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Transcranial direct current stimulation


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Trans Cranial Direct Current Stimulation

Published in: Health & Medicine
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Transcranial direct current stimulation

  2. 2. DISCLOSURES None
  3. 3. OUTLINE What CL Psychiatrists Need to Know Complications of tDCS Efficacy of tDCS Indications/Contraindications for tDCS Mechanism of Action of tDCS What is tDCS? Brief History of Electrical Stimulation
  5. 5. EARLY BRAIN STIMULATION Ancient civilizations applied the electric torpedo fish to the head to treat illness (Kellaway 1946) Kellaway P. The part played by electric fish in the early history of bioelectricity and electrotherapy. Bull Hist Med 1946; 20(2): 112-137.
  6. 6. 18-19TH CENTURIES Giovanni Aldini in 1803 used voltaic devices to stimulate patients and corpses (Aldini 1803) Rudolph Arndt in 1870 applied electrotherapy to the scalp to treat mental illness (Steinberg 2013) Stagg CJ, Nitsche MA. Physiological basis of tDCS. Neuroscientist 2012. Steinberg H. A pioneer work on electric brain stimulation in psychotic patients: Rudolph Gottfried Arndt and his 1870s studies. Brain Stim 2013; 6: 477-481.
  7. 7. 20TH CENTURY “Electrosleep Therapy” (1950s) • Russian experiments “Brain Polarization” (1970s) • British, US experiments “tDCS” (2000) • Nitsche, Paulus Clark VP, Parasuraman R. Neuroenhancement: enhancing brain and mind in health and disease. Neuroimage 2014; 85: 889-894.
  9. 9. WHAT IS TDCS? A form of brain stimulation: • Non-invasive • Non-focal • Non-convulsive Delivers low currents of electricity • Patient is conscious • Minimal discomfort Modulates spontaneous neuronal activity • Neurons become more or less likely to fire • Does not trigger action potentials • More charge over time ~ longer lasting effect
  10. 10. DIRECT CURRENT The electrode placement and direction of current flow has specific effects (George 2010) Anodal current = depolarizing Cathodal current = hyperpolarizing George MS, Aston-Jones G. Noninvasive techniques for probing neurocircuitry and treating illness: VNS, TMS, and tDCS. Neuropsychopharmacology 2010; 35: 301-316. Saote C, Turi Z, Paulus W, Antal A. Combining functional magnetic resonance imaging with tDCS. Front Hum Neurosci 2013; 7 (435): 1-7.
  11. 11. TDCS APPLICATION Clark VP, personal communication, 2014
  12. 12. CONSTANT CURRENT tDCS is not pulsatile, so there is no pulsewidth variable. Voltage varies to maintain current constant (V = IR) Current strength is varied depending on desired intensity of stimulation. Current duration is varied depending on desired total charge. Nitsche MA et al. TDCS: state of the art 2008. Brain Stimulation 2008; 1: 206-223.
  14. 14. ANIMAL STUDIES Applied cortical direct currents resulted in long-lasting changes in firing rates (Bindman 1963) Changes in firing rates dependent on protein synthesis, calcium handling, cAMP accumulation (Gartside 1968, Nitsche 2008) Bindman LJ, LIppold OCJ, Redfearn JWT. Long-lasting changes in the level of the electrical activity of the cerebral cortex produced by polarizing currents. Nature 1962; 4854: 584- 585. Gartside IB. Mechanisms of sustained increases of firing rate of neurones in the rat cerebral cortex after polarization: role of protein synthesis. Nature 1968; 220: 383-384.
  15. 15. POLARIZING CURRENT Electric fields penetrate the scalp and cause polarization of neurons, increasing or decreasing their excitability (de Berker 2013) de Berker AO, Bikson M, Bestmann S. Prediciting the behavioral impact of transcranial direct current stimulation: issues and limitations. Front Hum Neurosci 2013; 7(613): 1-6. Miranda PC, Lomarev M, Hallett M. Modeling the current distribution during tDCS. Clin Neurophys 2006; 117: 1623-1629. de. Pazzarini M, Fiocchi S, Rossi E, Paglialonga A, Ravazzani P. tDCS: estimation of the electric field and of the current density in an anatomical human head model. IEEE transactions on biomedical engineering 2011; 58(6): 1773- 1780.
  16. 16. TDCS MODULATES CORTICAL EXCITABILITY Priori A. Brain polarization in humans: a reappraisal of an old tool for prolonged non- invasive modulation of brain excitability. Clin Neurophys 2003; 114: 589-595. Wassermann EM, Grafman J. Recharging cognition with DC brain polarization. Trends Cog Sci 2005; 9(11): 503-505. Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 2000; 527(3): 633-639. Motor evoked potentials are facilitated by anodal tDCS and inhibited by cathodal (Nitsche 2000)
  17. 17. TDCS INDUCES LTP-LIKE NEUROPLASTICITY LTP is a persistent increase in neuronal transmission after synchronous stimulation. tDCS-induced changes in neuronal firing are dependent on NMDA, Ca++, and BDNF like LTP Monte-Silva K, Kuo MF, Hessenthaler S, Fresnoza S, Liebetanz D, Paulus W, Nitsche MA. Induction of late LTP-like plasticity in the human motor cortex by repeated non- invasive brain stimulation. Brain Stim 2013; 6: 424-432. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji YY, Cohen LG, Lu B. Direct current stimulation promotes BDNF- dependent synaptic plasticity: potential implications for motor learning. Neuron 2010; 66: 198-204.
  18. 18. TDCS FOCAL EFFECTS N-acetyl aspartate increased focally under the electrode (Clark 2011) Cerebral blood flow increases under the electrode (Lang 2005) Clark VP, Coffman BA, Trumbo MC, Gasparovic C. TDCS produces localized and specific alterations in neurochemistry: a 1H MRS study. Neurosci Lett 2011500: 67-71. Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN, Frackowiak RS. How does TDCS of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci 2005; 22: 495-504. Jang SH, Ahn SH, Byun WM, Kim CS, Lee MY, Kwon YH. The effect of TDCS on the cortical activation by motor task in the human brain: an fMRI study. Neurosci Lett 2009; 460: 117-120.
  19. 19. TDCS NONFOCAL tDCS effects are diffuse and spread over multiple regions and networks. (Lang 2005) Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN, Frackowiak RS. How does tDCS of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci 2005; 22: 495-504. Pena-Gomez C, Sala-Lonch R, Junque C, Clemente IC, Vidal D, Bargallo N, Falcon C, Valls- Sole J, Pascual-Leone A, Bartres-Faz D. Modulation of large-scale brain networks by tdcs evidenced by resting-state fMRI. Brain Stim 2012; 5: 52-63.
  21. 21. DC STIMULATORS Not FDA Approved for use in Psychiatric Disorders • Certain devices are FDA approved for iontophoresis Studied in: • Stroke rehabilitation • Memory/Alzheimers • Depression/Emotion • Learning/Perception • Pain/Fibromyalgia • Addiction/Impulsivity • Tinnitus • Epilepsy Exclusions from studies: • Metal implant • Pregnancy • Seizure disorder • Ongoing substance use
  23. 23. TDCS FOR STROKE Hummel F, Celnick P, Giraux P, Floel A, Wu WH, Gerloff C, Cohen LG. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 2005; 128: 490-499.Adeyemo BO, Simis M, Macea DD, Fregni F. Systematic review of parameters of stimulation, clinical trial design characteristics, and motor coutcomes in non- invasive brain stimulation in stroke. Front Psychiatry 2012; 3 (88): 1-27.
  24. 24. DEPRESSION 120 mod-severe nonpsychotic MDD pts received sertraline 50 mg daily (60) or placebo (60) (Brunoni 2013) 60: 12 tx tDCS: 2 mA DLPFC (L anodal/R cathodal) x 30min 60: sham tDCS Brunoni AR, Valiengo L, Baccaro A, Tamires AZ, Oliveira JF, Goulart A, Boggio PS, Lotufo PA, Bensenor IM, Fregni F. The sertraline versus electrical current therapy for treating depression study clinical study. JAMA Psychiatry 2013; 70(4): 383-391.
  25. 25. LEARNING fMRI of detection task in 96 pts revealed R Frontal and Parietal foci of activation (Clark 2012) Anodal 2 mA tDCS x 30 min to these areas led to faster learning Clark VP, Coffman BA, Mayer AR, Weisend MP, Lane TDR, Calhoun VD, Raybourn EM, Garcia C, Wasserman EM. tDCS guided using fMRI significantly accelerates learning to identify concealed objects. Neuroimage 2012; 59: 117-128.
  26. 26. LEARNING Clark VP, Coffman BA, Mayer AR, Weisend MP, Lane TDR, Calhoun VD, Raybourn EM, Garcia C, Wasserman EM. tDCS guided using fMRI significantly accelerates learning to identify concealed objects. Neuroimage 2012; 59: 117-128.
  27. 27. TDCS FOR MMTBI US: 1.7 million TBIs annually NM 2nd among 34 states in TBI deaths Suicide by firearm (38%) Motor vehicle accident (22%) Falls (17%) Homicide (12%) NM Brain Injury Advisory Council, Traumatic Brain Injury in the United States, Yeo RA, personal correspondence
  29. 29. SIDE EFFECTS Hypomania/Insomnia Drowsiness/Fatigue Skin Itching/Burning Nausea/Headache NO seizures NO autonomic/CV effects NO lasting cognitive changes **Both utilized Neuroconn devices Palm U, Keeser D, Schiller C, Fintescu Z, Reisinger E, Nitsche M, Padberg F. Skin lesions after treatment with tDCS. Brain Stim 2008; 1: 386-387. Frank Em Wilfurth S, Landgrebe M, Eichhammer P, Hajak G, Langguth B. Anodal skin lesions after treatment with tDCS. Brain Stim 2010; 3: 58-59. Arul-Anandam AP, Loo C, Mitchell P. Induction of hypomanic episode with tDCS. J ECT 2010; 26)7): 68-69. Vandermeeren Y, Jamart J, Ossemann M. Effect of tDCS with an extracephalic reference electrode on cardio- respiratory and autonomic functions. BMC Neurosci 2010; 11: 38. Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of TDCS concerning healthy subjects and patients. Brain Res Bull 2007; 72: 208-214.
  31. 31. NEED TO KNOW TDCS is: • Extremely safe • Induces neuroplasticity and modulates neuronal activity both focally and nonfocally • Not FDA approved for use on the brain • Potentially synergistic with medications • Likely to cause mild side effects • Most likely to affect your current practice—when video gamer comes into the ED with scalp burns from DIY TDCS • A potential therapy for many psychosomatic medicine disorders stimulation/
  32. 32. THANKS UNM Center for Brain Recovery and Repair Bill Shuttleworth Ronald Yeo Richard Campbell UNM Psychology Clinical Neuroscience Center Vince Clark Brian Coffman UNM Department of Psychiatry Mauricio Tohen Chris Abbott Alya Reeve Brant Hager MIND Research Network Andrew Mayer Stefan Klimaj
  33. 33. Murat Altinay, MD | Fellow in Mood Disorders and Neurosciences Cleveland Clinic Foundation Department of Psychiatry
  34. 34.  None.
  35. 35. Introduction VNS 1.0.1 (Vagus nerve anatomy and VNS basics) History Research Studies Clinical Use Safety/ Compli ance
  36. 36.  Major depressive disorder (MDD):  Common  Recurrent  Chronic  Leading contributor to disability  Current treatments fall short (~20 to 40% failing to respond to AD trials)  Psychotropic medications,  Psychotherapy,  ECT  STAR-D highlighted these limitations.  Failure of depression to respond to currently available treatment options-- major treatment challenge.
  37. 37.  VNS is an implantable neuromodulation device which has established efficacy in pharmaco-resistant epilepsy.  July 2005:  FDA approval as an adjunctive treatment of severe, recurrent unipolar and bipolar depression.  Other disorders (under investigation):  Anxiety,  Migraines  Alzheimer’s disease.
  38. 38. Innervation - larynx, - esophagus, - trachea, - heart, - aorta, and GI The right vagus: HR regulation  SA node (pace maker of the heart) The left vagus: AV node (less- no influence in HR)
  39. 39. NTS (bilaterally) Left Vagus nerve PAG Limbic regions Locus Cereleus Raphe Nuclei Cortex PBNhypothalamu s, thalamus, amygdala, and nucleus of the stria terminalis. Thalamus  insular, orbitofrontal, and prefrontal cortices, NE, 5HT Projections
  40. 40.  The VNS device:  generator  electrodes  low-frequency, chronic intermittent-pulsed electrical signals  left cervical vagus nerve.  Separate incision in the neck  stimulating electrodes wrapped around the left cervical vagus nerve.  Subcuteanous tunelling procedure  Electrodes are connected to the implanted generator.
  41. 41.  VNS was approved for pharmaco-resistant epilepsy in Europe in 1994 and in the US in 1997.  Anecdotal clinical observations of mood improvement in epilepsy patients after VNS implantation.  Role for VNS therapy in depression?? July 2005: FDA approval as an adjunctive treatment of severe, recurrent unipolar and bipolar depression.
  42. 42.  Epilepsy Studies  Harden et al. (2000)  A pilot prospective study  VNS effects on mood in epilepsy patients  VNS device vs. anti-epileptic drugs  Significant mood improvement in the VNS group at 3 months. (HAMD, HAMA, BDI, CDRS)  Elger et al. (2000)  11 epilepsy pts w/ mild MDD.  Baseline  9 /11 subjects had significant depressive symptoms  Only 2/10 at 6-months follow up.  Only 2/11 subjects in the trial could be classified as responders in terms of seizure reduction over the 6-months  These findings suggested that VNS has a separate and distinct effect on depressive symptoms not related to outcomes on seizures
  43. 43.  Open label Studies • 30 pts with chronic uni/bipolar depression who had failed ≥ 2 AD trials. • Implantation 2 week recovery (no stim) 10 weeks of stim + existing fixed med. • Results: Response rate of 40% and a remission rate of 17%. Rush et al (2000) • 30 TRD unipolar and bipolar patients for a total sample size of 60. • 12 weeks (2 week post-surgery w/o stim 10 weeks of VNS) to determine the acute response to VNS. • Response rate: 30% (HAM-D-28). 37% CGI-I and 34% on the MADRS. • Remission (HAM-D score <10) : 15%. O’Reardon et al
  44. 44.  Randomized Controlled studies  Rush et al. (2005)  A negative trial.  Multi-center trial of VNS (n=225)  Active vs. sham VNS  10-weeks of active stimulation the response rate on HAM-D24 was 15% (n=112) and the sham/placebo response rate was 10% (n=110), which did not differ from each other (p=0.238).  BUT– well tolerated + better response rate on self report measure IDS-SR-30.
  45. 45.  The first pilot study (Rush et al. 2000) followed patients over 12 months:  Response rates increase over time (HAMD24 response rate was 27.2% ; remission rate (HRSD(24) < or = 9) 15.8% )  10-week trials of VNS might underestimate its potential to treat TRD patients.  Marangell et al. (2002)  Additional 9-months of VNS (1 year total)  Response rate slightly increased from 40  46%  Remission rate increased 17% (3 months) to 29% at 1 year
  46. 46. 2 years Results remained similar: - response rate of 42% and a - remission rate of 22% - Overall response rate : 40-45% long term - 81% of patients who elect to keep their device active at 2-years. Additional 25% of patients (separate from the 42%), improvement in symptoms of 25 -49%, which is short of responder status meaningful in the context of severe, unremitting MDD?
  47. 47. 10 weeks - Response rate 15% - Remission rate 10% 12 months - Response rate: HAMD- 27% , CGI-I- 37% - Remission rate 15% 24 months - Response rate 42% - Remission rate 22% - Additional 25% of patients with inadequate (but meaningful) response.
  48. 48. Manufacturer FDA • One-year outcomes from its pivotal trial. One-year outcome: • VNS+ TAU (n=205)vs TAU (n=124) compared. Adjunctive VNS • Better outcomes compared to TAU only. • HAM-D the response rate with VNS was 30% vs. 13% with TAU • CGI-I the margin of superiority was greater, 37% versus 12% response rate. • IDS-SR-30, the response rate with VNS was 22% versus 12% for TAU Longer term, adjunctive VNS: • Increased response rate in TRD by 2-3 fold, • Fairly low absolute response rates, • Indicates impressive adjunctive benefit from VNS in this severely ill patient group
  49. 49.  The FDA approved the VNS implant for patients with chronic or recurrent depression, (uni/bipolar) with a history of failure of their depression to respond to at least 4 antidepressant interventions.  ECT failure is not a requirement to be eligible for VNS
  50. 50.  Indication  TRD patients with bipolar and unipolar depressive episodes as a long term adjunctive treatment option  Failure to respond to ECT is not a prerequisite for VNS eligibility,  It may be appropriate to use ECT as an acute treatment for severe depression to be followed by VNS as a long term maintenance intervention.
  51. 51. Relative Contraindications  Not approved for psychotic MDD or the depressed phase of SAD.  Paranoid ideation  Unstable axis II disorders  Borderline personality disorder or other disorders,  Not studied in pregnancy-  non-systemic treatment  potential effects on fetus should be limited  Limitations in post-surgery MRI  MRIs spine/joints prohibited.  MRI brain possible w/ special send-receive coils. (otherwise a CT scan would need to substitute for an MRI)  Dissatisfied?  Could be switched off (the implant left in place)  Pulse generator could be explanted.  The electrode is left in situ-- adhesions around the vagus nerve itself might increase risk of injury during removal .  Precautions with MRI remain in place indefinitely Special Precautions
  52. 52.  Dosing  4 principal settings 1. current charge (mA), 2. pulse width (microseconds), 3. frequency (Hz), 4. duty cycle (on time relative to off time - in seconds and expressed as a percentage).  Start at 0.25 mA,  increase gradually in 0.25 mA increments until a comfortable tolerance level is reached.  Maximum tolerable level has been exceeded  pain/ bouts of coughing.  The stimulating device is then reset to the highest ‘comfortable’ setting.
  53. 53. Surgery post 2 wks •0.25 mA titrations in current so that a target dose of 1.0 mA might be achieved at the end of the first month. Weekly for 1 month Q 2weeks for 1 month Month 3 •Monthly visits if effective •amplitude 1.0-1.5 mA range and no improvement  increase the duty cycle at the juncture by adjusting the on-off schedule. Significant proportion of responders to VNS only emerge in the second 6 months of stimulation and a full VNS trial may require at least 12 months
  54. 54. safety Surgery SE to Stimulation Ψ Adverse events
  55. 55. (Hypo)Mania Depression and Suicidality SI/SA Cognitive SE
  56. 56.  VNS device can remain functioning for up to 8 years.  Patients are unable to adjust the treatment settings independently.  In the one year pivotal study (Rush et al. 2005)  Continuation rate at 1 year was 90%.  3% discontinued secondary to adverse events  implant related infection,  hoarseness,  lightheadedness,  postoperative pain  chest and arm pain.  7% -- lack of efficacy or other reasons.  At 2 years (Nahas et al 2005)  >80% of patients had device in place and functioning  Most subjects electing to discontinue VNS because of lack of efficacy rather than side effects.
  57. 57.  Safe and effective treatment in TRD  FDA approved.  Better results when used long term (12 weeks-1 year)  Better results when combined with meds. (can be combined with any meds including MAOIs).  Safe with ECT but it needs to be turned off.  No cognitive side effects.  Can be used both for unipolar and bipolar depression  Dosing can be done in an outpatient setting.  Cautions  Surgical risks  Current and future MRI safety  Side effects for-treatment-resistant-depression-proves-effective-for-some-patients.html Vagal Nerve Stimulation for Seizures. Textbook of Stereotactic and Functional Neurosurgery. pp 2801-2822
  58. 58.  Safe and efficient neuromodulation modality in TRD.  Over the longer term at one and at two years the results observed with VNS appear reasonable in terms of realistic expectations for this population.  A controlled post marketing study as suggested by the FDA is being conducted by the device manufacturer.  Significant promise to treat TRD as a long term treatment.
  59. 59. 1.Murray C, Lopez A. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries and Risk Factors in 1990 and Projected to 2020. Cambridge, Massachusetts: Harcourt University Press, 1996. 2.Sackeim HA. The definition and meaning of treatment-resistant depression. Journal of Clinical Psychiatry 2001; 16:10-7. 3.O'Reardon JP, Cristancho P, Peshek A. Vagus nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond. Psychiatry 2006; vol 3 -issue 5 - 54-63 4.Groves DA, Brown VJ. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neuroscience & Biobehavioral Reviews 2005; 29:493-500. 5.Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Research 2000; 42:203-10. 6.Harden CL, Pulver MC, Ravdin LD, Blagovest N, Halper JP, Labar DR. A pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav 2000:93-99. 7.Rush AJ, George MS, Sackeim HA, et al. Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.[see comment]. Biological Psychiatry 2000; 47:276- 86. 8.Sackeim HA, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology 2001; 25:713-28. 9.Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biological Psychiatry 2005; 58:347- 54. 10.Marangell LB, Rush AJ, George MS, et al. Vagus nerve stimulation (VNS) for major depressive episodes: one year outcomes. Biological Psychiatry 2002; 51:280-7. 11.Neurological Devices Panel of Medical Devices Advisory Committee FDA. Report of 17th Meeting. 2004:1-433. 12.George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biological Psychiatry 2005; 58:364-73. 13.Nahas Z, Marangell LB, Husain MM, et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. Journal of Clinical Psychiatry 2005; 66:1097-104. 14.Maisel M. Medical Device Regulation: An introduction for the practicing physician. Annals of Internal Medicine 2004; 146:296-302. 15.Nemeroff CB, Mayberg HS, Krahl SE, et al. VNS Therapy in Treatment-Resistant Depression: Clinical Evidence and Putative Neurobiological Mechanisms. Neuropsychopharmacology (2006) 31, 1345-1355 16.Lenox RH, Frazer A. Mechanism of action of antidepressants and mood stabilizers (chapter 79). In: Davis KL, Charney D, Coyle JT, Nemeroftt C (eds). Neuropsychopharmacology: The Fifth Generation of Progress. lippincott Williams & Wilkins: Philadelphia. 2002: 1139-1163 17.George MS, Nahas Z, Bohning DE, et al. Mechanism of action of VNS. clin Neurosci Res 2004 4:71-79 18.Matthews K, Eljamel MS. Vagus nerve stimulation and refractory depression. Br J Psychiatr 2003 183: 181-183 19.Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety. Journal of Clinical Neurophysiology 2001; 18:415-8. 20.Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biological Psychiatry 2005; 58:355- 63. 21.Rudolph R. Food and Drug Administration Neurological Devices Panel Web site. Executive summary and discussion of the vagus nerve stimulation (VNS) therapy depression indication clinical data (updated to include information from deficiency letter response). 4047b1_01_Clinical%20Executive%20Summary-FINAL.pdf., 2005. 22.Sackeim HA, Keilp JG, Rush AJ, et al. The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsychiatry, Neuropsychology, & Behavioral Neurology 2001; 14:53-62 23.Cristancho P, Cristancho MA, Baltuch GH, Thase ME, O’Reardon JP. Effectiveness and Safety of Vagus Nerve stimulation for severe treatment resistant major depression in clinical practice after FDA approval: Outcomes at one year. J Clin Psychiatry 2011;72 (10):1376- 1382.
  60. 60.