Our Experience Contemporary Care 1 36 Old Kings Highway South Darien, CT (203) Valley Drive, Suite 304 Greenwich, CT Patients 19 Currently in TMS Treatment

Patient Outcomes N= % **Indicates 81% Response Rate 10% -60 Patients remitted -30 Patients improved -10 Patients had no response

Patient Videos 3 Patient is a 24 year old male student at Columbia University treated for severe medication resistant depression. After 6 weeks of high frequency rTMS, his Hamilton score improved from a 36 to a 3 indicating full remission.

Patient Videos 4 Patient is a 25 year old female nursing student with medication resistant depression, anxiety, and suicidal ideation. Her Hamilton score improved from a 46 to a 0. The patient continues to be in remission 4 months after completion.

Partial Response 5 Partial Responders * One patient exhibited recurring GI cancer, however is now off medication and doing well * 18 year old male was found to be abusing THC * 50 year old female was remitted (HAMD- 24 = 4) and then relapsed

Relapses 6 Four patients out of 44 completers relapsed after 1-3 months following completion of treatment. (10% Relapse Rate) 1.Man in 50s bipolar depression relapsed but achieved remission again after one treatment of TMS. 2.Woman in 40s with MDD and GAD relapsed after losing her job and her depression responded to 5 TMS treatments over a week but she remains anxious. 3.Man in 50s with severe MDD and anxiety NOS relapsed with severe MDD and has just begun TMS again. 4.Man in 40s with severe MDD and GAD relapsed mildly and is beginning TMS this week.

7 Evidence based support for other Applications Psychiatric Disorders Generalized Anxiety Disorder Bipolar Depression Post Traumatic Stress Disorder Social Anxiety Disorder Substance Abuse Panic Disorder Schizophrenia Attention Deficit Disorder Bulimia Neurological Disorders Asperger’s Disorder Autism Chronic Pain Migraines Tinnitus Tourette’s Alzheimer’s Disease Parkinson’s Disease Stroke

Bipolar Disorder 8 Nahas Study 23 patients with bipolar depression received rTMS or Placebo left prefrontal cortex low frequency, 10 treatments, ddays a week 2 weeks No difference between groups Active rTMS, compared with sham rTMS, produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment (t = 1.58, p = 0.13) Dolberg Study 20 patients received active or sham treatment Difference seen at week 2; change not significant by end of treatment (week 4) Brief report does not say low/high frequency or site of tms administration Cohen Study 22 patients received 3 weeks (15 sessions) of low frequency rTMS as an adjunctive therapy 16 showed improvements Tamas Study 4 patients on active treatment plan compared to 1 patient on placebo treatment plan Group difference seen at week 6 DLPFC, low frequency Dell’Osso Study 11 patients received low frequency rTMS in an open label study All patients showed reductions on all rating scales George study 16 manic patients greater efficacy of right sided TMS not replicated I follow-up study Conclusion: High frequency TMS maybe effective for Bipolar Depression while low frequency rTMS is somewhat effective as a mood stabilizer. Our Experience: 8/10 patients with Bipolar II Depression responded rapidly to TMS. Two pts had hypomanic episodes but responded to mood stabilizer, 1 relapsed (due to THC abuse).

9 General Anxiety Disorder (GAD) 9 Brystritsky et al. (2008): Found that fMRI-guided low-frequency rTMS (90% MT over frontal cortex) in 10 GAD patients produced significant decreases in anxiety measures. Methods: Patients were between the ages of years. Measures used: Hamilton Rating Scale for Anxiety (HAM-A) & the Clinical Global Impressions- Improvement of Illness (CGI-I) scale. Results: rTMS was associated with significant decreases in HAM-A scores (t = 6.044, p =.001) indicative of clinical improvement in symptoms. At endpoint, 60% of the participants who completed the study showed a reduction of 50% or more on the HAM-A and a CGI-I score of 1 or 2 ("very much improved" or "much improved," respectively). This study suggests that fMRI-guided rTMS treatment may be a beneficial technique for the treatment of anxiety disorders. Conclusion: Slow TMS to the right DLPFC has significant potential in treatment refractory patients Our experience: 12/14 patients with MDD and comorbid GAD showed responded to slow right sided TMS (and fast left for MDD) 3 patients relapsed but one improved after 4 follow up sessions.

PTSD 10 In a study which consisted of presenting pictures of faces depicting various emotional states, patients with PTSD showed significant deficits in mPFC activity as compared to normal controls. Neuroimaging studies have revealed abnormalities in the prefrontal cortex of patients with PTSD. Additionally, patients with PTSD showed significant deficits in mPFC activity as compared to normal controls. Grisaru Pilot Study (1998) 10 patients with PTSD received bilateral low-frequency (0.3Hz) rTMS therapy on the motor cortex. Transient improvements were seen. Rosenberg Study (2002) Frontal cortical rTMS therapy was used as an adjunctive therapy in patients with PTSD and MDD. Significant improvements in mood, anxiety and sleep symptoms but not in core PTSD symptoms Cohen Study (2004) 24 patients participated in a double-blind, placebo-controlled treatment study where they received low-frequency (1Hz), high-frequency (10Hz) or sham rTMS treatment over the right PFC for 2 weeks (10 sessions). Core symptoms of PTSD significantly improved. Most improvement was seen when rTMS was administered to the right prefrontal cortex at high frequency. Osuch Study (2009) Patients participated in a double-blind, sham-controlled cross over study where they received low frequency rTMS over the left prefrontal cortex in combination with exposure therapy. Patients who received active rTMS treatment showed greater improvement. Conclusion: rTMS both as monotherapy and as adjunctive therapy shows significant promise in the treatment of PTSD Our experience: 4/6 patients with PTSD did better with our customized TMS protocol than any other treatment

Substance Abuse Increased dopamine levels as a result of TMS therapy would reduce nicotine/drug cravings and consumption Seven studies (152 patients) Treated for nicotine/cocaine/alcohol addiction High Frequency rTMS to the left DLPFC Reduced craving and consumption of addictive substance-potentially by increasing dopamine produced in mesolimbic dopaminergic system Conclusion: TMS has shown efficacy for alcoholism, nicotine abuse, cocaine abuse. Our experience: 5/5 responded well to our customized a TMS protocol in patients with refractory polysubstance abuse for several weeks Hymen et al., 2006; Vandershuren and Kalivas et al., 2000; Wolf et al., 2004; Keck et al., 2002; Kano et al., 2004.

12 Schizophrenia Slotema et al., 2010 Moderate effects (p<0.001) for hallucinations Slotema et al., 2010)

Patient 13 This is a 52 year old women who was diagnosed with Schizoaffective Disorder. She experienced daily auditory hallucinations (AH) telling her to kill herself and other people, which ended up in a number of hospitalizations. Just 6 weeks after bilateral rTMS the patient's Hamilton score improved from a 24 to a 0 and her AH completely disappeared. Due to this result, and a re-analysis of the patient's symptoms, the patient was re-diagnosed with Severe Depression with psychotic features. She continues to be in remission to date, five months after she has completed TMS.

14 Chronic Pain (Fibromyalgia) 14 Pridmore et al (2005): In studies of TMS treatments for chronic pain, there is some evidence that temporary relief can be achieved in a proportion of sufferers. André-Obadia et al (2008): In a double-blind, randomized, cross-over study, evaluated the pain-relieving effects of high-rate, postero-anterio rTMS on neuropathic pain (n = 28). TMS decreased pain scores significantly more than placebo. TMS also outmatched placebo in a score combining: 1.Subjective criteria of treatment (pain relief, quality of life) 2.Objective criteria of treatment (rescue drug intake) Analgesic effects of postero-anterior rTMS lasted for approximately 1 week. Pain-relieving effects were observed exclusively on global scores reflecting the most distressing type of pain in each patient. Conclusions: TMS has potential in treating chronic pain by activating descending pathways that bare effective in suppressing proximal pain i.e. back pain, fibromylagia etc. Our experience: 4/4 patients responded rapidly to the same TMS protocol that is used for MDD.

Cost 15 Cost: $500 for treatment planning and $300-$500 per treatment session Course: Five sessions a week for 4-6 weeks for a total of sessions Total cost: $8,000 - $14,000 Insurance: Only covers treatment refractory unipolar depression. Almost never provides preapproval Most commercial plans that are not self-pay reimburse % of costs after the 3 rd appeal, which occurs 2-6 months after TMS completion Medicare may cover about 50%^ of costs about 50% of the time. Brunoni et al 2009

16 Conclusions TMS is effective in treating: Depression that is refractory to medications Depression in patients intolerant to medications Besides depression we have effectively treated: Anxiety Disorders (PTSD, GAD, Panic) Substance abuse Chronic pain (fibromyalgia) Eating disorders Parkinson’s Disorder TMS virtually no side effects and appears to be safe even in adolescents, pregnant women, and the elderly