pathological gamblers have deficits in the frontal lobe/reward system leading
 investigators to hypothesize that impairment of executive function may play an important role
 in the etiology of pathological gambling.

 Drawing from the field of drug dependence, it has been speculated that the underlying
 pathology in pathological gambling is a reduction in the sensitivity of the reward system.
 Reuter et al studied pathological gamblers and controls during a guessing game using
 functional magnetic resonance imaging and observed a reduction of ventral striatal and
 ventromedial prefrontal activation in the pathological gamblers that was negatively
 correlated with gambling severity, linking hypo-activation of these areas to disease severity
 [ ref11]. Studies in the field of addiction have shown that prefrontal regulation of behavior
 is reduced in basal conditions, thereby contributing to the reduced salience of non-drug
 motivational stimuli and reduced decision-making ability. However, when stimuli predicting
 drug availability are presented, there is profound activation of the prefrontal cortex and
 glutamatergic drive to the nucleus accumbens [ref12].

 Potenza et al in a functional magnetic resonance imaging study demonstrated that male
 pathological gamblers showed relatively reduced activity in the frontal and orbitofrontal
 cortex, caudate and basal ganglia and thalamus as compared to controls when presented with
 visual gambling cues [ref13].Recent neurobehavioral studies have demonstrated poor
 performance on tests of executive function in pathological gamblers suggesting that the
 financial risk-taking behavior seen in PG may be associated with both dorsolateral prefrontal
 and orbitofrontal cortex dysfunction [ref 14-17].Neuropsychological studies of PGs have
 demonstrated that PGs have deficits in the frontal lobe/reward system [ref18 ref10].Patients
 with pathological gambling demonstrated greater decreases in binding potential in the ventral
 striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater
 dopaminergic release. Ventral striatal bindings at baseline during control task were also
 lower in patients with pathological gambling [ref19].

 Reductions in right prefrontal activity during decision-making appear to be modulated by the
 presence of gambling problems and may reflect impaired working memory, stimulus reward
 valuation, or cue reactivity in substance dependent individuals [ref20].

 PG is related to response perseveration and diminished reward and punishment sensitivity as
 indicated by hypoactivation of the ventrolateral prefrontal cortex when money is gained and
 lost. Moreover, intact planning abilities and normal dorsal frontostriatal responsiveness
 indicate that this deficit is not due to impaired executive functioning. Response
 perseveration and ventral prefrontal hypo-responsiveness to monetary loss may be markers for
 maladaptive behavior seen in chemical and non-chemical addictions [ref21].

 In one study, subjects and 10 matched healthy control subjects underwent fMRI during visual
 presentations of gambling-related video alternating with video of nature scenes. Pathological
 gambling subjects and control subjects exhibited overlap in areas of brain activity in
 response to the visual gambling cues; however, compared with control subjects, PG subjects
 exhibited significantly greater activity in the right dorsolateral prefrontal cortex (DLPFC),
 including the inferior and medial frontal gyri, the right parahippocampal gyrus, and left
 occipital cortex, including the fusiform gyrus [R22].

 It has been reported that High-frequency (20-Hz) rTMS of left dorsolateral prefrontal cortex
 can reduce cigarette smoking significantly [ref23].In another study, found that multiple
 high-frequency rTMS of the DLPFC can attenuate nicotine craving [ref 24].Regarding cocaine
 addiction treatment with TMS, it has been shown that one session of 10Hz rTMS over right, but
 not left, DLPFC transiently reduces craving in cocaine dependent individuals [ref25].Politi
 et al. conducted a study including thirty-six subjects fulfilling DSM-IV criteria for cocaine
 dependence. Subjects were treated with 20 trains of TMS applied to the left prefrontal cortex
 in frequency of 15 Hz and intensity of 100% of the motor threshold. Repeated measures
 analyses of variance showed that cocaine craving were gradually reduced during sessions of
 TMS [ref26].

 Hypothesis Assuming substance addiction and pathological gambling share similar
 patho-physiology and considering the evidence that transcranial magnetic stimulation of left
 dorsolateral prefrontal cortex can ameliorate addiction in both smoking [ ref23 ] and
 cocaine[ ref26 ] we hypothesize that transcranial magnetic stimulation may also reduce
 gambling "craving" in pathological gamblers.

 H-coil placed over the frontal cortex exerts a significant effect over the entire ipsilateral
 cortical hemisphere, but significantly less over the contralateral hemisphere [ref27].Thus,
 the H-coil placed over the DLPFC is hypothesized to exert a direct and more consistent effect
 on cortical and subcortical regions such as the anterior cingulate and nucleus accumbens
 (ventral striatum), compared to the figure-8 coil. Because these regions are considered to
 play a role in drug craving and addiction, rTMS applied with the H-coil may be more effective
 in reducing drug craving than rTMS applied with the standard figure-8 coil.

 Deep TMS:

 Deep TMS is currently being evaluated as a treatment option in major depression. It has been
 shown to be a safe procedure [ref28, ref29]. The innovative design of Brainsway H-Coils is
 intended to generate sufficient magnetic field strength to stimulate neurons deep inside the
 brain mass without posing a hazard. This forms the basis of the Brainsway H-Coil used in
 their deep rTMS device. The 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 also minimizes the accumulation of electrical charge on the surface
 of the brain, which can give rise to an electrostatic field that might reduce the magnitude
 of the induced electric field both at the surface and inside, and reduce the depth
 penetration of the induced electric field [ref30]. The unique shape of the device's base
 includes wire coils containing several wire strips, set tangentially to the scalp's surface.
 Each set of strips is connected in series and contains current flowing in the same direction,
 therefore generating a field that extends into the brain in a specified orientation from each
 location along the scalp. Computerized theoretical calculations were made in order to
 optimize the coil design for maximizing the percentage of stimulation in depth relative to
 the cortical regions. These, in conjunction with tests performed in a phantom model, [ref 30,
 ref28, ref27] demonstrated the ability to stimulate, by means of the H-Coil, deep brain
 regions. It may be assumed then that the activation of deep brain regions and their
 interconnecting fibers may serve as a new approach in treating neuropsychiatry illnesses with
 prominent advantage over the standard coil, unable to affect regions as deep as the H-Coil.
 Deep TMS could be more effective than rTMS due to its deeper penetration into brain tissues
 [ref28]. The deeper penetration should produce greater action on nerve fibers connecting the
 prefrontal cortex to the limbic system.

 In a randomized controlled study of deep transcranial magnetic stimulation conducted in
 Israel, 32 healthy volunteers (9 of which were tested for H1 coil presented in this report)
 were evaluated for possible cognitive impairment. Cognitive evaluation was conducted using
 the Cambridge Neuropsychological Test Automated Battery (CANTAB), which is sensitive to
 cognitive changes caused by a wide range of Central Nervous System disorders and medication
 side-effects. No deterioration in cognitive functions was found, except for a transient
 short-term effect of the H1-coil on spatial recognition memory on the first day of rTMS (but
 not in the following treatment days). Questionnaires conducted for emotional or mood
 alterations, showed no significant changes except for reports on 'detachment' experienced by
 subjects treated with the H1-coil.In addition, stimulation with the novel H-coils was found
 to be well tolerated, with no adverse physical or neurological outcomes [ref29].

 Contraindications to deep TMS are essentially the same as those for rTMS. Absolute
 contraindications include history of any metal object in the head, known history of any
 metallic particles in the eye, implanted cardiac pacemaker or any intra-cardiac lines,
 implanted neurostimulators, surgical clips or any medical pumps, history of cochlear implants
 and a history of seizure or heat convulsion. Relative contraindications include epilepsy or
 seizure in first degree relatives, history of head injury; frequent or severe headaches,
 migraines; hearing loss; drug abuse or alcoholism, pregnancy or not using a reliable method
 of birth control and systemic and metabolic disorders.

 Methods:

 40 patients aged 18-65 years, diagnosed as suffering from pathological gambling according to
 DSM-IV-TR will be recruited from outpatient treatment programs at the Beer Yaacov Mental
 Health Center. Within 3 days prior to the first treatment session patients will be assessed
 by a rater blind to real /sham treatment with the following measures:

 1. SCID -version 2

 2. Hamilton Depression 24 items

 3. Hamilton Anxiety

 4. Y-BOCS

 5. SOGS (South Oaks Gambling Screen)

 6. DAGS (Dannon Ainhold Gambling Scale)

 7. VAS (visual analogue scale)

 8. CGI-I

 9. Social Adaptation Scale (SAS)

 10. Complete battery of Neurocognitive tests

 Following preliminary assessment, patients will be equally and randomly divided to 2 study
 arms as described below:

 Real TMS Sham TMS Gambling photos \ videos 20 Patients 20 Patients

 Real TMS will be given to the Dorso-lateral prefrontal cortex with the following parameters :

 -  Frequency: 1HZ

 -  Total number of stimulations per session: 600

 -  Motor threshold percentage: 120%

 -  Total duration of treatment session (minutes): 10

 -  Total number of treatment sessions: 15

 Deep TMS coil used in this study will be the H-ADD coil (Please see investigator's brochure).

 Patients will undergo 5 courses per week during 3 weeks.

 Evaluations (Including the Neurocognitive tests) will be performed 24 hours after the 15th
 session and again 1 week after the last session and 1 month after the last session.
Inclusion Criteria:

 -  Pathological gambling according to Diagnostic and Statistical Manual of Mental
 Disorders, Fourth Edition, Text Revision (DSM-IV-TR)

 Exclusion Criteria:

 -  History of a primary major psychiatric or cognitive disorder according to DSM IV apart
 from Pathological gambling.

 -  Current alcohol or other substance abuse or dependence.

 -  Alcohol or other substance abuse or dependence during the last 12 months before
 recruitment.

 -  History of or evidence of significant brain malformation or neoplasm, head injury,
 cerebral vascular events, neurodegenerative disorder affecting the brain or prior
 brain surgery.

 -  Significant neurological co-morbidity.

 -  psychiatric co-morbidity.

 -  psychotropic medications.

 -  Severe somatic co morbidity.

 -  Cardiac pace makers, other electronic implants, intracranial metallic particles.

 -  History of seizures or epileptiform activity.

 -  Pregnancy and lactation.

 -  Patients who cannot communicate reliably with the investigator or who are not likely
 to cope with the requirements of the experiment.

 -  Patients unwilling or unable to give written informed consent.

 -  Patients with a high risk for severe violence or suicidality as assessed during the
 screening interview.

 -  Participation in a clinical trial within the last 30 days before the beginning of this
 clinical trial or similar participation in another clinical trial.