Medial and Lateral Prefrontal Cortex Neuromodulation Therapies in Depression: A Continuum Ziad Nahas, MD, MSCR Professor and Vice Chair for Clinical Affairs Department of Psychiatry; University of Minnesota Grant funding: National Institute of Mental Health (NIMH); National Institute of Neurological Disorders (NINDS); National Alliance of Schizophrenia and Depression Research (NARSAD); Hope for Depression Research (HDRF); Neuronetics Inc (TMS); Magstim Inc (TMSfMRI); Cyberonics Inc (VNS); Medtronics (DBS, EpCS) & MECTA (ECT, FEAST), Pfizer, AUBMC Intramural Funds disclosures Medical University of South Carolina 1997-2011 1
American University of Beirut 2011-2017 University of Minnesota 2017 - present Depression: A complex landscape White Noise Simone Decker, 1999 2
Risk (Odds Ratio) How to Study Depression White Noise Simone Decker, 1999 depression is primarily a subjective experience 10 8 Likelihood of recent life stress precipitating depression Risk (OR) of depression onset per month 6 4 2 0 Female subjects only N=2395 0 1 2 3 4 5 6 7-8 9-11 Number of Previous Depressive Episodes don t need a reason to get depressed again Kendler et al Am J Psychiatry 2001 3
Rush, Trivedi et al Am JP 2006 diminishing returns with Rx: STAR*D a gravitational pole 4
Brain Stimulation: The Paradigm Shift o Electroconvulsive therapy (ECT) FDA APPROVED o Magnetic seizure therapy (MST) o Focal electrically-administered seizure therapy (FEAST) o Transcranial Direct Current Stimulation (tdcs) o Transcranial Alternative Current Stimulation (tacs) o Transcranial magnetic stimulation (TMS) FDA APPROVED 2008 o Vagus nerve stimulation (VNS) FDA APPROVED 2005 o Deep brain stimulation (DBS) HDE FDA APPROVED OCD 2009 o Epidural prefrontal cortical stimulation (EpCS) o Responsive Neurostimulation (RNS) brain stimulation tools for depression Technique Convulsive? Site MDE evidence ECT C Cortical + RCT rtms Cortical + RCT MST C Cortical Open Series DBS Subcortical Open Series tdcs Cortical T EpCS Cortical Open Series VNS Cranial Nerve Open Series EPI-fMRI Subcortical? Open Series FEAST C Cortical T Evidence 5
Treatment of Major Depression: Prefrontal Approach Continuum Treatment of Major Depression: A Continuum of Care tdcs Monotherapy TMS Adjunctive Rx Monotherapy DRUGS Polypharmacy FEAST ECT VNS EpCS DBS # Patients with MDD Treatment Resistance Continuum Treatment of Major Depression: A Continuum of Care 6
DBS Manji, Drevets, Charney, Nature Medicine 2001 Mayberg et al 1999 Accessing the network(s) Attending to internal environment Frontal pole (BA10) Higher level mnemonic control operations Control of emotion, memory and motivation Attending to external environment Middle frontal gyrus (BA9/46) Organization, monitoring and verification of information Integration of cognition and emotion to control thought and behavior critical regions in the experience of self P" A" P" A" P" A" P" A" Sawaya et al Int J of Neuropsychopharm, 2015 vmpfc Functional Connectivity in Depression 7
male female Nahas et al Frontiers of Psych 2010 REMT: Depressed show more ventral activation (red) compared to matched controls (blue) MDD versus Controls Chahine et al, 201 in preparation Occipital Alpha Rhythm EEG fmri Something is missing 8
The brain is a Self-Organizing Non-Stationary System Chervyakov et al. 2015 Pathological attractor state Complexity shape the floor upon which the activity takes place 9
in depressed participants in depressed participants in depressed participants in controls in controls in controls in depressed participants in depressed participants in depressed participants Taleb [increase play generates opportunities] Mandell [intermittency] and/or Freeman [intensity] channel EEG was collected te (0.2 mg/kg) led to undergo channel EEG collected from controls. Awake Under Anesthesia Health Controls Diminished complexity with anesthesia Figure 2: Topographical representation of Lyapunov Exponent (top), Akiki et al 2015 Figure 3: Topographical of Lyapunov Exponent Under Anesthesia Health Controls Depressed Diminished complexity with phical representation Exponent depression (top), Figure 3: Topographical representation of Lyapunov Exponent (top), Metric Significant Lyap survive FDR co DISCUSSIO As expected, complexity aft linear dynamics More interest decreased in should be di relationship be Akiki et al 2015 they relate to m Should antidep 10
Hypothesis: Changing the landscape, will increase strange attractors and can treat depression by shortening episode or increasing mental flexibility DBS Manji, Drevets, Charney, Nature Medicine 2001 Mayberg et al 1999 Accessing the network(s) How to get from A to B? R 11
WHERE you stimulate HOW you stimulate, WHEN you stimulate, & WHAT is the underlying functional activity of brain region at time of stimulation.. will determine how far can you reach transynaptically to modulate the network R How to get from A to B? How to get from A to B? WHERE you stimulate R N= 23 unmedicated depressed individuals FSL; random effects whole brain analysis.. All clusters corrected for multiple comparisons with p<0.05 and z>2.3 cluster forming threshold Left PFC TMS fmri in depression 36 12
Herbsman et al Biol Psych 2009 NIMH R01 MH62154 Antidepressant relationship to placement: R 2 =0.294, d.f.=2, F=5.20, p = 0.013 X (beta=-0.022; p=0.019); Y (beta=0.012; p=0.057) TMS optimal targeting Johnson et al Biol Psych 2013 TMS optimal targeting by visual inspection and coil position adjustment Riva Posse et al 2014 DBS optimal targeting 13
Shamaa, et. al., Fig. 4 Shamaa, et. al., Fig. 2 Shamaa, et. al., Fig. 6 P=0.045 DBS to AMN Thalamus (not VLN) leads to neurogenesis in the hippocampus Shamma et al, Brain Stimulatino 2015 Nahas et al 2009 How to get from A to B? HOW you stimulate R Relation of coil orientation and underlying white matter fibers R21- MH065630-01A1 (Herbsman et al, Human Brain Mapping 2009) 14
o Over 75% of the variance of MT is explained by SCD and fiber orientation Cortical Spinal Track: R 2 =0.824, F=20.3, p<0.001) [SCD (p<0.001) & PIC PDD-Y (p=0.008)]. Hand Knob: R 2 =0.767, F=14.3, p<0.001) [SCD (p=0.001) but not HK PPD-Y (p=0.058)]. 2002 The illustration was modified by permission from Ruohonen et al. Relationship between MT, SCD and Orientation of white fiber tracks TMS parameters of stimulation Nahas et al. J. Neuropsych & Clin Neurosciences 2001 Transcranial Magnetic Stimulation SPECT 15
Matrix Increases with HDRS Decreases with Time Increases with Intensity Nahas, 2007 Neuropsychopharmacolgy (Z>2.45) Vagus Nerve Stimulation fmri Right Insula and Middle Prefrontal Cortex relationship to antidepressant response and time P=0.045 Nahas et al 2009 Increase of BDNF in hippocampus after DBS for 7 days 16
WHEN you stimulate, & WHAT is the underlying functional activity of brain region at time of stimulation.. will determine how far can you reach transynaptically to modulate the network R How to get from A to B? Borckardt et al Pain 2011 Left PFC single session rtms in post-operative pain N-back alone Fox et al In preparation TMS alone TMS + N-back Brain Area BA Z score Talairach Coordinates (mm) X Y Z Insula R13 2.8 36.85 15.71 4.51 Postcentral Gyrus L40 3.63-56.22-34.24 53.16 Active state interaction 17
R L LTG > PLB TMS R BA 9 BA 9 L CNTRL Hippo Li et al Neuropsychoparm 2004 Enhanced functional connectivity with Lamotrigine. Role of adjunctive pharmacology? P<0.0001 Nahas et al 2009 24h DBS to infra-limbic w & w/o desipramine HOW you stimulate, WHERE you stimulate, & WHAT is functional activity of underlying activity.. will determine how far can you reach transynaptically to modulate the network And Determine your side effects R How to get from A to B? 18
Bejjani BP, et al. N Engl J Med. 1999;340:1476-1480. DBS at STN (or SN) Causes Acute Depression Won He Lee et al 2012 Separate Benefits / Risks o Electroconvulsive therapy (ECT) o Magnetic seizure therapy (MST) o Focal electrically-administered seizure therapy (FEAST) o Transcranial magnetic stimulation (TMS) o Focal electrically-administered therapy (FEAT) o Transcranial Direct Current Stimulation (tdcs) o Vagus nerve stimulation (VNS) o Deep brain stimulation (DBS) o Responsive Neurostimulation (RNS) o Epidural prefrontal cortical stimulation (EpCS) brain stimulation tools 19
Nahas et al Brain Stimulation 2013 Focally Electrically Administered Seizure Therapy (FEAST) Won He Lee et al 2012 FEAST * " # ) " # ( " # ' " # & " # % " # $ " # " # +, -. /01. # +, -. /01. #%# 23456$# 23456%# 23456&# 23456' # 23456( # 23456) # 23456*# 234567# 234568# 23456$ # 23456$$# 23456$%# NYPI + MUSC = 17 Nahas et al Brain Stimulation 2013 New cohorts MUSC = 30 (remission >50% AUB = 17 (ongoing) Focally Electrically Administered Seizure Therapy (FEAST) 20
Ictal L R A P L R A P Post-Ictal L R A P Chahine et al 2014 Brain Stim 2014 FEAST SPECT ' ' ' FEAST Bilateral ECT Unilateral ECT FEAST 64-channel EEG Interhemispehric coherence arcs with lead values in right hemisphere 21
Decreased right frontal drive with reversed electrodes placement o Electroconvulsive therapy (ECT) o Magnetic seizure therapy (MST) o Focal electrically-administered seizure therapy (FEAST) o Transcranial magnetic stimulation (TMS) o Focal electrically-administered therapy (FEAT) o Transcranial Direct Current Stimulation (tdcs) o Vagus nerve stimulation (VNS) o Deep brain stimulation (DBS) o Responsive Neurostimulation (RNS) o Epidural prefrontal cortical stimulation (EpCS) brain stimulation tools Bilateral Epidural Prefrontal Cortical Stimulation for TRD 22
January 1-15, 1976 June 1-15, 1977 November 1-15, 1978 April 1-15, 1980 September 1-15, 1981 February 1-15, 1983 July 1-15, 1984 December 1-15, 1985 May 1-15, 1987 October 1-15, 1988 March 1-15, 1990 August 1-15, 1991 January 1-15, 1993 June 1-15, 1994 November 1-15, 1995 April 1-15, 1997 September 1-15, 1998 February 1-15, 2000 July 1-15, 2001 December 1-15, 2002 May 1-15, 2004 October 1-15, 2005 March 1-15, 2007 cognition, executive control and integration of emotion: 2 complimentary networks NARSAD+Medtronic+GCRC+Neurosurgery+Anesthesia+CAIR+BSL 50 40 30 20 10 0-10 -20-30 -40-50 BEGINS MOOD STABILIZERS? NIMH Mood Chart: 30-year span 23
Mood Stabilizers VNS 1996 2001 2008 Antidepressants In the last 12 years Nahas et al 2010 Real-time identification of target direct connections to amygdala and subgenual cingulate 24
intra-operative testing These subjective changes with parametric modulation become more subtle over time negative neutral Hajcak et al 2011 emotional appraisal BA 46 stimulation down-regulates LPP 25
medial stimulation (BA 10) affects mentalizing 10Hz 100Hz Intermittency random transitivity paradigm Time Pre-operative baseline Week of EpCS activation 2 weeks post EpCS activation 4 months 7 months 5 years Hamilton depression scores Subject Subject Subject 1 2 3 23 33 33 22 32 38 14 36 38 2 4 7 33 3 1 Subject 4 29 29 24 23 19 38 29 30 27 Subject 5 24 28 14 10 9 8 Nahas et al 2010 Williams et al 2016 objective improvement over time 26
Rigidity Score (Nmm) Time May 1-15, 1976 September 16-30, 1976 February 1-15, 1977 June 16-30, 1977 November 1-15, 1977 March 16-31, 1978 August 1-15, 1978 December 16-31, 1978 May 1-15, 1979 September 16-30, 1979 February 1-15, 1980 June 16-30, 1980 November 1-15, 1980 March 16-31, 1981 August 1-15, 1981 December 16-31, 1981 May 1-15, 1982 September 16-30, 1982 February 1-15, 1983 June 16-30, 1983 November 1-15, 1983 March 16-31, 1984 August 1-15, 1984 December 16-31, 1984 May 1-15, 1985 September 16-30, 1985 February 1-15, 1986 June 16-30, 1986 November 1-15, 1986 March 16-31, 1987 August 1-15, 1987 December 16-31, 1987 May 1-15, 1988 September 16-30, 1988 February 1-15, 1989 June 16-30, 1989 November 1-15, 1989 March 16-31, 1990 August 1-15, 1990 December 16-31, 1990 May 1-15, 1991 September 16-30, 1991 February 1-15, 1992 June 16-30, 1992 November 1-15, 1992 March 16-31, 1993 August 1-15, 1993 December 16-31, 1993 May 1-15, 1994 September 16-30, 1994 February 1-15, 1995 June 16-30, 1995 November 1-15, 1995 March 16-31, 1996 August 1-15, 1996 December 16-31, 1996 May 1-15, 1997 September 16-30, 1997 February 1-15, 1998 June 16-30, 1998 November 1-15, 1998 March 16-31, 1999 August 1-15, 1999 December 16-31, 1999 May 1-15, 2000 September 16-30, 2000 February 1-15, 2001 June 16-30, 2001 November 1-15, 2001 March 16-31, 2002 August 1-15, 2002 December 16-31, 2002 May 1-15, 2003 September 16-30, 2003 February 1-15, 2004 June 16-30, 2004 November 1-15, 2004 March 16-31, 2005 August 1-15, 2005 December 16-31, 2005 May 1-15, 2006 September 16-30, 2006 February 1-15, 2007 June 16-30, 2007 November 1-15, 2007 March 16-31, 2008 August 1-15, 2008 December 16-30, 2008 May 1-15, 2009 September 16-21, 2009 February 1-15, 2010 June 16-30, 2010 October 1-15, 2010 50 40 30 NIMH Mood Charting over 30 years 20 10 0-10 -20-30 -40-50 VNS EpCS 5 0 EpCS EpCS -5-10 -15-20 Series1-25 -30-35 Less entropy? -40 January 1- August 1- March 1-15, 2004 15, 2004 15, 2005 October 1-15, 2005 May 1-15, 2006 December 1-15, 2006 July 1-15, 2007 February 1-15, 2008 September 1-15, 2008 April 1-15, 2009 November 1-15, 2009 Change is course of illness? Big clinical picture More emergence? June 1-15, 2010 December 1-15, 2010 0.38 CLR102v2 0.36 Model Mean Model Error Patient Data Model Minimum 0.34 0.32 0.3 0.28 0.26 0.24 0.22 0 20 40 60 80 100 120 140 160 Frequency (Hz) Closed loop feedback Increasing play will generate opportunities 27
Currently looking - Post-doc - Neuromodulation Medicine Fellowship Email me: znahas@umn.edu Thank you Interventional Psychiatry Program Treatment Resistant Depression Program 28