TheraMind Services, Inc. Energizing brains…Healing Minds TM Transcranial Magnetic Stimulation (“TMS”)

Major Depressive Disorder (“MDD”): Circuits and Neurotransmitters Monoamine dysfunction is linked to MDD Malfunctioning circuits lead to specific symptoms Monoamine Neurotransmitters: Serotonin (5-HT); Dopamine (DA); and, Norepinephrine (NE). monoamine neurotransmitter projections concentration pleasure/interests guilt suicidality worthlessness mood sleep appetite psychomotor fatigue (physical) pleasure/interests psychomotor fatigue (mental) mood Regions implicated in MDD are connected to the brainstem via monoaminergic circuits When there is an appropriate amount of monoamine neurotransmitter activity, neuronal activity throughout the brain functions normally.

Chemical Antidepressants improved mood weight gain sexual dysfunction insomnia nausea GI distress Blood pressure changes blurred vision reduced feelings of guilt, suicidality, and worthlessness weight gain insomnia agitation dry mouth fatigue

Neuron Rapidly pulsed magnetic fields from TMS : induce a local electric current in the cortex which depolarizes neurons elicit action potentials cause the release of chemical neurotransmitters Neurons are electrochemical cells that respond to either electrical or chemical stimulation Depolarization leads to action potentials in local neurons and thereby releases neurotransmitters

Depolarization of neurons in the Dorsolateral Prefrontal Cortex causes local neurotransmitter release Depolarization of pyramidal neurons in the DLPFC causes neurotransmitter release in deeper brain neurons Activation of deeper brain neurons then exerts secondary effects on remaining portions of targeted mood circuits Dorsolateral prefrontal cortex Cingulate cortex Kito (2008) J Neuropsychiatry Clin Neurosci These effects are associated with improvements in depressive symptoms TMS Releases Neurotransmitters in the Brain Brain SPECT

TheraMind Patient 101TheraMind Patient 102 ClassificationTotal ScoreLevel of Depression Low 0-10Normal 11-16Mild Mood Disturbance Moderate 17-20Borderline clinical depression 21-30Moderate Depression Significant Over 40 Severe Depression Extreme Depression

Optimization of TMS (‘OPT- TMS’) Study NIMH-funded, independent of industry N=190 patients, 4 premier academic sites Primary outcome measure: % Remission - Active 15% vs. Sham 4% (P = 0.015); Odds Ratio of achieving remission: 4.2 (95%CI, ) Major Findings: 30% of patients achieved remission in open-label extension phase Excellent safety, nearly 90% of patients adherent to acute phase treatment course Conclusion: “Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.” Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD; Martina Pavlicova, Phd; Berry Anderson, PhD, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD; Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD 10

John P. O’Reardon, H. Brent Sovason, Philip G. Janicak, Shirlene Sampson, Keith E. Isenberg, Ziad Nahas, William M. McDonald, David Avery, Paul B. Fitzgerald, Colleen Loo, Mark A. Demitrack, Mark S. George, and Harold A. Sackeim BIOL PSYCHIATRY 2007;62: ©2007 Society of Biological Psychiatry N=301 patients (ATHF 1 thru 4), 23 sites 22.1% reduction in MADRS total score with active NeuroStar TMS vs. 9.1% on sham at 4 weeks (in ATHF = 1 population) Conclusion: “Transcranial Magnetic Stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.” Clinically meaningful effect size = 0.52 (in ATHF = 1 population) In open label extension study, 1 in 2 patients responded, 1 in 3 patients achieved remission at 6 weeks Safety confirmed in 6 month follow- up Major Findings: Demitrack & Thase (2009) Psychopharm Bulletin 11 Randomized Controlled Trials

In a controlled clinical study, 1 in 2 patients suffering from clinical depression improved significantly, and 1 in 3 patients were completely free of depression symptoms after six weeks of treatment. Other TMS providers are reporting 80% of their patients treated have significantly improved in their mood, energy and motivation. 1. Demitrack, MA, Thase ME. “Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data.” Psychopharm Bull, 2009, 42(2): Premier Psych TMS, Walter Duffy, MD. Lincoln, Nebraska.

TheraMind Services TMS Therapy… Specifically targets the brain circuits involved in mood regulation Directly depolarizes cortical neurons and modulates neurotransmitter release in the brain Effects involve both the cortical and deep neural circuits in the brain Accomplishes these effects without unwanted systemic adverse effects Summary

Prospective, naturalistic study confirms prior trial results for both clinician- and patient- reported outcomes in real-world practice settings Some TMS providers are reporting 80% of their patients treated have significant improvement in their mood, energy and motivation. Premier Psych TMS, Walter Duffy, M.D., Lincoln, Nebraska Patient-reported outcomes showed improvements both in quality of life and functional status High level of treatment adherence, >80% of patients completed acute treatment TMS Benefits Patients in Real World Settings

No systemic side effects No adverse effect on cognition Most common adverse event associated with treatment was scalp pain or discomfort - <5% of patients discontinued due to adverse events Rare risk of seizure with TMS in post-market use (0.003% per treatment, <0.1% per patient) - (~100,000 treatments in post-marketing experience to date) Long term safety demonstrated in 6 months follow-up TheraMind TMS Systems: Safety Overview Janicak, et al J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010

Energizing brains...Healing minds.™