Our Experience Contemporary Care

1. Our Experience Contemporary Care 15 Valley Drive, Suite 304 Greenwich, CT 06831 • 100+ Patients • 19 Currently in TMS Treatment 36 Old Kings Highway South Darien, CT 06820 (203) 321-5063

2. Patient Outcomes N=100 10% 51% **Indicates 81% Response Rate -60 Patients remitted -30 Patients improved -10 Patients had no response

3. Patient Videos 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.

4. Patient Videos 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.

5. Partial Response • 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

6. Relapses • Four patients out of 44 completers relapsed after 1-3 months following completion of treatment. (10% Relapse Rate) • Man in 50s bipolar depression relapsed but achieved remission again after one treatment of TMS. • 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. • Man in 50s with severe MDD and anxiety NOS relapsed with severe MDD and has just begun TMS again. • 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

8. Bipolar Disorder • 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) • 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 18-56 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. 9

10. PTSD • 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

11. 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 12 Moderate effects (p<0.001) for hallucinations Slotema et al., 2010)

13. Patient 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) • 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: • Subjective criteria of treatment (pain relief, quality of life) • 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. 14

15. Cost Cost: $500 for treatment planning and $300-$500 per treatment session Course: Five sessions a week for 4-6 weeks for a total of 24-30 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 80-100% of costs after the 3rd 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