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Rapid mechanisms of DBS in OCD

de Koning, P.P.

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Citation for published version (APA):de Koning, P. P. (2016). Rapid mechanisms of DBS in OCD.

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Pelle de Koning

RapidMechanisms of

DBS in OCD

Pelle de KoningR

apid Mechanism

s of DBS in OC

D

Pelle de Koning

RapidMechanisms of

DBS in OCD

Uitnodiging voor de openbare verdediging van mijn proefschrift

Vrijdag 21 oktober 2016van 13:00 – 14:30 in

De Lutherse KerkSingel 411

1012 WN Amsterdam

Na afloop van de promotie bent u uitgenodigd voor de receptie ter plaatse

vanaf 21:00

Feest | Club de LoodsPapaverweg 18B

1032 KJ Amsterdam

ParanimfenEelco de Koning

Nellieke de Koning

Pelle de KoningDerde oosterparkstraat 147G

1092CW [email protected]

RapidMechanisms of

DBS in OCD

The studies in this thesis were performed at the Departments of Psychiatry, Radiology and Nuclear medicine, Experimental Immunology and Endocrinology and Metabolism, in collaboration with the Department of Neurosurgery. De Koning, Pelle

Rapid Mechanisms of DBS in OCD Research in this thesis was supported in part by grant 916.66.095 from the Netherlands Organization for Scientific Research ZON-MW VENI program. ISBN 978-94-6295-497-7Cover and Lay-out design by The Fat Moose | www.thefatmoose.nlPrinting by Uitgeverij Boxpress | www.proefschriftmaken.nl Copyright: Pelle de Koning, 2016. All rights reserved. No part of this publication may be reproduced in any form by any electronic or mechanical means without the prior written permission of the author.

Rapid Mechanisms of DBS in OCD

ACADEMISCH PROEFSCHRIFTter verkrijging van de graad van doctor

aan de Universiteit van Amsterdamop gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maexten overstaan van een door het College voor

Promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteitop vrijdag 21 oktober 2016, te 13:00 uur

door Pelle Paul de Koninggeboren te Huizen

Promotiecommissie:

PromotorProf. dr. D.A.J.P. Denys

Copromotoresdr. J.G. Storosum dr. M. Figee

Overige ledenProf. dr. J.M. Menchón Prof. dr. J.A. Swinkels Prof. dr. E. Fliers Prof. dr. T. van der Poll Prof. dr. H.A. Drexhage dr. C.H. Vinckers

Faculteit der Geneeskunde

Table of contents

Chapter 2. Current status of deep brain stimulation: a clinical review of different targetsCurrent Psychiatry Reports 2011

Chapter 3. Deep brain stimulation for obsessive-compulsive disorder is associated with cortisol changesPsychoneuroendocrinology 2013

Chapter 4. Rapid effects of deep brain stimulation reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorderTranslational psychiatry 2015

Chapter 1. General introduction 09

25

51

65

Part I: Efficacy and side effects in deep brain stimulation for obsessive-compulsive disorder

Part II: Neuroendocrine effects of deep brain stimulation for obsessive-compulsive disorder

Part III: Immune effects of deep brain stimulation for obsessive-compulsive disorder

Chapter 6. Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder Biological psychiatry 2014

Chapter 7. Summary, discussion and methodological considerations

Nederlandse samenvatting en conclusies

List of publications

Curriculum Vitae

Dankwoord

Chapter 5. Altered activity of the immune system with deep brain stimulation for obsessive-compulsive disorderSubmitted

83

105

129

157

163

169

173

Part IV: The role of dopamine in deep brain stimulation for obsessive-compulsive disorder

Part V: Discussion

Part VI: Appendix

General introductionChapter 1

Chapter 1. General introduction | 11

GENERAL INTRODUCTIONOCD is a heterogeneous, chronic, and disabling psychiatric disorder, characterized by recurrent intrusive thoughts or images (obsessions), anxiety or distress and repetitive behaviors (compulsions) that are severe, time-consuming and have a major impact on social life, family relationships and the capacity to function at work. The pathophysiology of OCD is characterized by dysfunctional dynamics in widespread brain networks that include the prefrontal and anterior cingulate cortex, striatum and thalamus, with various neurotransmitter systems, i.e. serotonergic, dopaminergic, glutamatergic and potentially also GABAergic systems involved. Specific treatments for OCD have been developed, such as cognitive-behavioral therapy and pharmacotherapy with serotonin reuptake inhibitors. However, even when the best available treatments are applied, approximately 10% of patients remain severely affected and suffer from treatment-refractory OCD (Denys, 2006). For a small proportion of treatment-refractory patients, deep brain stimulation (DBS) may be considered a last resort option. DBS is a neuromodulatory treatment that involves the implantation of electrodes that send electrical impulses to specific locations in the brain, selected according to the type of symptoms to be addressed. It is estimated based on published trials and case studies that more than 250 individuals have received experimental DBS treatment for OCD in five different targets: i) subthalamic nucleus (STN), ii) ventral capsule/ventral striatum (VC/VS), iii) Anterior limb on the internal capsule (ALIC), iv) Inferior Thalamic Peduncle (ITP) and v) Nucleus Accumbens (NAc). Over the past ten years, we have developed an extensive clinical expertise in DBS for OCD following the treatment of >50 DBS for OCD patients showing an optimal response in stimulating the ventral part of the ALIC (vALIC) (Denys, 2010). Subsequently we continuously leverage our clinical expertise in order to identify and investigate potential underlying working mechanisms of DBS for OCD.The basis of this thesis arose from the recurrent clinical observation that

12 | Rapid Mechanisms of DBS in OCD

DBS for OCD is capable of inducing astonishingly rapid symptom changes. Therefore, the following thesis comprises the investigation of various potential neurobiological working mechanisms underlying the remarkable clinical response of DBS for OCD, reflected by the story of Ms. V.

THE ACUTE AWAKENING OF MS. V. WITH DEEP BRAIN STIMULATION

I’m sitting in an examination room in the academic medical center (AMC) opposite to a trembling and severely anxious middle-aged woman. She has the desperate thought of never getting out of her dreadful and fully encompassing current state of anxiety. I ask Ms. V. how she would score her anxiety on a scale from 0 to 10. Without hesitating she answers 10. Meanwhile her shoulders remain lifted, as of bracing herself from the continuously recurring panic waves that have been overwhelming her for almost a full week now. Do you feel depressed, how’s your self-esteem, do you have hope for the future and what about your obsessive-compulsive symptoms? She answers, “My past and my future are in the dark”. “I feel so insecure, and my OCD-symptoms feel worse than before the surgery”. “To be honest I can’t believe that activation of the stimulation will do its work again”. I sit and look at this shivering woman, who is enduring the effect of DBS discontinuation for one week. The deep brain stimulation (DBS) she had implanted more than one year ago for treatment of her therapy-refractory OCD. Ms. V. was one of the initial responders to DBS. Only now, her continuously worrying that the forthcoming reactivation of the DBS will no longer redeem her from her symptoms is also affecting my own confidence in the DBS. I put the controller on her skin, just below the collarbone, where the battery is implanted. I re-check the parameters settings (voltage 4.5 V, impulse duration 90 μsec, frequency 130 Hz) and press the little digital lightning bolt figure on the screen of the controller that I hold in my hands in order to reactivate the battery. Pressing will reactivate the middle 2 out of 4 contact-points of the DBS electrodes, implanted in the anterior limb of the internal capsule of the right and left hemisphere. Next, I wait and observe…


By Medtronic

Fifteen seconds later Ms. V. looks up, her solid tensed facial expression softens and her shoulders lower. After 30 seconds she starts talking and looks directly at me. She starts laughing, “it works” she says, “it really works”. “My anxiety is gone, I feel solid ground under my feet again”. “I believe in myself and suddenly have faith in the future”. When I look at her, only several minutes after we reactivated the DBS, this severely anxious, introvert and avoidant person has changed into a worriless, optimistic and very talkative woman.

HOW DOES DBS RAPIDLY CHANGE PSYCHIATRIC SYMPTOMS?

Over the past decades, the potential of DBS has been bolstered by the strikingly rapid symptom changes so often reported in DBS for neurological movement disorders. For example, the comprehensive experience of DBS in Parkinson’s patients (>200.000) has taught us that DBS is capable of inducing an instant improvement of their tremor, rigidity or bradykinesia after finding optimal stimulation settings. In 1999, DBS was introduced for the treatment of psychiatric disorders, including obsessive-compulsive disorder (OCD). As opposed to the rapid full-scale effect of DBS for Parkinson’s disease (PD), the relatively sparse number of published DBS trials and case studies for


OCD (+/- 250 patients) generally report a sequential response pattern with early improvement of mood and anxiety followed by a delayed improvement of obsessions (days) and compulsions (weeks) following DBS parameter (voltage, pulse width, frequency) optimization (Denys 2010). Although this sequential response pattern has never been closely studied all DBS trials and mechanistic studies for OCD use designs with a >1-week interval between the DBS ON- and OFF-phase.However, as the story of MS. V. demonstrates, DBS may also have extremely rapid effects when used for the treatment of OCD. In agreement, I have frequently observed strikingly rapid symptom changes following DBS activation also in other OCD patients within our current cohort (N=55). These clinical observations made me question the delayed response assumption of DBS for OCD and encouraged me to hypothesize alternative working mechanisms.Therefore, in the following thesis I will set out my investigation on the rapidity of DBS for OCD, as well as the role of three alternative working mechanisms.

NEUROENDOCRINE EFFECTS

First, the rapid effects of DBS may be explained by changes in the neuroendocrine system. The neuroendocrine system, involved in acute stress regulation, consists of the hypothalamic-pituitary-adrenal (HPA)-axis and the sympathetic nervous system (SNS) (de Kloet et al., 2005). This system plays a central role in OCD pathophysiology. First, clinical observations show that various daily-life stressors negatively influence the onset and exacerbations of OCD symptoms (Cougle 2011). Also, the hormones cortisol, adrenalin and noradrenalin, being end-products of the HPA-axis and SNS, are increased in OCD (Fluitman 2010, Kluge 2007 and Lord 2011). Finally, the neuroendocrine system is linked to central serotonin regulation in OCD as blunted prolactin, and growth hormone (GH) levels to serotonin (5-HT) challenge tests are associated with central 5-HT activity and responsivity in OCD patients (Mathew, 2001 and Corregiari, 2007, Monteleone 1997). Potential neuroendocrine involvement in DBS is underlined by the results of a DBS for PD study showing DBS of the


subthalamic nucleus (STN) is associated with a significant decrease of cortisol levels (Novakova 2011). Interestingly, the STN is also an effective brain target in DBS for OCD (Mallet et al., 2008).

IMMUNE SYSTEM

Second, rapid DBS effects for OCD may be related to the immune system. Accumulating evidence suggests immune dysregulation to be involved in the pathophysiology of OCD as, i) Group A streptococcal infections affecting the basal ganglia have been associated with the development of the disorder (Murphy 2014), ii) OCD patients have increased anti basal ganglia-antibodies compared to healthy controls (Bjattarcharryya 2009), iii) an animal model links microglia dysfunction to compulsive behaviour (Chen 2010), iv) accumulating evidence associates OCD with altered cytokine levels (Denys 2004; Gray & Bloch 2012; Rao 2015) which may acutely affect the dynamics of brain networks in OCD, as cytokines are known to alter serotonergic and glutamatergic systems (Cavaillon 2001). Furthermore, a recent DBS study in Wistar rats further emphasizes immune system involvement as stimulation of the hypothalamic nucleus induced a systemic inflammatory response accompanied by decreased corticosteroid concentrations (Calleja-Castillo 2013).

DOPAMINE

Finally, the immediate changes in mood and motivation may be explained by DBS-induced dopaminergic changes. Dopamine involvement in OCD is largely based on the consistent findings that dopamine receptor antagonists are effective in OCD symptom reduction as an adjunct to SSRIs (Denys, 2006; Vulink et al., 2009) and molecular studies show decreased striatal D2/3 receptor availability in OCD patients (Denys 2013). Furthermore, we have previously found that DBS for OCD changes the brain motivational system in which dopamine is a key neurotransmitter (Figee 2013). The case of Ms. V. clearly


suggests that improved motivation is amongst the first acute observable effects of DBS, and dopaminergic changes may be associated to this.

GENERAL OUTLINE OF THE THESIS

1. The first question was to assess the rapidity as well as response pattern of clinical symptom change following DBS reactivation. In chapter 2, I first reviewed the efficacy, mechanism of action and side effects of DBS for OCD in five different brain targets. In chapter 3, I then evaluate the time course of rapid clinical changes (mood, anxiety and OCD) following DBS reactivation in more detail. I hypothesized that DBS reactivation would rapidly reduce clinical symptoms,

2. The second question I raised was whether acute and chronic effects of DBS for OCD are associated with neuroendocrine changes. In chapter 4, I start exploring the effect of long-term DBS on the HPA-axis by measuring 24-hour urinary cortisol levels using a DBS ON/OFF design with a 1-week interval. Furthermore, in chapter 3 I also assessed additional neuroendocrine parameters in association with the clinical response pattern of long-term and acute DBS. I hypothesized that effective DBS would be associated with decreased HPA-axis activity.

3. The third question I raised was whether acute and long-term effects of DBS for OCD are mediated by the immune system. In chapter 5, I measured a broad assay of circulating pro- and anti-inflammatory cytokines and chemokines after chronic DBS and after acute DBS reactivation. I hypothesized that acute and chronic DBS would decrease pro-inflammatory mediators.

4. The final question was whether acute and long-term effects of DBS for OCD are mediated by the neurotransmitter dopamine. In chapter 6, I examine dopaminergic effect of chronic and reactivated DBS using [123I]iodobenzamide single photon emission computed tomography ([123I]


IBZM SPECT), as well as measurements of the dopamine/noradrenaline metabolite homovanillic acid (HVA). I hypothesized that acute and chronic DBS for OCD would be associated with dopaminergic changes.


ReferencesDenys D. Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders. Psychiatr Clin North Am. 2006;29(2):553–84.

Denys D, Mantione M, Figee M et al.: Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 2010, 67(10):1061-1068.

Haq IU, Foote KD, Goodman WG et al.. Smile and laughter induction and intraoperative predictors of response to deep brain stimulation for obsessive-compulsive disorder. Neuroimage. 2011 Jan;54 Suppl 1:S247-55. Cougle JR, Timpano KR, Fitch KE et al.. , Hawkins K. A. Distress tolerance and obsessions: an integrative analysis. Depress. Anxiety. 2011 Oct 3;28(10):906-14.

De Kloet ER, Joels M, Holsboer F., 2005. Stress and the brain: from adaptation to disease. Nature Reviews Neuroscience; 6:463-75.

Lord C, Hall G, Soares CN et al., 2011. Physiological stress response in postpartum women with obsessive-compulsive disorder: A pilot study. Psychoneuroendocrinology. Jan;36(1):133-8.

Kluge M, Schussler P, Kunzel HE et al.., 2007. Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder. J Psychiatr Res. Dec;41(11):928-33.

Fluitman SB, Denys D, Heijnen CJ et al.., 2010. Disgust affects TNF-alpha, IL-6 and noradrenaline levels in patients with obsessive-compulsive disorder.

Mathew SJ, Coplan JD, Perko KA. Neuroendocrine predictors of response to intravenous clomipramine therapy for refractory obsessive-compulsive disorder. Depress Anxiety. 2001;14(4):199-208.


Corregiari FM, Gattaz WF, Bernik M. Acute hormonal changes after IV citalopram and treatment response in OCD. Psychopharmacology(Berl). 2007 Sep;193(4):487-94.

Monteleone P, Catapano F, Bortolotti F et al.. Plasma prolactin response to d-fenfluramine in obsessive-compulsive patients before and after fluvoxamine treatment. Biol Psychiatry. 1997 Aug 1;42(3):175-80.

Murphy TK, Gerardi DM, Leckman JF. Pediatric acute-onset neuropsychiatric syndrome. Psychiatr Clin North Am. 2014 Sep;37(3):353-74.

Bhattacharyya S, Khanna S, Chakrabarty K et al.. Anti-brain autoantibodies and altered excitatory neurotransmitters in obsessive-compulsive disorder.Neuropsychopharmacology. 2009 Nov;34(12):2489-96.

Chen SK, Tvrdik P, Peden E et al.. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010 May 28;141(5):775-85.

Denys D, Fluitman S, Kavelaars A et al.. Decreased TNF-alpha and NK activity in obsessive-compulsive disorder. Psychoneuroendocrinology. 2004 Aug;29(7):945-52.

S.M. Gray & M.H. Bloch. Systematic Review of Proinflammatory Cytokines in Obsessive-Compulsive Disorder, Curr Psychiatry Rep (2012) 14:220–228.

Rao NP, Venkatasubramanian G, Ravi V et al.. Plasma cytokine abnormalities in drug-naïve, comorbidity-free obsessive-compulsive disorder. Psychiatry Res. 2015 Jul 8.

Denys D, de Geus F, van Megen HJ et al.. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry. 2004 Aug;65(8):1040-8.

Vulink NC, Denys D, Fluitman SB et al.. Quetiapine augments the effect of citalopram in non-refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled study of 76 patients. J Clin Psychiatry. 2009 Jul;70(7):1001-8.

Denys D, de Vries F, Cath D et al.. Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder. Eur Neuropsychopharmacol. 2013 Nov;23(11):1423-31.

Figee M, Vink M, de Geus F et al.. Dysfunctional reward circuitry in obsessive-compulsive disorder. Biol Psychiatry. 2011 May 1;69(9):867-74.

Part IEfficacy and side

effects in deep brain stimulation

for obsessive-compulsive

Current status of deep brain stimulation for

obsessive-compulsive disorder: a clinical review

of different targets

Chapter 2

Current Psychiatry Reports, 2011 Aug;13(4):274-82

Pelle P. de Koning, Martijn Figee, Pepijn van den Munckhof, P. Richard Schuurman, Damiaan Denys

Chapter 2. Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets | 27

CURRENT STATUS OF DEEP BRAIN STIMULATION FOR OBSESSIVE-COMPULSIVE DISORDER: A CLINICAL REVIEW OF DIFFERENT TARGETSObsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Despite optimal cognitive-behavioral and pharmacologic therapy, approximately 10% of patients remain treatment resistant. Currently, deep brain stimulation (DBS) is being investigated as an experimental therapy for treatment-refractory OCD. This review focuses on the efficacy and adverse events of all published DBS targets for OCD: anterior limb of the internal capsule, ventral striatum/ventral capsule, nucleus accumbens, nucleus subthalamicus and inferior thalamic peduncle. Small studies with various designs indicate an overall average Y-BOCS decrease ranging from 6.8 to 31 points. The average overall responder rate was ± 50%. The frequency of adverse events appears to be limited. Larger prospective studies including neuroimaging are needed to estimate adequately the true potential of DBS for OCD and to elucidate its underlying mechanism of action and optimal brain target. We conclude that DBS may be a promising and safe therapy for treatment resistant OCD.

INTRODUCTION

Obsessive-Compulsive Disorder (OCD) is a heterogeneous, chronic and disabling anxiety disorder. According to the DSM-IV definition, the essential features of OCD are recurrent obsessions and/or compulsions that are severe and time consuming (more than one hour a day) or cause marked distress or significantly interfere with the person’s normal routine, occupational functioning, usual social activities or relationships. At some point during the course of the disorder, the person has recognized that the obsessions or compulsions are excessive or unreasonable. OCD has an estimated lifetime


prevalence of 2% and afflicts men and women equally (Fullana et al., 2009; Ruscio et al., 2010). If left untreated, OCD can destroy a person’s capacity to function at work, socially, and even at home. Specific treatments for OCD have been developed, such as cognitive-behavioral therapy and pharmacotherapy with serotonin reuptake inhibitors. It is estimated that these treatments provide an average 40-60% symptom reduction in half of patients (Denys et al., 2006). However, even when the best available treatments are applied, approximately 10% of patients remain severely affected and suffer from treatment-refractory OCD. For a small proportion of treatment-refractory patients, deep brain stimulation (DBS) may be appropriate. DBS is a neurosurgical treatment involving the implantation of electrodes that send electrical impulses to specific locations in the brain, selected according to the type of symptoms to be addressed (Lipsman et al., 2007). It is estimated that over 100 subjects have received experimental DBS treatment for OCD in five different targets (figure 1). This paper offers a review of DBS-studies in treatment-refractory OCD. It discusses the history and efficacy of the different anatomical targets, the adverse events, the current hypotheses on the mechanisms of action of DBS, and finally the future directions and areas of uncertainty.

METHOD

Data for this review were identified by searches on Medline using different combinations of the following Mesh and free text terms: deep brain stimulation, obsessive-compulsive disorder, neurosurgery, nucleus accumbens, internal capsule, ventral capsule, ventral striatum, subthalamic nucleus, inferior thalamic peduncle, neuroimaging, ‘PET’ (Positron Emission Tomography), ‘MRI’ (Magnetic Resonance Imaging), ‘SPECT’(Single Photon Emission Computed Tomography), Parkinson, responder, ‘Y-BOCS’ (Yale-Brown Obsessive Compulsive Scale) and adverse events. By using various combinations of these search terms, all Medline-listed studies as of January 2011 on DBS in OCD were identified and the reference lists of the relevant publications were


screened. We included human studies that assessed the efficacy of DBS in OCD and accepted case studies if they included some estimate of efficacy. Due to differences in outcome measures, we solely included studies that had used the Y-BOCS for the efficacy analysis. The primary outcome measure was the mean improvement of the Y-BOCS score after follow-up. The secondary outcome measure was the responder rate defined as the proportion of patients with a minimum of 35% decrease on the Y-BOCS

Figure 1. Deep Brain Stimulation targets in obsessive-compulsive disorder

Figure: Deep Brain Stimulation targets in Obsessive Compulsive Disorders

A. Coronal T2-weighted magnetic resonance imaging (MRI) at 3 mm anterior of the anterior commissure (AC) showing the nucleus accumbens (NAc), anterior limb of the internal capsule (ALIC) and ventral striatum (VS) or ventral caudate.

B. Axial T2 MRI at the level of the AC showing the ALIC, VS, bed nucleus of the stria terminalis (BST) and inferior thamalic peduncle (ITP).

C. Axial T2 MRI at 4 mm below the AC showing the nucleus subthalamicus (STN).

A B C

NAc VS

ALIC

ITP

BST STN

EFFICACY OF DBS FOR OCD

We identified 9 open (case-) studies (table 1) and 7 controlled studies with a blinded on-off phase (table 2). These studies used five different brain targets and differed in responder rate. Responder rate was generally measured by a minimum 35% reduction on the Y-BOCS scores after surgery. One study defined response by a 25% decrease on the Y-BOCS and another reported clinical observation only.


Anterior limb of internal capsule (ALIC)

The ALIC is part of the internal capsule in front of the genu, between the head of the caudate nucleus and the lenticular nucleus. It contains fibers connecting the prefrontal cortex and the subcortical nuclei, including the dorsomedial thalamus. The choice for the ALIC as a brain target for DBS was based on the experience with the anterior capsulotomy for refractory OCD. This neurosurgical procedure had shown positive response in approximately 50% of the subjects (Mindus et al., 1994). The first experimental DBS for OCD was performed in Stockholm in 1998 at the Karolinska Hospital. Two patients received bilateral stimulation of the ALIC with use of external batteries. The results were never published, but there were no significant effects on OCD-symptoms after 3-4 weeks of stimulation in these patients (personal communication by Andreewitch and Meyerson, Karolinska Hospital). One year later, Nuttin et al. (1999) published the first article on bilateral ALIC DBS in four patients. The authors reported ’some beneficial effects’ in three out of four subjects. Symptom severity scores were not based on a validated questionnaire such as the Y-BOCS but on clinical observation only. Another study by the same group in 2003 described six patients with DBS in the ALIC for a period of 21 months (Nuttin et al., 2002). Four patients participated in the cross-over design phase. Three out of four patients showed a ≥35% reduction of symptoms on the Y-BOCS after follow-up. An average of 40% symptom decrease was observed in the double-blind controlled on-off phase of the study. In 2003 a single case study by Anderson et al. of ALIC DBS reported 79% reduction of symptoms after three months of open stimulate (Anderson et al., 2003). There was an overall symptom decrease of 23 pts on the Y-BOCS (Yale-Brown Obsessive compulsive Scale) at 10 months follow-up. Abelson et al. (2005) reported two responders out of four patients in 2005. Patients in this study received stimulation in a randomized on-off sequence of four 3-week blocks, followed by an open stimulation phase. Only one patient had a decrease of ≥35% (13 pts decrease on the Y-BOCS) in the double-blind


phase. This patient was the only subject with monopolar stimulation settings. He had a 73% (22 pts) improvement during open-phase follow-up. Another patient failed to show improvement until the open-phase, with a final reduction of 44% (16 pts) compared to baseline.

Table 1. Open case studies of deep brain stimulation in the treatment of obsessive-compulsive disorder

Year

Author

(n)

Target

Electrode

Parameters

FU

(mos)

Follow-up Δ Y-BOCS

(all subjects)

Responders

(≥35% Y-BOCS ↓)

2002

Mallet et al.

2

STN

NM

185+130Hz 60+90μsec 3.1+3.2V

6

↓ 20 pts

2 (100%)

2003

Anderson

et al

1

ALIC

MDT 3387

100Hz, 210μsec,

2V

10

↓ 27 pts

1 (100%)

2003

a

Sturm et al.

5

NAc

NM

130Hz 90μsec 2-6.5V

24 - 30

no Y-BOCS-

scores

3 (60%)

2004

Fontaine

et al.

1

STN

MDT 3389

185Hz 60μsec

R=3.5,L=1.3V

12

↓ 31 pts

1 (100%)

2004

Aouizerat

e et al.

1

NAc

MDT 3387

130Hz 120μsec

4V

27

↓ 13 pts

1 (100%)

2006

Greenber

g et al.

10

VC/VS

MDT 3387

100-130Hz 90-210μsec

8-17mA

36

↓ 12.3 pts

4 (40%)

2009

Jiménez-Ponce et al.

5

ITP

MDT 3387

130Hz 450μsec

5V

12

↓ 17.2 pts

5 (100%)

2010

Greenberg et al.

(combined)

26

ALIC/VC/VS

MDT 3387

100-130Hz 310-180μsec 8.4-7.3-4.7V

3 – 36

↓ 13.1 pts

16 (62%)

2010

Franzini et

al.

2

NAc

MDT 3389

130Hz 90μsec

5.0+5.5V

24 - 27

↓ 13 pts

1 (50%)

a : unilateral stimulation b : Combined study FU: follow-up

NM: not mentioned FU: Follow-up Responders: intention to treat analysis

STN: subthalamic nucleus à NAc: nucleus accumbens

VC/VS: ventral capsule/ventral striatum à ITP: inferior thalamic peduncle

MDT 3387: Medtronic leads: 4 electrodes à electrode length: 1.5mm / electrode spacing: 1.5mm



Ventral Capsule/Ventral Striatum (VC/VS)

In subsequent years, adjacent structures of the internal capsule were targeted for DBS. One of these adjacent regions is the ventral striatal (VS) area. The VS contains the ventral caudate nucleus and nucleus accumbens and is thought to be associated with reward and motivation. Combined with the ventral capsule, it is referred to as the VC/VS region. This brain target was chosen based on positive results following gamma knife capsulotomy at the ventral region of the ALIC for refractory OCD. (Greenberg et al., 2003). In 2006, Greenberg et published the results of 10 patients with bilateral stimulation of the VC/VS. Eight of them were followed for 3 years. Four out of eight patients were considered responders (≥ 35% symptom reduction). There was an overall average decrease of 12.3 points on the Y-BOCS during follow-up. In 2010, combined long-term results from 26 patients with VC/VS implantation were published by the same American-Belgian group (Greenberg et al., 2010). There was an overall responder rate of 62% after mean 31.4 months follow-up. The overall average Y-BOCS decrease for all subjects was 13.1 points. Of importance was that results generally improved for patients implanted more recently, which resulted in lower pulse width and voltage settings. Refinement of the implantation site to a more posterior location towards the junction of anterior capsule, anterior commissure (AC) and bed nucleus of the stria terminalis (BST), seemed to be the main factor accounting for this gain. A recent pilot study by Goodman et al. (2010) using a blinded, staggered onset design of 6 OCD-patients with VC/VS DBS, showed four out of six responders after 12 months follow-up. Stimulation had started under blinded conditions at either 30 or 60 days post surgery. The overall symptom decrease was 46% (15.7 points).

Nucleus Accumbens (NAc)

The NAc is part of the ventral striatum. It is located where the head of the caudate and the anterior portion of the putamen meet just beneath the ALIC


and is involved in functions ranging form reward processing to motivation and addiction. The NAc is considered a promising target for DBS because there is evidence of dysfunction of the reward system in OCD. In a study by Figee et al. (2011), using a monetary incentive delay task and functional magnetic resonance imaging, OCD patients showed attenuated reward anticipation activity in the nucleus accumbens compared with healthy control subjects. In 2003 Sturm et al. published the first DBS results of unilateral, right-sided nucleus accumbens implantation in four OCD patients. In this open study, after 24 to 30 months, three of four patients were considered responders, though no Y-BOCS scores were reported in the article. In 2010 the same group published a double-blind study on unilateral right-sided NAc DBS in 10 OCD patients Huff et al., 2010). The symptom improvement observed in the double-blind part of the study was, however, limited to an average of 10%. The mean Y-BOCS score went from 27.9 in the active stimulation to 31.1 during sham stimulation. At 1-year follow-up, only 1 patient showed ≥35% symptom improvement. Five patients were considered partial responders (≥ 25% symptom improvement). The average Y-BOCS symptom decrease for all subjects at 1-year follow-up was 21% (6.8 points). An earlier open stimulation case study by Aouizerate et al. (2004) on NAc/ventral caudate DBS for OCD and depression had reported a delayed 52% decrease of symptoms at 15 months follow-up. In 2010, Franzini et al. (2010) reported of NAc DBS for OCD in 2 patients. They reported an average symptom improvement of 38% (12 points). Denys et al. (2010)

published a study on 16 patients with NAc DBS for OCD in 2010. This study consisted of an open 8-month treatment phase, followed by a double blind cross-over phase with randomly assigned 2-week periods of active or sham stimulation. It ended with an open 12-month maintenance phase. This resulted in an average 46% symptom decrease after 8 months. Nine out of 16 patients were responders during follow-up. These nine subjects had a mean Y-BOCS score decrease of 72% (23.7 points). The average symptom decrease at 21 months follow-up for all 16 subjects was 48% (17.5 points). In the double blind, sham controlled phase (n=14), the mean Y-BOCS difference between


active and sham stimulation was 25% (8.3points).

Table 2. Controlled studies with blinded on-off phase of deep brain stimulation in treatment of obsessive-compulsive disorderTable 2: Controlled studies with blinded on-off phase

Year

Author

(n)

Target

Electrode

Parameters

FU

(mos)

FU Δ Y-

BOCS all

subjects

FU Respond-

ers

Blinded on/off-phase

Y-BOCS on vs

off

1999

Nuttin et al.

4

ALIC

MDT 3387

100Hz

210μsec 4.7-5.0V

NM

NA

NA

1 patient: duration unknown

No Y-

BOCS scores

2003

Nuttin et al.

6

ALIC

MDT

3487A & 3887

100Hz 210/450 μsec

4.0-10.5V

3-31

NS

NA

4 patients: 3 months

on 5-10weeks

off

19.8 vs

32.3

2005

Abelson et al.

4

ALIC

MDT 3387

130/150Hz 60/210μsec 5.0-10.5V

4-23

↓ 9.8 pts

2 (50%)

4 blinded on-off

periods (duration ?)

26.5 vs

29.3

2008

Mallet et al.

16

STN

MDT 3389

130Hz 60μsec

2.0±0.9V

3

↓ 8.9 pts

NA

3 months

on &

3 months off

19.8 vs

28.7

2010

Goodman et al.

6

VC/VS

MDT (NS)

130-135Hz 90-210μsec

2.5-8.5V

12

↓ 15.7 pts

4 (67%)

stagerred-onset:

stim. 30 or 60days post-

surgery

NM

2010a

Huff et al.

10

r-NAc

MDT 3387

145Hz

90-140μsec 3.5-6.5V

12

↓ 6.8 pts

1

(10%)

3 mos. on &

3 mos. off

27.9 vs

31.1

2010

Denys et al.

16

NAc

MDT 3389

130Hz 90μsec 3.5-5.0V

21

↓ 17.5 pts

9

(56%)

2 weeks on

& 2 weeks off

8.3 pts diff.

between

on & off FU: Follow-up a : Unilatereal stimulation Δ: change in

NA: Not applicable NM: Not mentioned Responder: ≥ 35% Y-BOCS decrease

STN: subthalamic nucleus NAc: nucleus accumbens VC/VS: ventral capsule / ventral striatum,

ITP: inferior thalamic peduncle

MDT 3487A: Medtronic leads: 4 electrodes à electrode length: 3.0mm / electrode sparing: 6.0mm

MDT 3887: Medtronic leads: 4 electrodes à electrode length: 3.0mm / electrode sparing: 4.0mm




Subthalamic Nucleus (STN)

The STN is located ventral to the thalamus, dorsal to the substantia nigra and medial to the corticospinal tract and is part of the basal ganglia. Studies of DBS in Parkinson’s disease (PD) have by serendipity highlighted the presumable role of the subthalamic nucleus in behavioral alteration and reducing OCD symptoms. In 2002 and 2004, two case-reports were published targeting the STN. The STN is an effective target for PD and was chosen as implantation site for three patients with PD who also had OCD. Mallet et al. (2002) reported 2 out of 2 responders with an average Y-BOCS decrease of 82% (20 points) after 6 months of stimulation. Fontaine et al. (2004) reported a 97% (31 points) Y-BOCS decrease after 12 months in a single case study. In 2006 Mallet et al. reported on the efficacy of bilateral STN stimulation in 16 OCD patients. Twelve out of 16 subjects were defined responders, although responders were defined by a mean decrease of ≥ 25% on the Y-BOCS score in this study. The overall average Y-BOCS decrease from the active- vs. sham-phase was 31% (8.9 points).

Inferior Thalamic Peduncle (ITP)

The ITP is part of the orbitofrontal-thalamic system and links the thalamus to the OFC. Because these structures and system are central in the pathofysiology of OCD (Greenberg et al., 2010) it was hypothesized that electrical stimulation of this white matter bundle could reduce OCD symptoms. The group of Jiménez-Ponce (2009) performed the only study on DBS for OCD in the ITP. They reported 5 out of 5 responders on the Y-BOCS, after 12 months follow-up. The average decrease on Y-BOCS was 49% (17.2 points).

ADVERSE EVENTS

Deep brain stimulation is an invasive procedure. It is associated with different types of adverse events: procedure-related complications, device related problems (technical problems) and undesired effects due to stimulation or


cessation of stimulation. There is a clear difference in knowledge of adverse events related to DBS in movement disorders and obsessive-compulsive disorders, because of the extensive literature of patients implanted for movement disorders (>80.000) and the relatively small number of DBS procedures for OCD (<100). Although different implantation sites are used, many operating procedures are similar. Therefore the risk of procedure related complications and devise related problems could be derived from the comprehensive experience of DBS for the treatment of movement disorders.

Procedure-related complications

Several groups have reported on surgical complications in large series of patients who underwent DBS for movement disorders. Infection, misplaced leads and seizures can occur in up to 30% of the patients (Seijo 2007) A potential serious risk of the introduction of the electrodes is intracerebral hemorrhage. In patients with movement disorders, recent literature reports a 0-5% risk for intracerebral hemorrhage (Maldonado et al., 2009; Ben-Haim et al., 2009) with sulcal and transventricular electrode trajectories, elevated blood pressure and older age as major risk factors (Ben-Haim et al., 2009). In OCD patients intracerebral hemorrhage was only reported in one of 10 patients by Greenberg et al. (2006) and in one patient in the study of Mallet et al. (2002). Superficial wound infection was reported in one of 10 OCD patients by Greenberg et al. (2006) and in two of 16 OCD patients by Mallet et al.. (2002) In the latter study, the implanted electrodes had to be removed in one patient.

Device related problems

Lead breakage and failure of the neurostimulator, reported to be as high as 8% in 2002 (Oh et al., 2002), have rarely been noted in more recent literature. Greenberg et al. (2006) reported a break in the electrode and subcutaneous extension cable requiring a replacement in one OCD patient. Nuttin et al. (2002) reported that OCD patients disturbingly felt the material within their body; to


the extent that one patient (one out of four) wanted it to be removed.

Undesired stimulation effects

Undesired stimulation effects vary widely (physical to mental) and can be divided in acute effects and effects of chronic stimulation. The latter can be divided in effects on mood and cognition. Usually these effects are reversible by cessation or adjustment of stimulation (-parameters). Okun et al. (2007) reported acute olfactory, gustatory and motor sensations, which were strongly associated with the most ventral electrode positions, as well as physiological responses. All effects reversed after DBS cessation or parameter changes.

Mood effects

Acute mood changes during the first few days of stimulation of the ALIC and NAc have been reported such as transient sadness, anxiety (Shapira et al., 2006), and euphoria, sometimes to the extent of hypomanic and manic symptoms Okun et al., 2007). Transient mania or hypomania after DBS implantation has been reported in several targets, including the globus pallidus, STN and the ALIC-NAc region (Haq et al., 2010). In 2010, a case-report by Tsai et al. (2010) reported a hypomanic episode following bilateral ALIC stimulation. The hypomanic symptoms diminished after lowering the voltage from 4.0 to 2.0 Volts, but the OCD-symptoms persisted during follow-up. All hypomanic and manic episodes, associated with DBS stimulation, dissolved after readjusting field density through changing the voltage and/or the active contact. Transient hypomania is the most commonly observed side effect immediately after stimulation. Transient hypomanic episodes seem to occur more often in the VC/VS-NAc region. Occurrence is estimated to be as high as 50-67% in ALIC-NAc DBS, as contrasted with 4-8% in STN DBS patients (Haq et al., 2010).Chronic mood improvement is an unintended but favourable side effect of DBS because most treatment refractory OCD patients suffer from comorbid major depression. Denys et al.,(2010) Abelson et al.(2005) and Greenberg et al.


(2006) reported improvement of depression after accumbens, ALIC and VS/VC stimulation, respectively. Anti-depressive effects seem thus to be especially related to DBS of the ventral striatum (Goodman et al., 2010; Aouizerate et al., 2004; Franzine et al., 2010; Mallet et al., 2002) because no mood improvement was observed following STN stimulation (Mallet et al., 2002). Stimulation cessation can result in severe worsening of mood,[7,9] though this can be reversed by activation of the stimulation.

Cognition effects

Apart from transient diminished concentration and verbal perseverations Greenberg et al., 2010). DBS has not been associated with evident cognitive decline and/or cognitive function improvement. However, the literature on this topic is sparse. Analysis of neuropsychological testing in the study by Aouizerate et al. (1 subject) showed no deterioration in memory, attentional or executive function tests (Aouizerate et al., 2004). Abelson et al. (2005) administrated a large battery of tests at baseline and 6 months follow-up in all 4 subjects. They reported no obvious patterns of cognitive changes following stimulation. Goodman et al. (2010) performed extended neuropsychological tests in 6 subjects. Overall, results indicated that the clinical effectiveness in this population was achieved without significant neuropsychological dysfunctions. All patients in the study by Greenberg et al. (2006) completed neuropsychological assessment before implantation and after a mean 10 months of chronic DBS. Analysis found no pattern of pervasive decline or improvement in any one patient. Denys et al. (2010) reported mild forgetfulness in 5 out of 16 patients and word-finding problems in 3 out of 16 patients, following NAc DBS. An extensive neuropsychological test battery was performed, but given the extensiveness of the data, the outcomes will be published in an upcoming separate article


Positive side- effects

Remission of alcohol dependency[33] and unintended effortless smoking cessation was observed following bilateral stimulation of the NAc (Mantione et al., 2010; Kuhn et al., 2009).

RESPONSE PREDICTION

Thusfar, no proven response predictors for DBS in OCD have been identified. One American group (Okun et al., 2003; Haq et al., 2010) observed that the onset of laughter during the neurosurgical procedure and optimisation of DBS settings predicted improvement in OCD symptoms. More intense laughter was associated with a greater reduction in Y-BOCS scores 2 years post-implantation. They hypothesized that laughter is an epiphenomenon of stimulation of a putative “sweet spot”, a region that ameliorates OCD symptoms when chronically stimulated

MECHANISM OF ACTION

Circuits connecting orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), basal ganglia and thalamus are central to OCD pathophysiology and treatment response (Greenberg et al., 2010). Although the mechanism of DBS is still unknown, a widely accepted hypothesis is that OCD is associated with hyperactivity of the cortical-striatal-pallidal-thalamic-cortical (CSTC) network (Whiteside et al., 2004). It is plausible that DBS inhibits or functionally overrides this pathological network hyperactivity (Mcintyre et al., 2010). Stimulation frequency seems to be a key factor in determining clinical efficacy. Low frequencies are considered to activate neurons, whereas high-frequency stimulation results in neuronal inhibition (Meissner et al., 2005). Combined imaging and DBS studies that may confirm the inhibitory characteristics of DBS are sparse. Le Jeune et al. (2010) found a hyperactivity in the OFC of patients with severe and refractory OCD compared to healthy controls. The


same study compared the metabolic effects of STN DBS (n=10) in the ON vs OFF stimulation conditions. During ON stimulation, a significant decrease in glucose metabolism was observed in the anterior cingulated gyrus. In addition, therapeutic effects correlated to a decrease in OFC metabolism. Abelson et al. (2005) showed decreased PET-activity in the OFC after 3 to 6 weeks of ALIC DBS in two OCD-responders, but not in non-responders. The involvement of other brain areas, such as the orbitoftontal cortex, anterior cingulated cortex, striatum, pallidus and thalamus was seen in a PET-study in six OCD-patients, two weeks after implantation of the electrodes in the VC/VS (Rauch et al., 2006). Increased activity in the frontal cortex and striatum after ALIC DBS-activation was seen during post-operative MRI (Nuttin et al., 2002). In the same study, clinical response after 3 months of continuous stimulation was related to a relative decrease of OFC hyperactivity. Thus, as of yet, sparse neuroimaging research suggests that hyperactivity in the OFC correlates with the severity of OCD, and that OFC activity normalizes following DBS.

CONCLUSION

The 16 identified efficacy studies used different brain targets, study design, number of subjects, duration of follow-up, on-off phase duration, electrode models and stimulation parameters. The reported percentages of responding patients and mean Y-BOCS decrease also differed considerably (Table 1 and 2). Although one should be careful interpreting these studies due to the different design and brain targets, an improvement of 35% of Y-BOCS was observed in 34 out of 63 patients, with a Y-BOCS decrease that ranged from 6.8 to 31 points. Can we determine the currently optimal DBS brain target for OCD from these results? Monopolar NAc DBS with electrode model 3389, as reported by our group, resulted in a mean Y-BOCS decrease of 72% in the 56% responding patients, the largest follow-up Y-BOCS decrease thus far published (Denys et al., 2010). Interestingly, clinical improvement was only observed when the upper two (i.e. dorsal) electrode contacts were used, suggesting active stimulation at the border of the NAc core and ventral ALIC. Greenberg


et al. (2010) reported more responders (from 33.3 to 75%) and a larger mean Y-BOCS decrease in responders (from 29 to 54.3%) when the implantation site of their ALIC/VC/VS electrodes was moved posteriorly to the junction of anterior capsule, anterior commissure (AC) and BST.However, the large size of their 3887 electrode contacts impedes pinpointing the site of active stimulation to a specific anatomical structure. Jimenez-Ponce et al. (2009) reported a mean Y-BOCS decrease of 49% in 100% responding patients following bipolar ITP DBS using electrode model 3387, with active stimulation just posterior of BST.

Thus far, the mechanism of action of DBS for OCD is still unclear. Functional imaging studies of DBS in ALIC (Abelson et al., 2005) and STN (Le Jeune et al., 2010) showed normalization of OFC hyperactivity, suggesting a final common cortical-striatal pathway. Serious procedure related events are rare and side-effects can be reversed by cessation or adjustment of the stimulation parameters. The present data suggest no decline or improvement on cognitive function by DBS. DBS may be a promising and safe therapy in patients with treatment-refractory OCD. Further research is necessary to optimize this therapy with respect to patient selection and management, target location, and investigation of its mechanism of action.


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Part IINeuroendocrine effects of deep

brain stimulation for obsessive-

compulsive disorder

Deep Brain Stimulation for obsessive-compulsive

disorder is associated with cortisol changes

Chapter 3

Psychoneuroendocrinology, 2013, 38, 1455-1459

Pelle P. de Koning, Martijn Figee, E. Endert, J.G. Storosum, E. Fliers, Damiaan Denys

Chapter 3. Deep brain stimulation for obsessive-compulsive disorder is associated with cortisol changes | 53

DEEP BRAIN STIMULATION FOR OBSESSIVE-COMPULSIVE DISORDER IS ASSOCIATED WITH CORTISOL CHANGES Deep brain stimulation (DBS) is an effective treatment for obsessive-compulsive disorder (OCD), but its mechanism of action is largely unknown. Since DBS may induce rapid symptomatic changes and the pathophysiology of OCD has been linked to the hypothalamic-pituitary-adrenal (HPA) axis, we set out to study whether DBS affects the HPA axis in OCD patients. We compared a stimulation ON and OFF condition with a one-week interval in 16 therapy-refractory OCD patients, treated with DBS for at least one year, targeted at the nucleus accumbens (NAc). We measured changes in 24-hour urinary excretion of free cortisol (UFC), adrenaline and noradrenaline and changes in obsessive-compulsive (Y-BOCS), depressive (HAM-D) and anxiety (HAM-A) symptom scores. Median UFC levels increased with 53% in the OFF condition (from 93 to 143 nmol/24h, p= 0.12). There were no changes in urinary adrenaline or noradrenaline excretion. The increase in Y-BOCS (39%), and HAM-D (78%) scores correlated strongly with increased UFC levels in the OFF condition. Our findings indicate that symptom changes following DBS for OCD patients are associated with changes in UFC levels.

INTRODUCTION

Obsessive-Compulsive Disorder (OCD) is a chronic disabling disorder characterized by recurrent intrusive thoughts and repetitive compulsory behaviors. Recently, deep brain stimulation (DBS) has become a successful treatment strategy for treatment refractory OCD (Denys et al., 2010). DBS is a neurosurgical treatment involving the implantation of electrodes that send electrical impulses to specific locations in the brain selected according to the type of symptoms to be addressed. However, its underlying mechanism remains largely unclear. One of the most striking observations when OCD patients are treated with DBS is that symptoms decline dramatically within


minutes or hours following DBS activation, and may immediately reoccur after DBS cessation (De Koning et al., 2011). These extreme changes include fluctuations in mood and anxiety (Denys et al., 2010).The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system regulate peripheral concentrations of the main stress hormones cortisol, adrenaline and noradrenaline (de Kloet et al., 2005). Although the literature on the function of the HPA system in OCD is inconsistent, several recent papers report an increase in HPA axis activity (Fluitman et al., 2010; Kluge et al., 2007; Lord et al., 2011). On this basis, we set out to study whether DBS affects the HPA axis in OCD patients. Determining concurrent changes in stress hormones and OCD symptoms induced by DBS is likely to enhance our understanding of the underlying mechanism of DBS for therapy-refractory OCD patients. We addressed the following research questions. (1) Is DBS (ON vs OFF) associated with changes in urinary free cortisol, adrenaline and noradrenaline excretion? (2) Are these changes associated with alterations in obsessive-compulsive, depressive and anxiety symptoms?

METHOD

Participants

We included treatment-refractory OCD patients who were treated with deep brain stimulation (DBS) targeted at the border between the accumbens core and the ventral part of the internal capsule (Denys et al., 2010). Subjects were chosen from a larger clinical sample of DBS-treated OCD patients and were included if they had been treated with DBS for at least one year. All patients consented to participate in this study and signed an informed consent form. All participants were diagnosed as having primary OCD according to DSM-IV criteria using the Structured Clinical Interview for DSM-IV Axis I disorders (First et al., 1997). In total we included 16 participants, 7 women and 9 men, aged between 32 and 56 years. Six had one or more


comorbid disorders: major depressive disorder (N=4), dysthymia (N=1) and panic disorder (N=1). Seven participants used psychotropic medication (6 selective serotonin reuptake inhibitors (SSRIs) and 1 atypical antipsychotic). Participants were asked to stop smoking during the investigation, as nicotine is a strong activator of the HPA axis (Rohleder and Kirschbaum, 2006) and to restrict coffee intake to one cup per day. Other substances influencing vigilance such as alcohol or excessive exercise were prohibited. Five out of 16 participants were excluded because they showed more than 150% 24-hour urine creatinine excretion difference (see ‘analytical methods’ section) between two consecutive urine collections, and another 3 were excluded because they continued smoking excessively. As a result, we used data from 8 out of 16 participants for final analysis of UFC and urinary (nor)adrenaline. Participant characteristics and an overview of the DBS-induced changes in psychiatric symptoms, UFC and urinary catecholamines are presented in Table 1.

Procedure

While the DBS had been constantly activated for at least one year, participants collected 24-hour urine samples (DBS ON) on two consecutive days. The following day the DBS was turned off. After one week of DBS cessation, two more consecutive 24-hour urine samples were collected (DBS OFF) (fig. 1). Although 24-hour urine cortisol sampling is the gold standard for an integrative measure of total free cortisol, it is also a fairly blunt method for measuring HPA axis activity. During the DBS ON and OFF 24-hour urine sampling a psychiatrist assessed obsessive-compulsive, anxiety- and depressive symptoms with the Yale-Brown Obsessive-Compulsive Symptom Scale (Y-BOCS), the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D) (Goodman et al., 1989a; 1989b; Hamilton, 1960). DBS parameters varied between participants in voltage (3.5 – 6.2 Volts), frequency (90 – 150 Hz) and pulse width (130-185 µsec). Medication was


continued during the DBS OFF condition.

Figure 1. Schematic study design

DBS ON (> 1 Year)

SAMPLE 1 (DBS ON)

2x 24h urine (Cortisol/adrenaline/noradrenaline)

+ Y-BOCS/HAM-A/HAM-D

Switch DBS ON èOFF

DBS OFF (1 week)

SAMPLE 2 (DBS OFF)

2x 24h urine (Cortisol/adrenaline/noradrenaline)

+ Y-BOCS/HAM-A/HAM-D

Analytical methodsEach urine collection container had been acidified with 6 mol/L hydrochloric acid to prevent catecholamine degradation, and the containers were kept cool or refrigerated during collection. Total urine volumes as well as concentrations of free cortisol, adrenaline, noradrenaline and creatinine were measured. The mean 24h urinary excretion of the two samples was used for statistical analysis. If total creatinine excretion in the sample with the highest creatinine excretion was more than 150% of the creatinine excretion of the other sample, the samples were considered unreliable and the subject was excluded from the study. The reasoning behind exclusion was that intra-individual variability in renal excretion of creatinine could be assigned to variation in the amount of ingested creatinine, which may account for 15 to 20% of the between-day variation (Burtis and Ashwood, 1994). In view of the outpatient setting of the present study, an additional 30% between-day variation resulting from inaccuracy of the collection was accepted (De Bos Kuil et al., 1998).We measured cortisol using an in-house high-performance liquid chromatographic (HPLC) method with a detection limit of 5 nmol/L. Total assay variation was 5,8% at 58 nmol/L and 6,9% at 180 nmol/L. Urinary noradrenaline (NA) and adrenaline (A) were determined by an in-house HPLC method after derivatization and with electrochemical detection. Detection limits for NA and A: 5 nmol/L. Total assay variation NA: 13% at 195 nmol/L and 14% at 539 nmol/L; total assay variation A: 16% at 29 nmol/L and 9% at 112 nmol/L.


Reference values 24-hour urinary free cortisol (UFC)

We compared the observed 24-hour UFC excretions with reference values obtained in 48 subjects as reported by De Bos Kuil et al. (1998), using similar analytical methods as our study. They reported a median UFC excretion of 56 nmol/24h (range: 56 – 145), without any significant age or sex effects.

Statistical analysis

For measurement of association we used Spearman’s correlation coefficient, for comparisons of 2 related samples we used non-parametric Wilcoxon-Signed-Rank test in view of the small samples sizes. The analyses were recalculated with parametric methods with approximately the same inferential results. There were no non-detectable or missing data.

RESULTS

Compared to the DBS ON condition Y-BOCS scores increased significantly (39%), from modest to severe symptoms, in the OFF condition (DBS ON 20.5, range 6-32; DBS OFF 28.5, range 28-40); p = 0.02, r=0.63). In addition, median HAM-A scores increased significantly with 55% from modest to severe symptoms (DBS ON 18, range: 4-31; DBS OFF 28, range: 18-51; p = 0.01, r=0.56) and median HAM-D scores increased significantly (78%) from mild to modest symptoms (DBS ON 11.5, range: 0-30; DBS OFF 20.5, range: 16-40; p = 0.01, r=0.53). Median 24-hour UFC levels increased with 53% in the OFF condition (143 nmol/24h, range: 74-236) compared to the ON condition (93 nmol/24h, range: 49-219; p = 0.12, r=0.25). During the ON condition, 6 out of 8 patients had UFC levels within the reference range, in contrast to the OFF condition, when UFC levels increased to levels exceeding the upper limit of the reference range in 4 out of 8 patients. We found no significant changes in mean adrenaline excretion (DBS ON 23.4 nmol/24h, SD±19.0; DBS OFF 28.4 nmol/24h, SD±21.0; p=0.31, r=0.12) and


noradrenaline excretion (DBS ON 209.0 nmol/24h, SD±100.6; DBS OFF 211.1 nmol/24h, SD±95.5; p=0.96, r=0.01).

Table 1. Baseline characteristics, and changes in psychiatric symptoms and endocrine parameters after one week of DBS cessation

∆ = difference DBS ON-OFF (1 week DBS cessation); SRI Serotonin Reuptake Inhibitor; AP atypical antipsychotic medication; Med. medication.

Subjects Age (years) Sex Med. Y-BOCS

ON-OFF HAM-A ON-OFF

HAM-D ON-OFF

Cortisol (nmol/24h) ON-OFF

Adrenaline (nmol/24h) ON-OFF

Noradrenaline (nmol/24h) ON-OFF

1. 45 M None 9 7 14 37 -4

4

2. 50 F None 6 12 2 3 -4 19

3. 50 F None 23 14 21 125 -3 -36

4. 41 M SRI AP 15 21 17 4 10 -31

5.

56

M

None

4

-2

3

-89

-3

19

6.

32

F

SRI

4

11

7

0

-3

2

7.

41

F

None

13

20

17

116

33

-193

8. 39 M None 14 23 11 43 13 262

Correlations

24-hour UFC levels in the ON as well as the OFF condition correlated significantly with the Y-BOCS scores (rs=0.55, p=0.02) and nearly significant with HAM-D scores (rs=0.46, p=0.06). By contrast, HAM-A scores did not correlate with 24-hour UFC excretion (rs=0.09, p=0.71). In addition, the increase in Y-BOCS and HAM-D scores after DBS cessation correlated significantly with the increase in 24-hour UFC excretion (rs=0.83, p=0.01 and rs=0.80, p=0.01, respectively) (Fig. 2) and not with HAM-A scores (rs=0.59, p=0.12). In contrast to the UFC findings, (changes in) Y-BOCS, HAM-A and HAM-D scores correlated weakly with 24-hour urinary adrenaline and noradrenaline


excretion (n.s.; p=0.10 – 0.82).

Figure 2. DBS ON/OFF condition induced changes in Y-BOCS/HAM-A and 24-h urinary free cortisol levels.

Δ 24hr UFC: absolute urinary free cortisol change (nmol/24hr); Δ Y-BOCS: absolute changes in points; Δ HAM-D: absolute change in points.

DISCUSSION

To our knowledge, this is the first study to examine HPA axis activity in therapy-refractory OCD patients treated with DBS. Our study suggests that DBS is associated with changes in 24-hour UFC and that these changes are in strong association with obsessive-compulsive and depressive symptom changes measured with the Y-BOCS and HAM-D. 24-hour UFC excretion increased in the DBS OFF condition compared to the DBS ON condition, without concomitant changes in urinary adrenaline or noradrenaline excretion. UFC excretion during active stimulation was within the reference range of healthy individuals. In the OFF condition, UFC excretion exceeded the upper limit of the reference range (145nmol/24h) in 4 patients, reflecting hypercortisolism. Despite finding no significant changes in adrenaline and noradrenaline excretion between the DBS ON and OFF situation, several individual subjects


did show sizeable differences. However, these levels remained well below the maximum excretion reference range (adrenaline: <275nmol/24hour & noradrenaline: <890nmol/24hour).Our results are in accordance with several recent studies supporting HPA hyperactivity in OCD (Fluitman et al., 2010; Kluge et al., 2007; Lord et al., 2011) and indicate that symptom improvement in DBS for OCD is related to normalization of hypercortisolism. Unfortunately the design of our study did not permit us to elucidate the causality between DBS induced changes in symptoms and cortisol excretion. DBS may affect the HPA axis activity directly or indirectly. As the DBS electrodes are located at the border between the NAc core and the ventral part of the internal capsule, stimulation may affect the HPA axis via projections from the NAc to the hypothalamus. These projections have been described in rodents (Groenewegen et al., 1999), although specific projections to the CRH secreting cells of the hypothalamic paraventricular nucleus are to the best of our knowledge unknown. Alternatively, NAc stimulation could activate the HPA axis through indirect projections to the ventral pallidum (Groenewegen et al., 1999), amygdala and from there to the paraventricular nucleus (Gray et al., 1989). Furthermore, our findings of HPA axis alterations following DBS are in agreement with study results obtained by Novakova et al. (2011) on subthalamic nucleus (STN) stimulation in 27 subjects with Parkinson’s disease. They reported a significant decrease in cortisol levels compared to baseline, appearing after 2 months and persisting after 12 months of stimulation. Interestingly, the STN is also an effective brain target in DBS for OCD (Mallet et al., 2008).One alternative explanation for HPA axis activation comprises that physical and psychological stress, may initiate an endocrine response by activating the HPA axis (de Kloet et al., 2005). Since all subjects were aware of their DBS cessation, as well as experiencing increased psychiatric symptoms, an increase in stress levels could be expected. This, however, seems to be unlikely as adrenaline and noradrenaline levels remained unchanged. Also,


major depressive disorder (MDD) is linked to an over activated HPA axis, therefore we cannot ultimately rule out that the activation of the HPA axis might be related at least to some extent to the depressive symptomatology.

Limitations

First of all, the study is small. At the end, the findings are based on eight participants due to exclusion of smokers (N=3) and participants (N=5) with an unreliable sample collection. Secondly, our design lacks a control group; each subject served as his/her own control. As DBS involves an invasive neurosurgical procedure it is not feasible to include a DBS control group. Also, the small group of patients is a common limitation of DBS for OCD research, as these patients are scarce and difficult to involve in a DBS ON/OFF study. Finally, our stringent 24-h urinary collection criteria (less than 50% creatinine difference between 2 consecutive samples) resulted in further reducing the number of subjects for final analysis.

CONCLUSION

Despite these limitations, the findings of the present pilot study may stimulate further research on HPA axis involvement in DBS for OCD. As our findings suggest an association between DBS-induced changes in urinary free cortisol and OCD symptoms, a next step in research could be to investigate (1) the causality between DBS induced symptom and cortisol changes (2) if cortisol is a possible response predictor in DBS for OCD.


REFERENCESBurtis CA, Ashwood ER., 1994. Tietz Textbook of Clinical Chemistry, 2nd Ed. Saunders: Philadelphia.

First MB, Spitzer RL, Gibbon MG et al.. 1997. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I): Clinical Version. Washington DC: American Psychiatric Press.

Fluitman SB, Denys DA, Heijnen CJ et al.. 2010. Disgust affects TNF-alpha, IL-6 and noradrenaline levels in patients with obsessive-compulsive disorder. Psychoneuroendocrinology. Jul;35(6):906-11.

De Bos Kuil MJ, Endert E, Fliers E, Prummel MF et al.. 1998. Establishment of reference values for endocrine tests. I: Cushing Syndrome. Neth J Med (53):153-163.

De Kloet ER, Joels M, Holsboer F. 2005. Stress and the brain: from adaptation to disease. Nature Reviews Neuroscience; 6:463-75.

De Koning PP, Figee M, van den Munckhof P et al.. 2011. Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Curr Psychiatry Rep. Aug;13(4):274-82.

Denys D, Mantione M, Figee M et al.. 2010. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. Oct;67(10):1061-8.

Goodman WK, Price LH, Rasmussen SA et al.. 1989a. The Yale-Brown Obsessive Compulsive Scale II. Validity. Arch Gen Psychiatry, 46: 1012–1016.

Goodman WK, Price LH, Rasmussen SA et al.. 1989b. The Yale-Brown Obsessive Compulsive Scale I. Development, use, and reliability. Arch Gen Psychiatry, 46, pp. 1006–1011.


Groenewegen HJ, Wright CI, Beijer AV et al.. 1999. Convergence and segregation of ventral striatal inputs and outputs. Ann N Y Acad Sci. Jun 29;877:49-63.

Hamilton M., 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry, 23, pp. 56–62.

Kluge M, Schüssler P, Künzel HE et al.. 2007. Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder. J Psychiatr Res. Dec;41(11):928-33.

Lord C, Hall G, Soares CN et al.. 2011. Physiological stress response in postpartum women with obsessive-compulsive disorder: A pilot study. Psychoneuroendocrinology. Jan;36(1):133-8.

Mallet L, Polosan M, Jaafari N et al.. 2008. Subthalamic Nucleus Stimulation in Severe Obsessive–Compulsive Disorder. N Engl J Med. Nov 13;359(20):2121-34.

Novakova L, Haluzik M, Jech R et al.. 2011. Hormonal regulators of food intake and weight gain in Parkinson’s disease after subthalamic nucleus stimulation. Neuro Endocrinol Lett.;32(4):437-41.

Rohleder N, Kirschbaum C. 2006. The hypothalamic-pituitary-adrenal (HPA) axis in habitual smokers. Int J Psychophysiol. Mar;59(3):236-43.

Chapter 4

Translational Psychiatry. 2016 Jan 26;6:e722

Pelle P de Koning, Martijn Figee, Erik Endert, Pepijn van den Munckhof, P(Rick) Schuurman, Jitschak G Storosum, Damiaan Denys, Eric Fliers

Ultra-rapid effects of deep brain stimulation (DBS)

reactivation on symptoms and neuroendocrine

parameters in obsessive-compulsive disorder

Chapter 4. Ultra-rapid effects of deep brain stimulation (dbs) reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorder | 67

ULTRA-RAPID EFFECTS OF DEEP BRAIN STIMULATION (DBS) REACTIVATION ON SYMPTOMS AND NEUROENDOCRINE PARAMETERS IN OBSESSIVE-COMPULSIVE DISORDERImprovement of obsessions and compulsions by DBS for OCD is often preceded by an ultra-rapid and transient mood elevation (hypomania). In a previous study we showed that improvement of mood by DBS for OCD is associated with decreased activity of the hypothalamus-pituitary adrenal (HPA) axis. The aim of our present study was to evaluate the time course of rapid clinical changes following DBS reactivation in more detail and to assess their association with additional neuroendocrine parameters. We included therapy-refractory OCD patients treated with DBS (>1 year) and performed a baseline assessment of symptoms, as well as plasma concentrations of thyroid-stimulating hormone (TSH), prolactin, growth hormone, copeptin and homovanillic acid. This was repeated after a 1-week DBS-OFF condition. Next, we assessed the rapid effects of DBS reactivation by measuring psychiatric symptom changes using visual analogue scales as well as repeated neuroendocrine measures after 30 minutes, 2 hours and 6 hours. OCD, anxiety and depressive symptoms markedly increased during the 1-week OFF condition and decreased again to a similar extent already 2 hours after DBS-reactivation. We found lower plasma prolactin (41% decrease, p=0.003) and TSH (39% decrease, p=0.003) levels during DBS-OFF, which increased significantly already 30 minutes after DBS reactivation. The rapid and simultaneous increase in TSH and prolactin is likely to result from stimulation of hypothalamic thyrotropin-releasing hormone (TRH), which may underlie the commonly observed transient mood elevation following DBS.


INTRODUCTION

Deep brain stimulation (DBS) is an effective treatment for therapy-resistant obsessive-compulsive disorder (OCD), with a mean 50% improvement of obsessive-compulsive symptoms (de Koning et al., 2011). After finding optimal DBS parameter settings, improvement in obsessions and compulsions usually occurs within days to weeks (Denys et al., 2010). This clinical response is often preceded by an ultra-rapid (minutes to hours) transient mood elevation or even hypomania (Haq et al., 2011). These rapid mood alterations have been suggested to predict long-term response of DBS for OCD. For example Haq and colleagues (2011) reported intra-operative stimulation induced smile and laughter induction in DBS of the anterior limb of the internal capsule and the nucleus accumbens region (ALIC-NA) to predict long-term OCD response. To date, no study has systematically investigated the ultra-rapid effects of DBS on psychiatric symptoms. Moreover, the underlying mechanism of this transient mood elevation remains unknown. Recently we showed that mood improvement following long-term DBS of the accumbal area is strongly correlated with decreased hypothalamic-pituitary-adrenal (HPA)-axis activity, reflected by decreased urinary free cortisol (UFC) levels (de Koning et al., 2013). This effect may well result from inhibition of hypothalamic corticotropin-releasing hormone. Thus, the hypothalamus may also be involved in the mediation of acute clinical effects of DBS. The aim of this study was to evaluate ultra-rapid clinical changes (OCD, anxiety, mood) following DBS and to assess various other neuroendocrine parameters related to the hypothalamic-pituitary axis as well as their association with DBS induced rapid clinical changes.

METHODS

Study Participants

We included 16 treatment-refractory OCD patients, treated with deep brain stimulation (DBS) targeted at the border between the accumbens core and the


ventral part of the internal capsule (vALIC) (Denys et al., 2010). Participants were chosen from a larger clinical sample of DBS-treated OCD patients and were included if they had been treated with DBS for more than 1 year. Participants provided written informed consent before participation, and the local ethics committee approved this study. We included 7 women and 9 men, aged between 32 and 56 years. The mean duration of illness was 25.9 years (range 8-48 years). Six participants had one or more comorbid disorders: major depressive disorder (N=4), dysthymia (N=1) and panic disorder (N=1). Nine participants had been medication-free for more than 1 year. Seven participants used psychotropic medication (3 clomipramine, 3 selective serotonin reuptake inhibitors (SSRIs) and 1 atypical antipsychotic). Five participants smoked cigarettes. None of the participants suffered from metabolic, endocrine or inflammatory disorders. DBS parameters varied between participants in voltage (3.5 – 6.2 Volts), frequency (90 – 150 Hz) and pulse width (130-185 µsec). Medication was continued during the DBS OFF condition. Participants were not allowed to consume alcohol, coffee, and nicotine or perform excessive exercise 24 hours before each measure.One participant dropped out during the study phase and was therefore excluded. As a result, we used data from 15 out of 16 participants for final analysis.

Procedure:

The study had a 2-phase design (see fig. 1) In phase 1 we measured psychiatric symptoms and neuroendocrine parameters when the DBS had been constantly activated for at least 1 year (DBS ON) and then after one week of DBS discontinuation (DBS OFF). Three blood samples (sample 1, DBS-ON) were collected in 4,5 ml tubes (1 ice-chilled EDTA, 1 plain and 1 heparin tube). These samples were collected in the morning (10:00 AM) from a peripheral intravenous catheter (PVC). The PVC had been placed more than 1 hour in advance of drawing the blood sample and all participants had rested for a minimum of 1 hour to minimize the effects of stress and physical


activity. The following day the DBS was turned off. After one week of DBS cessation, the second blood sample (sample 2, DBS-OFF) was taken in the morning, following the same PVC procedure. After each blood sample collection, the samples were centrifuged for 10 minutes at 3000 rpm. Next the plasma was pipetted and stored in 0.5ml aliquots at -50°.Following each sample collection a trained psychiatrist assessed obsessive-compulsive, anxiety- and depressive symptoms with the Yale-Brown Obsessive-Compulsive Symptom Scale (Y-BOCS), the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D) (Goodman et al., 1989; Goodman et al., 1989; Hamilton 1960).In phase 2, we investigated the acute effects of DBS reactivation. After one week of DBS discontinuation and the collection of sample 2, the DBS was reactivated. We then took 3 consecutive samples after 30 minutes (sample 3), 2 hours (sample 4) and 6 hours (sample 5). As the HAM-A, HAM-D and Y-BOCS are not applicable for measuring acute symptom changes, we used visual analogue scale (VAS) scores in this phase to measure clinical effects. During each of these 4 blood samples every participant assessed his/her actual level of anxiety, depression, obsessive thoughts and need to perform compulsions through a 10-point VAS-scoring (0= no symptoms - 10= most symptoms ever experienced).

Data acquisition and analysis:

We investigated the long-term as well as the acute effects of DBS on plasma thyroid stimulating hormone (TSH), prolactin, growth hormone (GH), copeptin (a stable peptide derived from the vasopressin precursor reflecting vasopressin plasma concentrations) (Morgenthaler et al., 2006) and the dopamine metabolite homovanillic acid (HVA). TSH, prolactin and GH were determined with a solid phase time-resolved fluoroimmunoassay (Delfia, PerkinElmer, Wallac Oy, Turku, Finland). Detection limits: TSH 0.01 mU/L, prolactin 0.1 µg/L, growth hormone 0.1 mU/L. Copeptin was measured by an immunoluminometric assay (BRAHMS CT-proAVP LIA, BRAHMS GmbH, Thermo Scientific, Henningsdorf,


Germany); detection limit 0.4 pmol/L. All assays were performed in heparin plasma with a total assay variation of < 10%. Plasma levels of HVA were determined by liquid chromatography (Shimadzu, Eindhoven, The Netherlands) and electrochemical detection (DECADE 1 equipped with a VT03 cell at a potential setting of 700mV vs Ag/Agcl reference electrode at 40°; ANTEC Leyden, Zoeterwoude, The Netherlands). The sensitivity of the method for HVA was 2ng/ml plasma, and the coefficient of variations was less then 6%.

Statistical analysis:

Normality of the data was assessed using the Kolgomorov-Smirnov test. If normality was violated, Mann-Whitney U-tests were performed in place of student’s t-tests. Data is expressed as mean ± standard deviation (SD) or median (min – max) and results are considered significant at P<0.05 (two-tailed). Correlation analyses were performed applying Pearson’s correlation. All statistical tests were computed with SPSS for Windows 21.0 (SPSS Inc., Chicago, Illinois).

Figure 1. Study design.

Hormones: thyroid-stimulationg hormone, prolactin, growth hormone and copeptin.

HVA homovanillic acid; VAS visual analog scale.


RESULTS

Psychiatric symptoms

Ten out of 15 participants were initial DBS responders defined as a minimum 35% Y-BOCS decrease (mean ΔY-BOCS = 17.0 ±6.0) after >1 year of DBS compared to pre-DBS Y-BOCS scores (mean PRE DBS Y-BOCS = 33.1 ±3.4). The other 5 participants were non-responders defined as showing <25% decrease on the Y-BOCS (mean ΔY-BOCS = 6.2 ±5.2SD).

DBS ON à DBS OFF

DBS cessation for 1 week compared with DBS ON was related to an increase from mild-moderate to severe obsessive-compulsive symptoms (Y-BOCS = 19,7 ±7.0 vs 28.6 ±5.1, p=0.001). Mean anxiety symptoms increased from mild to severe after 1-week DBS cessation (HAM-A = 16.3 ±9.1 vs 30.2 ±10.2, p=0.000). Mean depressive symptoms increase from mild to severe (HAM-D = 13.8 ±8.7 vs 26.0 ±8.9, p=0.002)

DBS reactivation

Thirty minutes after DBS reactivation we observed a mean 51% (p=0.002) reduction on obsessions and 55% (p=0.001) reduction on need to perform compulsions (VAS-scores). Six hours after reactivation there was a further decrease of obsessions to a total of 59% (p=0.003) while compulsions did not decrease any further but remained 54% lower than DBS OFF (p=0.005). DBS reactivation resulted in a 44% (0.002) reduction on anxiety symptoms (VAS-score, figure 2.) after 30 minutes, mounting to a 64% reduction (p=0.002) after 6 hours. DBS reactivation resulted in a 48% reduction (p=0.005) on depressive symptoms (VAS-score) after 30 minutes, mounting to 69% (p=0.005) after 6 hours. Eight out of 10 of the initial DBS responders and 3 out 5 non-responders reported >50% improvement of obsessive-compulsive, anxiety and depression VAS-scores within 2 hours after DBS reactivation.


Figure 2. Acute effects of deep brain stimulation (DBS) reactivation (phase 2) on anxiety, depression, obsessions and compulsions using the mean visual analog scale (VAS) scores (±s.e.).

Abbreviations: DBS deep brain stimulation, VAS visual analog scale.

Neuroendocrine changes

DBS ON à DBS OFF. The mean TSH plasma levels decreased by 61% (p=0.003) from DBS ON to DBS OFF (Table 1 and fig 3a), whereas the mean prolactin levels decreased by 59% (p=0.003) (fig 3b) and median GH levels were 360% lower during OFF relative to active stimulation, although the difference failed to reach statistical significance. We found no significant changes in mean copeptin levels. Finally, mean HVA levels decreased by 11% (p=0.02) from active stimulation to DBS OFF.


Table 1. Overview of DBS-induced neuroendocrine changes Sample 1

DBS ON (>1yr)

Sample 2 DBS OFF

(1wk)

P-value 1 à 2

Sample 3 DBS ON (1/2hr)

P-value 2 à 3

Sample 4 DBS ON

(2hrs)

P-value 2 à 4

Sample 5 DBS ON

(6hrs)

P-value 2 à 5

TSH (mE/L)

2.20 (±1.10)

1.36 (±0.78)

P=0.003** 1.56 (0.80)

P=0.057 1.58 (0.98)

P=0.037* 1.68 (1.21)

P=0.070

Prolactin (μg/L)

13.40 (6.22)

8.43 (5.11)

P=0.003** 15.13 (6.42)

P=0.001** 12.25 (4.44)

P=0.000** 13.65 (6.59)

P=0.001**

Growth Hormone (mE/L)

3.6 (0.1-24.5)

1.0 (0.1-30)

P=0.112 2.7 (0.3-29)

P=0.629 1.1 0.2-12.6

P=0.706 0.8 (0.1-7.2)

P=0.239

Copeptin (pmol/L)

4.9 (1.9-79.3)

6.2 (1.4-28.6)

P=0.158 5.0 (0.6-30.5)

P=0.451 5.3 (1.3-28.6)

P=0.798 5.2 (1.7-29.2)

P=0.410

HVA (nmol/L)

10.42 (3.67)

9.33 (3.38)

P=0.018* 9.63 (3.02)

P=0.722

10.06 (6.93)

P=0.727 12.30 (5.29)

P=0.097

Abbreviations: DBS deep brain stimulation, GH growth hormone, HVA homovanillic

acid, max maximum, min minimum, TSH thyroid-stimulating hormone. Values are the mean levels (s.d.). For GH and copeptin we present the median levels (min-max).

*P≤0.05,**P≤0.05.

DBS REACTIVATION:

At thirty minutes and 2 hours after DBS reactivation mean TSH levels increased (near-significantly) by 15% (p=0.06) and16% (p=0.06) respectively. Six hours after DBS reactivation TSH levels remained 23% higher (p=0.07) compared to DBS OFF (fig 3a). DBS reactivation increased TSH to levels still within the reference range (0.5 – 5.0 mU/L).At thirty minutes, 2 hours and 6 hours after DBS reactivation mean prolactin levels increased significantly compared to DBS OFF by 79% (p=0.001), 45% (p=0.000) and 62% (p=0.001), respectively (fig 3b).We found no significant changes after DBS reactivation for GH or copeptin. Six hours after DBS reactivation HVA levels had increased to 31% (p=0.09), although the difference failed to reach statistical significance.

CORRELATIONS:

Y-BOCS, HAM-A, HAM-D or VAS symptom scores were not correlated with any of the endocrine changes during DBS ON to DBS OFF or after DBS reactivation. A subgroup analysis yielded no significant difference in DBS induced


neuroendocrine changes between DBS responders and non-responders. We found a strong negative association between prolactin and HVA levels during long-term DBS ON (rs -0.667, P=0.007). Furthermore, the increase in plasma TSH and prolactin, 30 minutes after DBS reactivation, was strongly correlated ( R 0.682, P=0.005).

Figure 3. (a) Time course of deep brain stimulation (DBS)-induced thyroid stimulating hormone (TSH) changes (mean ±s.e.m.). (b) Time course of DBS induced prolactin changes (mean ±s.e.m).

a)

b)


DISCUSSION

We are the first to investigate the ultra-rapid effects of DBS reactivation. Our results demonstrate that after one week of DBS discontinuation, DBS reactivation results in a rapid and simultaneous ±50% improvement of anxiety, depression and obsessive-compulsive symptoms in 8 out of 10 initial DBS responders. These clinical changes are associated with changes in TSH and prolactin levels. Interestingly, 3 out of 5 participants who failed to show a clinically relevant response after the first year of DBS still showed 50% symptom decrease within the first 2 hours of DBS reactivation. These findings appear to be in line with several clinical observations reporting acute, but transient DBS effects in eventual non-responders during the DBS optimization phase or after DBS reactivation following a period of DBS cessation. One participant from the current study even turned off the stimulator every evening, reactivating it every next morning, in order to induce a transient improvement of affective symptoms that subsequently lessened his OCD symptoms during daytime. These findings suggest that DBS is capable of inducing rapid psychiatric symptom changes through an alternative or additional underlying mechanism. This concept also supports the clinical observation that acute effects of DBS do not necessarily predict long-term effects. In parallel with the acute clinical effects of DBS reactivation, discontinuation of DBS results in neuroendocrine changes that reversed acutely after DBS reactivation. TSH and prolactin decreased after switching off the DBS and increased again, although TSH to a lesser extent, within 30 minutes after DBS reactivation. This suggests that DBS changes are mediated, at least in part, via the hypothalamus, as both TSH and prolactin secretion are stimulated by hypothalamic thyrotropin-releasing hormone (TRH) and inhibited by dopamine released from neuroendocrine neurons projecting to the median eminence of the hypothalamus (Fliers et al., 2006; Freeman et al., 2000). The strong negative association between HVA and prolactin levels in our study suggests involvement of dopamine in the DBS changes, which is in agreement with


our previous demonstration of DBS–induced dopamine release (Figee et al., 2014). However, a stimulatory effect of TRH on TSH and prolactin by DBS cannot be excluded at present especially since we found no association of TSH with HVA levels.Interestingly, a significant body of preclinical and human data indicates that intravenous or intrathecal TRH administration has antidepressant effects, with some studies even reporting a mean HAM-D decrease of >50% (MArangell et al., 1997; Szuba et al., 2005). Although responses to TRH administration were rapid and clinically robust, they only lasted for several days. In the study by Marangell et al. (1997) mood elevation coincided with a rapid increase of both plasma prolactin and TSH after intrathecal TRH administration. TRH-induced transient mood elevation is especially interesting as stimulation initiation in DBS for OCD is associated with mood elevation and hypomanic symptoms, also lasting for several days (Denys et al., 2010;Haq et al., 2011). Therefore, we hypothesize on the basis of the present findings that TRH secretion may be a major determinant of the transient mood changes during DBS for the treatment of OCD. A limitation of our study was the small samples size, which is, however,common for DBS studies. Furthermore, our design lacks a healthy control group, but each subject served as his/her own control. As participants were aware of their stimulation settings, we cannot exclude the pronounced effects of DBS reactivation being (partially) based on the sense of expectancy or the recognition of symptom improvement. The small sample size did not permit us to exclude several confounding factors, including medication use or comorbid psychiatric disorders. While 3 participants used clomipramine during DBS ON and OFF conditions, clomipramine treatment is associated with a significant decrease in TSH concentrations in OCD patients (McCracken et al., 2005).Despite these limitations, the findings of the present study may stimulate further research on neuroendocrine changes of DBS, especially with a focus on TRH as a potential initiator in the mechanism of rapid symptom improvement and transient mood elevation.


REFERENCESDe Koning PP, Figee M, van den Munckhof P, Schuurman PR, Denys D. Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Curr Psychiatry Rep. 2011 Aug;13(4):274-82.

Denys D, Mantione M, Figee M, van den Munckhof P, Koerselman F, Westenberg H et al.. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2010 Oct;67(10):1061-8.

Haq IU, Foote KD, Goodman WG, Wu SS, Sudhyadhom A, Ricciuti N et al.. Smile and laughter induction and intraoperative predictors of response to deep brain stimulation for obsessive-compulsive disorder. Neuroimage. 2011 Jan;54 Suppl 1:S247-55.

De Koning PP, Figee M, Endert E, Storosum JG, Fliers E, Denys D. Deep brain stimulation for obsessive-compulsive disorder is associated with cortisol changes. Psychoneuroendocrinology, 2013 Aug;38(8):1455-9.

Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P Heninger GR et al.., 1989. The Yale-Brown Obsessive Compulsive Scale II. Validity. Arch Gen Psychiatry, 46: 1012–1016.

Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al.. 1989. The Yale-Brown Obsessive Compulsive Scale I. Development, use, and reliability. Arch Gen Psychiatry, 46, pp. 1006–1011.

Hamilton M. 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry, 23, pp. 56–62.

Morgenthaler N, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clinical Chemistry. 2006;52:112–119.

Fliers E, Alkemade A, Wiersinga WM, Swaab DF. Hypothalamic thyroid hormone feedback in health and disease. Prog Brain Res. 2006;153:189-207.


Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000 Oct;80(4):1523-631.

Figee M, de Koning P, Klaassen S, Vulink N, Mantione M, van den Munckhof P et al.. Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder. Biol Psychiatry. 2014 Apr 15;75(8):647-52.

Marangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia PJ, L’Herrou TA et al.. Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients. Arch Gen Psychiatry. 1997 Mar;54(3):214-22.

Szuba MP, Amsterdam JD, Fernando AT 3rd, Gary KA, Whybrow PC, Winokur A. Rapid antidepressant response after nocturnal TRH administration in patients with bipolar type I and bipolar type II major depression. J Clin Psychopharmacol. 2005 Aug;25(4):325-30.

McCracken JT & Hanna GL. Elevated thyroid indices in children andAdolescents with obsessive-compulsive disorder: effects of clomipraminetreatment. J Child Adolesc Psychopharmacol. 2005 Aug;15(4):581-7.

Part IIIImmune effects

of deep brain stimulation

for obsessive-compulsive disorder

Submitted

De Koning PP, Lutter R, Figee M, van den Munckhof P, Schuurman PR, Versluis A, Endert E, van der Poll T, Hamann J, Denys D

Chapter 5

Altered Activity of the Immune System upon

Deep Brain Stimulation for Obsessive-

Compulsive Disorder

Chapter 5. Altered activity of the immune system upon deep brain stimulation for obsessive-compulsive disorder | 85

ALTERED ACTIVITY OF THE IMMUNE SYSTEM UPON DEEP BRAIN STIMULATION FOR OBSESSIVE-COMPULSIVE DISORDERObsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that has been associated with immune dysregulation. Over the past decade, deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) has become an effective treatment for therapy-resistant OCD. Recently we showed that vALIC DBS alters activity of the hypothalamic-pituitary-adrenal (HPA)-axis and the HPA-axis communicates bidirectionally with the immune system. In the current study we investigated the effect of DBS on the immune system. We included 16 OCD patients who were treated with vALIC DBS for more than one year (DBS ON). Patients were taken off DBS for 1-week (DBS OFF) and subsequently DBS was reactivated (DBS-R). Obsessive-compulsive, anxiety and depressive symptoms were determined by clinician rated questionnaires during DBS ON and visual analogue scales during DBS-R. Plasma was collected after DBS ON, after DBS OFF and 30 minutes, 2 and 6 hours after DBS-R. We determined 15 key cytokines and inflammatory mediators, the activation marker soluble (s)CD163 and catecholamines. We found higher levels of IL-8 (62%, p= 0.01), GRO-α (117%, p=0.03), MIP-1β (18%, p= 0.01), MCP-1 (44%, p= 0.05) and sCD163 (26%, p=0.009) during DBS ON compared to DBS OFF. In addition, IL-8 (94%, p= 0.01) and GRO-α (140%, p= 0.04) increased significantly already 30 minutes after DBS-R. sCD163 levels increased 16% (p=0.001) 6 hours after DBS-R. None of the other cytokines and inflammatory mediators were affected. Increased IL-8 and MCP-1 levels during chronic DBS correlated with DBS-related improved obsessive-compulsive symptoms (rs -0,578 p=0.02) and anxiety (rs -0.582 p=0.02). DBS causes a rapid and reversible increase in inflammatory mediators, in particular chemokines, suggesting an inverse correlation between immune activation and psychiatric symptoms.


INTRODUCTION

Obsessive-compulsive disorder (OCD) is a chronic and disabling psychiatric disorder that is characterized by intrusive thoughts or images (obsessions), anxiety or distress and repetitive behaviors (compulsions). Neuroimaging, neuropsychological and treatment studies have implicated the cortico-striatal circuit in the pathophysiology of OCD and serotonergic, dopaminergic and glutamatergic systems play a central part in the functioning of this circuit (Pauls et al., 2014).Several lines of evidence suggest that immune dysregulation is critically involved in the pathophysiology of the disorder as: (1) accumulating data associate altered cytokine levels with OCD (Denys et al., 2004; Gray & Bloch 2012; Rao et al., 2015), (2) an animal model (Hoxb8 mutant mice) links microglia dysfunction to compulsive behavior (Chen et al., 2010), (3) pro-inflammatory mediator levels may affect the underlying circuit of OCD by modifying serotonergic and glutamatergic systems through stimulating indoleamine 2,3-dioxygenase-1 (IDO-1) (Cavaillon et al., 2001; Chakrabarty et al., 2005), (4) streptococcal infections have been associated with the development of OCD (Murphy 2014) and (5) OCD patients have increased anti-basal ganglia-antibody levels compared to healthy controls (Bjattarcharryya et al., 2009). Over the past decade, deep brain stimulation (DBS) for treatment-refractory OCD has emerged as an effective therapy, with an approximate mean response rate of 50% (de Koning et al., 2011). One of the most striking observations of DBS in OCD patients is that symptoms decline dramatically within minutes to hours following DBS activation and may rapidly reoccur after DBS cessation (de Koning et al., 2016).A recent study from our group showed that DBS alters hypothalamic-pituitary-adrenal (HPA)-axis activity. Active stimulation decreased 24-h urinary excretion of free cortisol, which was strongly associated with OCD symptom changes (de Koning et al., 2013). The HPA-axis and the sympathetic nervous system have been implicated in the cross-talk between the brain and the immune system


(Pavlov et al., 2003; Tracey 2002). HPA-axis activity and cytokines have a bidirectional relation as inflammatory cytokines stimulate adrenocorticotrophic hormone (ACTH) and cortisol secretion, while in turn cortisol suppresses the synthesis of pro-inflammatory cytokines (Haddad et al., 2002; Melief et al., 2013). Alternatively, the sympathetic nervous system is capable of altering both pro- and anti-inflammatory gene expression through its main neurotransmitter noradrenalin (Sanders and Straub 2002), potentially through stimulation of β-adrenergic receptors on immune cells (Elenkov et al., 2000).Despite the aforementioned indications of immune involvement, no studies exist that have investigated the effect of DBS on the immune system in OCD patients. If DBS is able to alter immune function this may help to further clarify the underlying working mechanism of DBS for OCD, as well as to increase our understanding of the processes underlying neuro-inflammation in psychiatric disorders. In the current exploratory study we investigated the effect of DBS on the immune system in OCD patients. For this, we measured DBS-induced symptom changes and associated changes in plasma levels of cytokines representative of various inflammatory and immune paths as well as catecholamines and soluble (s)CD163, indicative of microglia/macrophage activation.

METHODS

Study Participants

We included 16 treatment-refractory OCD patients who were treated with DBS for more than 1 year, targeted at the border between the nucleus accumbens and the anterior limb of the internal capsule (vALIC). Participants provided written informed consent before participation, and the local ethics committee approved this study. In- and exclusion criteria for DBS were described recently (de Koning et al., 2016). Participants included 9 men and 7 women, aged between 32 and 56 years. Six participants had one or more comorbid psychiatric disorders: major depressive


disorder (N=4), panic disorder (N=1) and dysthymia (N=1). Nine participants were medication-free for more than 1 year. Seven used psychotropic medication (6 selective serotonin reuptake inhibitors and 1 atypical antipsychotic drugs). No participants suffered from metabolic, endocrine or inflammatory disorders. One participant dropped out of the current study after experiencing severe clinical symptoms following DBS cessation and was therefore excluded from final analyses.

Procedure

The study had a 2-phase design (Figure 1). In phase 1 (P1) we compared a DBS ON and OFF condition with a one-week interval. In phase 2 (P2), we investigated the acute effects of DBS reactivation after 30 minutes, 2 hours and 6 hours. The first measure was performed after the DBS had been constantly activated for at least 1 year: Two blood samples (4.5 ml in EDTA and 6 ml in heparin) (sample 1) were taken in the morning (10:00 AM) from a peripheral intravenous catheter (PVC). The PVC had been placed more than 1 hour in advance of conducting the blood sample and all participants had rested for a minimum of 1 hour. The following day the DBS was turned off. After 1-week of DBS cessation, another blood sample (sample 2) was taken in the morning (mean 11:00 AM), following the same PVC procedure. The PVC remained in place afterwards. After the collection of sample 2 the DBS was reactivated, followed by 3 more consecutive blood sample collections after 30 minutes (sample 3), 2 hours (sample 4) and 6 hours (sample 5). Samples were centrifuged immediately for 10 minutes at 3.000 rpm. The plasma fraction was collected and stored in 0.5-ml aliquots at -50°C. In P1, a trained psychiatrist assessed obsessive-compulsive, anxiety- and depressive symptoms with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D) (Goodman et al., 1989a; Goodman et al., 1989b; Hamilton 1960). As the aforementioned questionnaires are not


applicable for measuring acute symptom changes, we used visual analogue scales (VAS) in P2. Following each blood sample collection in P2, participants assessed their current level of anxiety, depression, obsessive thoughts and need to perform compulsions through a 10-point VAS-scoring (0= no symptoms - 10= most symptoms ever experienced). DBS parameters varied between participants in voltage (3.5–6.2 V), frequency (90–150 Hz) and pulse width (130–185 µsec). We tried to minimize the influence of external factors by leaving medication unchanged during the whole study period, not allowing alcohol, coffee, nicotine or performing excessive exercise 24 hours before each measurement and by measuring CRP values to exclude acute inflammatory episodes.

Figure 1. Summary of the study design (see text for details)

Analytical methods

EDTA-plasma levels of C-reactive protein (CRP) (Alpha Diagnostic, SanAntonio,TX, USA) and sCD163 (eBiosciences, San Diego, CA, USA) weredetermined by enzyme-linked immunosorbent assay (ELISA) according to therespective manufacturer’s instructions. Fifteen cytokines and inflammatorymediators, representative of various inflammatory and immune pathways,


were determined using Luminex on a Bioplex 200 reader (BioRad, Hercules, CA, USA)): interferon-γ(IFN-γ), tumor necrosis factor- α (TNF-α), monocyte chemo-attractant protein-1 (MCP-1/CCL2), IFN-γ induced protein 10 (IP-10/CXCL10), growth-related oncogene- α (GRO-α /CXCL1), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein 1α and 1β(MIP-1α/CCL3, MIP-1β/CCL4) and interleukin (IL)- 1β, IL-4, IL-6, IL-8 (CXCL8), IL-10, IL-12p40 and IL-17A. Adrenalin and noradrenalin were determined with an in-house HPLC method, intra-assay variation: 2-8%, inter-assay variation: 4-9%, detection limit: 0.05 nmol/L.

Statistical analysis

Normality of the data was assessed using the Kolgomorov-Smirnov test. If normality was violated, Wilcoxon signed-rank tests were performed in place of student’s t-tests in P1. We performed a repeated measures analysis of variance for P2. Data is expressed as mean ± standard error of mean (SEM and results are considered significant at p<0.05 (two-tailed). For statistical purposes, out-of-range low cytokine levels were assigned an arbitrary value corresponding to half of the lower limit of detection. All statistical tests were performed with SPSS for Windows 21.0.0.0 (SPSS, Chicago, IL, USA).

RESULTS

CRP

We found no significant changes for median CRP levels in P1 and P2.In all participants, CRP levels were below 5mg/L, except for three participants who had CRP values of 16.2 mg/L, 7.9 mg/L and 28 mg/L during DBS ON in P1. As we found no other markedly increased neuroinflammatory markers we included these participants for further analysis

Cytokines

A number of cytokines were undetectable: IL-1β, IL-6 TNF-α, IL-12p40, IL-


10, IL-17A, G-CSF .The following cytokines were detectable: MIP-1α. IL-4, GRO-α, IL-8, IP-10, IFN-γ, MIP-1β and MCP-1 and were eligible for statistical analyses. We found no significant changes for median IL-4, IP-10 and IFN-γ levels in P1 and P2. Mean IL-8 level (Figure 2A) was (62%) higher during active stimulation (p=0.01) in P1. Thirty minutes of DBS-R resulted in a 94% increase of IL-8 (p=0.01)). At two and 6 hours of DBS-R, IL-8 was still enhanced, but no significant changes occurred anymore compared to 30 minutes of DBS-R. Median Gro-α level was 117% higher during active stimulation (p=0.03) in P1. At 30 minutes and 2 hours of DBS-R, median GRO-α levels were increased by 140% (p=0.04) and 100% (p=0.06), respectively, but at 6 hours significance was lost (Figure 2B). Mean MIP-1β level was 16% (18%) higher (p=0.01) during active stimulation in P1. We found no significant changes during DBS-R. Mean MCP-1 level was 56% (44%) higher (p=0.02 / p=0.05) during active stimulation in P1. We found no significant changes after DBS-R.

sCD163

Mean sCD163 level was 26% higher (p=0.009) during active stimulation in P1. Thirty minutes and 2 hours of DBS-R revealed a trend-wise (p=0.08 and p=0.11) increase of mean sCD163 levels, resulting in a significant 16% increase (p=0.001) 6 hours after DBS-R (Figure 2C).

Catecholamines

We found no significant changes for adrenalin in P1 and P2. Mean noradrenalin levels were 34% higher (p=0.03) during active stimulation in P1 and 39% (p=0.05) and 32% (p=0.03) higher 2 hours and 6 hours following DBS-R, respectively (Figure 2D).


Figure 2. DBS induced changes in plasma levels of (A) IL-8, (B) GRO-α, (C), sCD163 and (D) noradrenalin (D).

Data are depicted as mean (±SEM), * = significant value <0.05, ** = significant value

<0.01.

Psychiatric symptoms

Table 1 summarizes clinical changes related to DBS. All symptom scores changed significantly following long-standing DBS as well as DBS-R. In P1 we found a strong negative association between changes in IL-8 and Y-BOCS scores (rs -0,578 p=0.02) as well as changes in MCP-1 and HAM-A (rs -0.582 p=0.02) (Figure 3A/B). In P2 we found no associations between levels of IL-8, GRO-α, sCD163 and VAS scores.


Table 1. DBS induced changes in psychiatric symptoms during phase 1 and phase 2.

Data are provided as mean (±SD). DBS deep brain stimulation, N/A not applicable, Y-BOCS Yale-Brown Obsessive-Compulsive Scale, HAM-A Hamilton Anxiety Rating, Scale HAM-D Hamilton Depression Rating Scale,VAS Visual Analog Scale, Obs. obsessions, Comp. compulsions, Anx. anxiety, Depr. Depressive.

DISCUSSION

To our knowledge, this is the first exploratory study to evaluate the immune-modulatory effect of DBS in OCD-patients. We found increased levels of pro-inflammatory mediators, particularly chemokines following chronic DBS as compared to DBS OFF (IL-8, MCP-1, MIP-1β) as well as following acute DBS-R (IL-8 and GRO-α). Noradrenalin levels were significantly higher during chronic DBS, as well as 2 and 6 hours following DBS-R. Furthermore, the macrophage/microglia activation marker sCD163 was enhanced during

Sample

1 DBS ON

(>1yr)

Sample

2 DBS OFF

(1wk)

P-value 1à2

Sample

3 DBS ON

(30min)

P-value 2à3

Sample

4 DBS ON

(2hrs)

P-value

2à4

Sample

5 DBS ON

(6hrs)

P-value

2à5

Y-BOCS 19.7

(7.0)

28.6

(5.1)

P=0.001 N/A N/A N/A N/A N/A N/A

HAM-A 16.3

(9.1)

30.2

(10.2)


HAM-D 13.8

(8.7)

26.0

(8.9)


VAS

Obsession

3.4

(2.3)

6.1

(2.5)

P=0.005 3.0

(1.9)

P=0.001 2.6

(2.1)

P=0.001 2.5

(1.5)

P=0.002

VAS

Compulsio

n

3.3

(2.3)

5.6

(2.1)

P=0.004 2.5

(1.9)

P=0.000 2.6

(2.1)

P=0.001 2.6

(1.7)

P=0.002

VAS

Anxiety

2.8

(1.8)

6.1

(2.5)

P=0.001 3.4

(2.3)

P=0.002 2.4

(1.5)

P=0.000 2.0

(1.1)

P=0.001

VAS

Depression

2.6

(2.1)

5.8

(2.9)

P=0.002 3.0

(2.2)

P=0.003 2.0

(1.5)

P=0.001 1.8

(0.9)

P=0.001


chronic DBS and raised slowly (6 hours) following DBS-R. Immunomodulatory cytokines, including TNF-α, IL-1β, IL-6, IL-10, 12p40 and IL-17A, remained unchanged or showed out of lower limit levels. Finally, increases of IL-8 and MCP-1 during chronic DBS inversely correlated with changes in obsessive-compulsive (Y-BOCS) and anxiety symptoms (HAM-A), respectively. Our data suggest a direct effect of DBS on the immune system through either peripheral or local circuits. Firstly, decreased HPA-axis activity may underlie a peripheral pro-inflammatory response, as its end-product cortisol is known to suppress neuro-inflammation (Haddad et al., 2002). This hypothesis is in line with the results of a previous study by our group, showing that long-standing DBS decreased 24-hour urinary cortisol levels (de Koning et al., 2013) as well as with a recent study in Wistar rats showing that DBS of the hypothalamic nucleus induced a systemic inflammatory response accompanied by decreased corticosteroid concentrations (Calleja-Castillo et al., 2013). In the

Figure 3. Association between changes in (A) IL-8 plasma levels and OCD-symptoms (Y-BOCS) ,as well as between changes in (B) MCP-1 plasma levels and anxiety levels (HAM-A), both in phase 1.

Il-8 interleukin-8, OCD obsessive-compulsive disorder, Y-BOCS Yale-Brown Obsessive-Compulsive Scale, MCP-1 monocyte chemo-attractant protein-1, HAM-A Hamilton Anxiety Rating Scale.


current study we did not assess HPA-axis activity, as the design of our study did not permit us to measure cortisol levels due to the interference with the circadian rhythm of cortisol. However, the rapidity of the pro-inflammatory response (<30min) makes it unlikely that there is key role for the indirect, and therefore relatively slow, HPA-axis pathway. Moreover, glucocorticoids affect chemokine production by macrophages in a complex and not solely inhibitory manner (van de Garde et al., 2014).Alternatively, the sympathetic nervous system may alter peripheral pro-inflammatory expression through its main neurotransmitter noradrenalin. Notably, noradrenalin levels were higher in the chronic DBS condition compared to DBS-OFF and increased again following acute DBS reactivation. Although we found no significant associations between changes in plasma noradrenalin level with changes in plasma cytokine and sCD163 levels, they all followed a strikingly parallel course. The sympathetic nervous system is known to be a fast-acting immune pathway because noradrenalin, stored in vesicles, can be released immediately upon stimulation from noradrenergic nerve terminals (Sanders and Straub et al., 2002). Although noradrenalin generally inhibits type 1 and stimulates type 2 cytokine secretion, in certain local responses, noradrenalin may actually boost regional immune responses, primarily through IL-8 production by various cell types (Elenkov et al., 2000). Finally, the significant DBS-related changes of the macrophage/microglia marker sCD163 would be in line with local microglia involvement underlying the pro-inflammatory DBS response. Microglia, being the resident macrophages of the brain, are a source of cytokines in the brain (Kim & de Vellis 2005) and due to their low molecular weights IL-8 (11kDa), MIP-1β (7.8kDa), MCP-1 (12kDa) and GRO-α (7.9kDa) can pass the blood brain barrier following local release. Microglia may directly alter corticostriatal circuit activity by (1) secreting cytokines/neurotransmitters that control synaptic functions (Santello et al., 2011), (2) recruiting astrocytes, through ATP secretion, that induce a release of presynaptic glutamate (Piccinin et al., 2010 / Ragozzino et al., 2006) or (3) physically contacting synaptic elements through their processes (Béchade et


al., 2013). The role of microglia in DBS for OCD remains worth investigating as accumulating evidence hints at microglia dysfunction in several psychiatric disorders (Reus et al., 2015 / Beumer et al., 2012), while an OCD mouse model demonstrates a role for Hoxb8-expressing microglia in modulating OCD-like behavior (Chen et al., 2010). Alternative sources of local cytokine production in the brain are astrocytes, which are known regulators of neuronal synaptic networks through release of ATP and glutamate (Fellin et al.,2009). Astrocyte involvement is especially interesting as individual human astrocytes are capable of interacting with up to two million synapses and they can be directly activated by high frequency electrical stimulation (DBS) (Vedam-Mai et al., 2012). As opposed to a direct stimulation effect, microglia or astrocyte activation underlying the observed immune changes may be the result of DBS-induced local brain tissue damage or inflammation as mentioned by several studies indicating DBS is able to indirectly affect glia cells this way (Cicchetti et al., 2014).The rapid secretion following DBS reactivation suggests the release of préformed cytokines. De novo synthesis seems less likely as it takes up to several hours before cytokines are released. Similarly, the increase in sCD163 is likely due to enhanced proteolytic cleavage rather than CD163 gene expression. This is also suggested by the fact that CD163 gene expression is induced by glucocorticoids and correlates with glucocorticoid levels and HPA-axis activity (Etzerodt et al., 2013; van de Garde et al., 2014). Of note, the fast kinetics of pro-inflammatory mediators upon DBS-R show a strikingly inverse-parallel course with decline in symptoms within minutes to hours that is seen in OCD patients upon DBS-R. The rapidity of the observed symptom changes makes peripherally secreted pro-inflammatory chemokines through HPA-axis or SNS involvement less likely. Especially as the plasma level of circulating inflammatory mediators following stimulation are relatively low and the amount of cytokines entering the brain is modest (Banks et al., 1995). More so, the hypothesis of DBS activating microglia or astrocytes, that subsequently alter


neuronal OCD networks seems promising. However, the causality of these rapid immune and clinical changes remains to be determined.Our study comprises several limitations. First of all, the small sample size did not permit us to exclude for several possible confounders, such as medication use and comorbid depressive disorders (Gray & Bloch 2013). Our study contained 4 patients with a comorbid depressive disorder, 1 patient with dysthymia and 7 participants used psychotropic medication. Therefore, we cannot exclude that these factors partially biased our results. However, we each participant acted as his/her own control. Furthermore, we did not measure circulatory levels of acetylcholine and cortisol. Therefore, we were unable to further explicate the contribution of the HPA-axis and the vagus nerve as cholinergic signaling controls immune function and pro-inflammatory responses via the inflammatory reflex (Pavlov & Tracey 2012).In conclusion, our findings suggest that DBS has pro-inflammatory effects that correlate with DBS-induced OCD symptom improvement. The strikingly rapid alterations in inflammatory mediators following DBS strongly imply a causal relationship between DBS, immune modulation and OCD, which warrants further mechanistic investigation.


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Part IVThe role of

dopamine in deep brain stimulation

for obsessive-compulsive disorder

Chapter 6

Biological Psychiatry, 2014 Apr 15;75(8):647-52

Figee M, de Koning P, Klaassen S, Vulink N, Mantione M, van den Munckhof P, Schuurman PR, van Wingen G, van Amelsvoort T, Booij J,

Denys D

Deep brain stimulation induces striatal

dopamine release in obsessive-compulsive

disorder

Chapter 6. Deep Brain Stimulation Induces Striatal Dopamine Release In Obsessive-Compulsive Disorder | 107

DEEP BRAIN STIMULATION INDUCES STRIATAL DOPAMINE RELEASE IN OBSESSIVE-COMPULSIVE DISORDERObsessive-compulsive disorder is a chronic psychiatric disorder related to dysfunctional dopaminergic neurotransmission. Deep brain stimulation (DBS) targeted at the nucleus accumbens (NAc) has recently become an effective treatment for therapy-refractory obsessive-compulsive disorder, but its effect on dopaminergic transmission is unknown. We measured the effects of NAc DBS in 15 patients on the dopamine D2/3 receptor availability in the striatum with [123I]iodobenzamide ([123I]IBZM) single photon emission computed tomography. We correlated changes in [123I]IBZM binding potential (BP) with plasma levels of homovanillic acid (HVA) and clinical symptoms. Acute (1-hour) and chronic (1-year) DBS decreased striatal [123I]IBZM BP compared with the nonstimulated condition in the putamen. BP decreases were observed after 1 hour of stimulation, and chronic stimulation was related to concurrent HVA plasma elevations, implying DBS-induced dopamine release. BP decreases in the area directly surrounding the electrodes were significantly correlated with changes in clinical symptoms (45% symptom decrease). NAc DBS induced striatal dopamine release, which was associated with increased HVA plasma levels and improved clinical symptoms, suggesting that DBS may compensate for a defective dopaminergic system.

INTRODUCTION

Deep brain stimulation (DBS) has recently become an effective treatment for therapy-refractory obsessive-compulsive disorder (OCD) (de Koning et al., 2011). The effects of DBS are substantial, with on average almost 50% improvement of obsessive-compulsive symptoms (Denys et al., 2010). Despite these promising clinical observations, remarkably little is known about the underlying mechanism of action. OCD has been related to abnormalities in dopaminergic neurotransmission, predominantly on the basis of clinical


evidence and molecular imaging studies. For example, dopamine receptor antagonists are effective as an adjunct to selective serotonin reuptake inhibitors in reducing symptoms in OCD (Vulink et al., 2009), and dopamine agonists may induce obsessive-compulsive behavior (Bocherding et al., 1990). Molecular imaging studies consistently showed decreased dopamine D2/3 receptor (D2/3R) binding in OCD (Denys et al., 2004), most prominently in the ventral striatum (Perani et al., 2008). Most effective DBS targets for OCD are in or around the ventral striatum (de Koning et al., 2011), and animal studies suggest that DBS in this area increases dopamine levels in the stimulated area or prefrontal cortex (Sesia et al., 2010 & van Dijk et al. 2011). We therefore hypothesized that striatal dopamine release may be one of the key mechanisms of action behind DBS for OCD. We analyzed dopaminergic changes of DBS targeted at the border of the nucleus accumbens (NAc) core and anterior limb of the internal capsule in OCD patients, using [123I]iodobenzamide single photon emission computed tomography ([123I]IBZM SPECT) and plasma measurements of the dopamine metabolite homovanillic acid (HVA), which is thought to partially reflect central dopaminergic and noradrenergic changes.

METHODS AND MATERIALS

Study Participants

We included 15 DBS-implanted patients with OCD and 18 age- and gender-matched healthy control subjects (Table 1). Patients were recruited from the outpatient clinic for DBS at the Academic Medical Center, Amsterdam, The Netherlands. Healthy control subjects were only included if they were free of any mental disorder, had no family history of any psychiatric disorder, and reported no history of head trauma, neurological or other medical disorders, or alcohol or other substance abuse. Participants provided written informed consent before participation, and the local ethics committee approved this study.


Table 1. Demographics of the study sample

Patients(n=15) Controls(n=18) Statistic

Age,mean(SD),years 43.8(10.1) 38.3(17.9) t=1.048P=0.303

Gender,Male:Female,Number 7:8 9:9 χ2=0.133

P=0.716

All included patients had a primary diagnosis of OCD, according to DSM-IV criteria using the Structured Clinical Interview for DSM-IV Axis I disorders (First et al., 1997). Eight patients had predominantly OCD symptoms of the subtype contamination fear, four patients had predominantly high-risk assessment and checking symptoms, two patients mainly suffered from perfectionism, and one patient had somatic obsessions. Mean duration of illness was 25.9 years (range 8–48 years). Four patients were diagnosed with comorbid major depressive disorder, one patient was diagnosed with comorbid panic disorder, and three patients were diagnosed with comorbid obsessive-compulsive personality disorder. Nine patients were medication-free for at least 1 year at the time of this investigation. Six patients had been using medication before the study for 11 to 63 months (mean 23 months). Because of potential interference with [123I]IBZM binding to dopamine D2/3R, medication was discontinued according to its pharmacological half-life: 16 days before the first scan for clomipramine (three patients), 12 days for paroxetine (one patient), 24 days for fluoxetine (one patient), and 1 week for fluvoxamine (one patient). At the day of the imaging session and within 24 hours before each scanning session, participants were not allowed to consume coffee, alcohol, or nicotine because these substances have been associated with increased striatal dopamine release. Four patients and two control subjects smoked. Patients were chosen from a larger clinical DBS sample when they had finished the treatment optimization phase and remained clinically stable after at least 1


year of stimulation. At this stage, 12 patients had decreases on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) of more than 25%, corresponding to responder status, and 3 patients experienced less than 25% decrease (12% in 1 patient and 17% in 2 patients).

DBS Settings

All patients had electrode implantation in the same target area [for details, see Denys et al. (2)]: two quadripolar electrodes (Model 3389, Medtronics Inc., Minneapolis, Minnesota) with contact points 1.5-mm long and separated from adjacent contacts by .5 mm were implanted bilaterally following the anterior limb of the internal capsule into the target nucleus, with an anterior angle of approximately 75° to the intercommissural line. Target coordinates for the electrode tip were 7 mm lateral to the midline, 3 mm anterior to the anterior border of the anterior commissure, and 4 mm inferior to the intercommissural line. We included only patients who had completed the optimization phase of 1 to 2 years during which they were evaluated every 2 weeks for severity of symptoms and optimal stimulation parameters. For all 15 patients, receiving monopolar stimulation on the two dorsal contact points, the most effective stimulation area was located at the border of the NAc core and anterior limb of the internal capsule. At time of entrance of the study, patients were stimulated with an average of 4.8 V (range 3.5–6.2), a frequency of 130 hertz (11 patients) or 185 hertz (4 patients), and a pulse-width of 90 microseconds (12 patients), 130 microseconds (2 patients), or 150 microseconds (1 patient).

Symptom Measures

We assessed symptom severity in patients during chronic stimulation (Session 1: clinically stable after at least 1 year of stimulation), during DBS OFF (Session 2: after 8 days of DBS discontinuation), and during acute stimulation (Session 3: 1 hour after turning the stimulator back on). Symptom severity was assessed using the Y-BOCS Goodman et al., 1989 & Goodman et al., 1989), the Hamilton


Depression Rating Scale (Hamilton, 1960), and the Hamilton Anxiety Rating Scale (Hamilton, 1959).

SPECT Data Acquisition

All patients were scanned on three separate occasions: during chronic stimulation, DBS OFF and acute stimulation (Sessions 1-3). All healthy control subjects were scanned once. Subjects received a potassium iodide solution to block thyroid uptake of free radioactive iodide. For administration of the radiotracer, we used a sustained equilibrium/constant infusion technique to achieve stable regional brain activity levels during scanning (Boot et al., 2008 & Booij et al., 1997). In Session 1, D2/3R were measured with the well-validated radiotracer [123I]IBZM, whereas the patients were on chronic DBS stimulation. In this session, approximately 80 MBq [123I]IBZM (specific activity >200 MBq/nmol and radiochemical purity >95%) was administered intravenously as bolus, followed by 3 hours of continuous infusion of 20 MBq/hour [123I]IBZM. Acquisition of the images started 2 hours after the bolus injection when a state of sustained binding equilibrium can be expected (Booij et al., 1997). Also the healthy control subjects were scanned using this paradigm. In Session 2, patients were scanned after 8 days DBS discontinuation (DBS OFF). In Session 3, 1 hour after Session 2, patients were scanned after 1 hour of acute stimulation. For Sessions 2 and 3, approximately 80 MBq [123I]IBZM was administered intravenously as bolus, followed by 5 hours of continuous infusion of 20 MBq/h [123I]IBZM. In the interval 2 to 3 hours after [123I]IBZM bolus injection, patients were scanned to measure D2/3R in the DBS OFF situation. The stimulation was then reactivated, and 1 hour later (i.e., the interval between 4 and 5 hours after [123I]IBZM bolus injection), the patients were scanned again to assess the effects of acute stimulation because previous [123I]IBZM SPECT studies have shown that 1 hour after the induction of dopamine release, a new steady state is established (Booij et al., 1997). The SPECT scans were acquired on a 12-detector single-slice brain-dedicated scanner (Neurofocus 810, which is an upgrade of the Strichmann Medical Equipment, Medfield,


Massachusetts), with a full-width at half maximum resolution of approximately 6.5 mm, throughout the 20 cm field-of-view (http://www.neurophysics.com). After positioning of the subjects with the head parallel to the orbitomeatal line, axial slices parallel and upward from the orbitomeatal line to the vertex were acquired in 5-mm steps. Each acquisition consisted of approximately 10 to 12 slices with 5-minute scanning time per slice, acquired in a 64 × 64 matrix. The energy window was set at 135 to 190 keV.

Magnetic Resonance Imaging Data Acquisition

Coregistered T1-weighted structural images of all implanted patients were acquired on a 1.5-Tesla Siemens MAGNETOM Avanto Scanner (Siemens AG, Healthcare Sector, Erlangen, Germany). To minimize exposure of the DBS device to the pulsed radiofrequency field, we scanned all subjects using a transmit/receive head coil. Two minutes before patients entered the scanner, the DBS system was turned off and programmed at 0 V in bipolar mode. Specific absorption rate levels were limited to .1 W/kg. For T1-weighted structural images, the following parameters were used: field of view 256 mm, voxel size 1 × 1 × 1 mm3, slice thickness = 1 mm.

SPECT Data Analysis

SPECT data were reconstructed and analyzed while blind to clinical data. Our primary outcome parameter was nondisplaceable binding potential (BPND) of [123I]IBZM, as a measure of D2/3R availability. BPND was calculated as [123I]IBZM binding in the target tissue minus activity in the reference tissue divided by activity in the reference tissue. We used binding in the occipital cortex, which is devoid of D2/3R, as reference tissue. We first performed attenuation correction of all SPECT images and then reconstructed them in three-dimensional (3D) mode (http://www.neurophysics.com) (Boot et al., 2008 & Booij et al., 1997). With these 3D images, we performed two different region of interest (ROI) analyses. First, for quantification of BPND in the striatum and its


subdivisions in patients and controls, we used standard templates with fixed ROIs on the 3D SPECT images (Figure 1A). Striatal BPND was calculated by first selecting three consecutive SPECT slices, representing the most intense striatal binding. Next, standard templates with fixed ROIs were manually placed on the striatum and occipital cortex, which we used for the calculation of the ratio of specific striatal (caudate nucleus and putamen) to occipital binding (BPND). Second, for quantification of BPND in the stimulated area of the patients, we defined ROIs based on the individual coregistered magnetic resonance imaging (MRI) scans (Figure 1B). We manually realigned each individual SPECT scan to the MRI data in all three dimensions followed by an automated registration based on a mutual information algorithm with in-house software (van Herk et al., 2000). We calculated the radius of the electrode activation centers for each patient using the individual DBS voltage settings in the following formula: R (mm) = √(Voltage/3) * 3 (Butson et al., 2006). Next, ROIs were manually delineated on the MR image by drawing a 3D sphere of radius R around the centers of the active electrode points. We also manually delineated ROIs around the occipital cortex on each MRI slice and then calculated the ratio of specific binding in the ROI to occipital binding (BPND).

HVA Data Acquisition and Analysis

Ten milliliters of blood was collected for assessment of peripheral HVA levels during the three sessions (chronic stimulation, DBS OFF, acute stimulation), right after each SPECT scan acquisition. Timing of HVA samples was standardized to limit diurnal variation. The blood samples were collected in ice-chilled polypropylene tubes containing ethylenediamine tetraacetate. Tubes were centrifuged at 3000 rpm for 15 min at 4°C and plasma was stored at −20°C until analysis. Plasma levels of HVA were determined by liquid chromatography (Shimadzu, Eindhoven, The Netherlands) and electrochemical detection (DECADE 1 equipped with a VT-03 cell at a potential setting of 700 mV vs. Ag/AgCl reference electrode at 40°C; ANTEC Leyden, Zoeterwoude, The Netherlands). The sensitivity of the method for HVA was 2 ng/mL plasma,


and the coefficient of variation was less then 6% (Westenberg et al., 1988).

Figure 1. (A) Example of transverse single photon emission computed tomography slice with fixed regions of interest placed on the striatum, caudate nucleus, putamen and occipital cortex. (B) Example of two corresponding coronal magnetic resonance imaging and single photon emission computed tomography slices with regions of interest of stimulated area (red) based on a manually delineated sphere around the active contact points (white asterisk)

Statistics

We used repeated-measures analysis of variance to analyze symptomatic and dopaminergic changes between the three sessions and a two-sample t test for comparing patients and healthy control subjects. We included hemisphere in our analyses of DBS-induced [123I]IBZM binding because the stimulation was applied in the left and right hemisphere, and based on previous studies, we expected that this would result in different effects on either side (Kuhn et al., 2012). Correlation analyses were performed applying Pearson’s correlation. All statistical tests were computed with SPSS for Windows 18.0 (SPSS Inc., Chicago, Illinois).


RESULTS

Symptom Changes

Figure 2 summarizes clinical changes related to DBS. Active stimulation (acute or chronic stimulation) compared with DBS OFF was related to an average 35% improvement of obsessive-compulsive symptoms, 49% improvement of depressive symptoms, and 46% improvement of anxiety symptoms. All symptom scores changed significantly over the three sessions, with increases from chronic stimulation to DBS OFF, and decreases from DBS OFF to acute stimulation (Y-BOCS F2,13 = 10.42, p = .002; Hamilton Depression Rating Scale F2,13 = 13.08, p = .001; Hamilton Anxiety Rating Scale F2,13 = 9.16, p = .003).

Figure 2. Deep brain stimulation–induced symptom changes.

DBS OFF deep brain stimulation discontinuation for 8 days, HAMA Hamilton Anxiety Rating Scale;HAMD Hamilton Depression Rating Scale; YBOCS Yale-Brown Obsessive-Compulsive Scale. Error bars indicate SEM.


Table 2. [123]iodobenzamide Binding Potential in Control Subjects and Patients

BPND(SEM)ROI

controls 1.chronicstimulation

2.DBSOFF

3.acutestimulation

P1 change1»2

change2»3

Caudateleft 1.28(0.06) 0.89(0.10) 1.01(0.16) 0.86(0.10) 0.082 13.5% -14.9%

right 1.16(0.04) 0.78(0.10) 0.87(0.15) 0.85(0.09) 0.001 11.5% -2.3%

Putamenleft 1.43(0.06) 0.91(0.10) 1.03(0.13) 0.90(0.08) 0.015 13.2% -12.5%

right 1.20(0.06) 0.87(0.10) 0.96(0.11) 0.95(0.07) <0.001 10.3% -1.0%

Stimulatedregion 0.52(0.15) 0.62(0.17) 0.41(0.13) 19.2% -21.0%

BPND, nondisplaceable binding potential; DBS, deep brain stimulation; ROI, region of interest. P1 is for BPND difference between control subjects and the average of Sessions 1 through 3 in patients (independent t test).

Changes in Dopamine D2/3 Receptor Binding

Active stimulation (acute or chronic) compared with DBS OFF was related to an average 10.2% decrease of striatal BPND and an average 20.1% decrease of BPND in the stimulated area. Repeated-measures analysis of variance for the three scanning sessions showed a significant time by hemisphere interaction in the putamen (F2,13 = 6.34, p = .012). Contrasts showed an increase of BPND in the putamen from chronic stimulation to DBS OFF in both hemispheres (p = .044), which reversed more rapidly in the left than right putamen after acute stimulation (p = .002). Although we found a similar pattern of results in the caudate and in the stimulation area (i.e., BPND increases from chronic stimulation to DBS OFF followed by a reversal from DBS OFF to acute stimulation), these changes were not significant. Nevertheless, we found a positive correlation between [123I]IBZM BPND changes and Y-BOCS changes in the stimulation area between chronic stimulation and DBS OFF (r = .536, p = .039). BPND changes in putamen and caudate were not correlated to changes in Y-BOCS scores. BPND changes in the putamen remained statistically significant when including medication, OCD subtype, treatment response, age, or duration of illness as covariates.


Figure 3. D2/3 receptor binding potential in controls and patients.

BPND nondisplaceable binding potential; DBS deep brain stimulation. Error bars indicate SEM.

Peripheral Dopaminergic Changes (HVA)

Patients with or without stimulation had higher plasma HVA levels than healthy control subjects (Figure 4). Our results of lower [123I]IBZM BPND during stimulation indicate increased dopamine. Therefore, we tested the hypothesis that stimulation would increase plasma HVA levels as a peripheral indication of dopamine release. Active stimulation (acute or chronic) compared with DBS OFF induced an average 17.8% increase in plasma HVA levels. HVA decreased significantly from chronic stimulation to DBS OFF (t13 = 2.37, p = .034), which correlated with increases in obsession scores (r = –.699, p = .013). HVA did not change significantly from DBS OFF to acute stimulation.


Figure 4. Plasma homovanillic acid (HVA) levels in control subjects and patients.

DBS deep brain stimulation. Error bars indicate SEM.

DISCUSSION

This study shows that DBS targeted at the NAc for OCD induces a reduction in striatal D2/3R binding. Patients who had received stimulation for either 1 hour or 1 year had improved symptom scores and lower availability of striatal D2/3 receptors as measured by [123I]IBZM binding, compared with DBS OFF for 1 week.To the best of our knowledge, no other study has investigated in vivo dopaminergic changes of acute and chronic DBS using a combination of central and peripheral measures. Increased postmortem tissue concentrations of dopamine have been found in the NAc shell of rats after acute stimulation of that area (7), and acute stimulation of the NAc core increased dopamine release in prefrontal areas but not in the stimulated area, as measured with in vivo microdialysis (van Dijk et al., 2011). Comparable to our findings, chronic DBS


decreased D2/3R availability in the putamen of three patients with Parkinson’s disease with globus pallidus internus electrodes (Nakajima et al., 2003) and of two patients with Tourette’s disorder with thalamic electrodes (Kuhn et al., 2012), although the latter study found opposite results in the thalamus. Decreased D2/3R availability in these studies may reflect increased competition with the radiotracer caused by dopamine release, or alternatively, diminished D2/3R affinity or a structural receptor decrease due to downregulation. BP decreases in our study likely reflect dopamine release because they occurred already during the first hour of stimulation. Although concurrent HVA increases during stimulation also indicate dopamine release, results in the chronic stimulation condition may still be explained by D2/3R downregulation.Dopamine release in the putamen suggests direct excitatory effects of DBS on this structure, which is situated adjacent to the stimulation site at the border of the NAc and internal capsule. Alternatively, stimulation may have spread from the ventral to the dorsal striatum through spiraling striato-nigro-striatal pathways (Haber et al., 2000) given that there is evidence for functional hyperconnectivity between these regions in OCD (Harrison et al., 2009).The finding of stimulation related D2/3 decreases, away from values in healthy control subjects, may seem paradoxical and warrant clarification. Similar to our finding, lower striatal D2/3R BP in OCD patients relative to control subjects has been consistently reported in other studies (Denys et al., 2004 & Perani et al., 2008 & Schneier et al., 2008), which is usually interpreted as D2/3R downregulation due to increased dopaminergic neurotransmission. However, recent acute dopamine depletion studies indicate that lower D2/3R availability might actually also be related to decreased endogenous dopamine (Martinez et al., 2009). Pharmacological-induced dopamine depletion can induce obsessive-compulsive symptoms (de Haan et al., 2005) and habitual responding (de Wit et al., 2012), whereas dopamine agonists can improve compulsive behaviors in drug-addicted subjects (Erschke et al., 2011). These lines of evidence and the fact that our OCD patients were all nonresponders to dopamine antagonizing agents imply an underlying dopaminergic deficit


in this refractory group that is compensated by stimulatory dopamine release. Lower D2/3R availability in patients without stimulation (DBS OFF) may thus reflect increased receptor occupancy or downregulation related to intrinsic compensatory dopamine release, which is further aggravated by DBS. Finally, the observed dopamine release induced by DBS in our study may compensate for serotonergic deficits because OCD has been related to serotonergic deficits combined with dopaminergic hyperactivity (Perani et al., 2008). DBS-induced dopamine release might also explain why higher voltages can induce behaviors that have been linked to excessive striatal dopaminergic activity, such as impulsivity, pathological buying (Luigjes et al., 2011), and tics (unpublished observation).This study has a number of potential limitations. We have only scanned our healthy control subjects once, so we cannot rule out that changes over the three sessions in patients are not related to stimulation but rather to spontaneous fluctuations in time. However, we found D2/3R BP changes in the range of 10% to 21%, which is highly unlikely in case of spontaneous fluctuations because the reproducibility of the measurement of dopamine release with the bolus/constant infusion [123I]IBZM SPECT technique is high in humans (Kegeles et al., 1999). Moreover, D2/3R and HVA changed in the same direction during acute and chronic stimulation. Together these characteristics strongly support an effect of stimulation. Variance in BPND values was larger in the stimulation area than the putamen and caudate nucleus, which could be related to the lower BPND compared with the putamen and caudate nucleus and may explain why BPND changes in the stimulation area failed to reach significance levels. In addition, our current nonstimulation condition of 8 days of DBS discontinuation is not a true baseline pretreatment measure for comparison with stimulation conditions. Other results may have been found when comparing patients before implantation with acute and continued stimulation. Nevertheless, symptom severity during DBS OFF in the present study was comparable to severity that patients reported before implantation (Denys et al., 2010). Also, DBS discontinuation longer than 8 days may have yielded stronger


dopaminergic changes; however, we felt that the severity of symptom relapse had to be balanced against scientific value. Notably, DBS discontinuation or acute activation was followed by changes in anxiety and mood within seconds or minutes, and changes in obsessions and compulsions occurred within the first minutes to hours. Thus, our measures appear to reflect clinical relevant changes. Another potential limitation is that we cannot completely rule out the possibility that the plasma HVA changes we found reflect not only central dopaminergic changes but also noradrenergic changes. Finally, we could not accurately delineate striatal areas on coregistered MRI scans because of artifacts around the electrodes, and for safety reasons images were acquired on a 1.5-T MRI scanner with low specific absorption rate values, resulting in relatively low gray to white matter contrast in the striatum.In conclusion, DBS targeted at the NAc appears to release dopamine in the striatum, which is related to improved control over obsessive-compulsive behaviors. These changes hint at a causal role of dopamine in the therapeutic efficacy of DBS, but future research should clarify whether they co-occur with other mechanisms.


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Part VDiscussion

Chapter 7

Summary, Discussion and Methodological considerations

Chapter 7. Summary, Discussion and Methodological considerations | 131

SUMMARY, DISCUSSION AND METHODOLOGICAL CONSIDERATIONS

SUMMARY

In the introduction I presented the extraordinary DBS response of Ms. V. who was experiencing a severe relapse of affective and obsessive-compulsive symptoms following the discontinuation of the stimulation. We observed that reactivation of the DBS relieved her from her agonizing symptoms within seconds to minutes after stimulation initiation, which further enticed my interest in exploring the underlying mechanism of DBS for OCD. The main aim of this thesis was to investigate the rapidity of the DBS response as well as various potential working mechanisms. We used clinician rated questionnaires and visual analogue scoring for assessing clinical symptom response, peripheral plasma and urine measures to investigate involvement of the hypothalamic-pituitary-adrenal (HPA)-axis, other neuroendocrine mechanisms and the immune system, and nuclear imaging (SPECT) for investigating striatal dopamine. As our aim was to generate hypothesis we focused on characterizing and possibly linking of the different pathways with each other in connection with clinical symptoms and the cortical-striatal circuit.

DBS IS AN EFFECTIVE, SAFE AND RAPID ACTING TREATMENT MODALITY FOR TREATMENT-REFRACTORY OCD

In the first part of this thesis, I focus on the efficacy and adverse events of all published DBS targets in a review article of nine open (case) and seven controlled trials of DBS for OCD (total N=63) (Chapter 2). I found a global percentage of responders of 54% (>35% Y-BOCS decrease). The frequency of adverse-events was limited, with transient hypomania being the most commonly observed side effect following stimulation activation. Serious procedure-related events are rare, and side effects can be reversed by cessation or adjustment of the stimulation parameters. In chapter 4 I investigated the


effect of long-term DBS, as well as rapid clinical symptom changes following DBS reactivation (DBS-R). The results demonstrate that after one-week of active DBS, stimulation discontinuation substantially increased mood, anxiety and OCD symptoms, while 30 min of DBS-R already resulted in a rapid and simultaneous ±50% improvement of clinical symptoms.

DBS INDUCES WIDESPREAD NEUROENDOCRINE CHANGES

In Chapter 3 I reported that long-term DBS is associated with a decrease in 24-hour urinary free cortisol (UFC) and that this change is in strong association with obsessive-compulsive and depressive symptom changes measured with the Y-BOCS and HAM-D. We found no changes in 24-hour urinary adrenaline or noradrenaline excretion.In Chapter 4, I assessed neuroendocrine parameter changes of DBS. We showed that clinical changes were inversely associated with changes in plasma TSH and prolactin, both following DBS OFF as well as already 30 min after DBS-R. Subsequently we hypothesized that the rapid and simultaneous increase in prolactin and TSH is likely to result from stimulation of hypothalamic thyrotropin-releasing hormone (TRH), which may underlie the commonly observed transient mood improvement following DBS.

DBS INDUCES RAPID LOCAL IMMUNE CHANGES:

In chapter 5 I measured long-term and rapid effects of DBS for OCD on the immune system. Our findings suggest that DBS has pro-inflammatory effects that correlate with DBS-induced OCD symptom improvement. The strikingly rapid alterations in inflammatory mediators following DBS strongly imply a causal relationship between DBS, immune modulation and OCD, possibly through astrocyte or microglia regulation.

DBS INDUCES STRIATAL DOPAMINE RELEASE

In chapter 6 we showed that both central and peripheral dopamine measures


suggest that DBS induces striatal dopamine release. Patients on long-term DBS, compared to a 1-week DBS OFF condition, showed improved OCD symptom scores and lower availability of the SPECT radiotracer [123]IBZM that binds to striatal D2/3 receptors, as well as increased plasma levels of the dopamine/noradrenaline metabolite HVA.

GENERAL DISCUSSION AND FUTURE DIRECTIONS

DBS EFFICACY, RAPIDITY AND ITS CLINICAL RELEVANCE

The first part of this thesis comprises a general review on the efficacy and adverse events of all published DBS targets for OCD: ventral striatum/ventral capsule, anterior limb of the internal capsule, nucleus accumbens, subthalamic nucleus and inferior thalamic peduncle. We enclosed nine open (case) and seven controlled DBS trials (total of 63 patients) using different brain targets, study designs, number of participants, duration of follow-up, on-off phase duration, electrode models and stimulation parameters (Chapter 2). Responder rate was generally defined by a minimum 35% reduction in Y-BOCS score after surgery. Although one should be careful interpreting these studies because of the aforementioned differences in designs and brain targets, the global percentage of responders was 54%. Unfortunately, due to the differences in designs and relative small numbers we were unable to compare responder rates between the various DBS targets. However, our findings are in concordance with a recent meta-analysis of 31 DBS for OCD studies involving 113 patients (Alonso et al., 2015) reporting a global percentage of responders at 60% and finding no significant differences in efficacy between targets. Regarding side-effects, we were especially interested in undesired effects caused by the stimulation or cessation of stimulation, because procedure-related complications and device-related problems have already been assessed from the extensive literature on patients implanted with DBS for movement disorders (n>150.000). Undesired stimulation effects can be largely


divided into effects on mood and effects on cognition. DBS may be considered a safe method in terms of cognition with solely minor reduced performance on executive functioning, possibly associated with the surgical intervention (Mantione et al., 2015). Transient mood improvement, sometimes to the extent of hypomanic or manic symptoms, is the most frequently described side-effect of DBS of the ALIC, NAc and STN (Okun et al., 2007; Tsai et al., 2014). Although Alonso et al. (2015) reported a 19.8% prevalence of hypomanic symptoms in a recent meta-analysis involving 113 OCD patients with DBS, they did not speculate on the clinical relevance of this finding. Clinical observations, as well as DBS efficacy studies report a typical sequential response pattern in DBS for OCD in the DBS optimization phase (Denys et al., 2010). This sequential improvement is characterized by an acute improvement of mood (minutes), a subsequent decrease of anxiety (hours), a decelerated decrease in obsessions (days-weeks) and finally compulsions (weeks-months). More so, Haq et al. (2011) even hypothesized that this very rapid mood elevation, reflected in acute laughter induction following DBS activation, could be a predictor of DBS response. Despite growing interest in these transient mood effects, its clinical relevance, as well as its underlying mechanism remain unknown. This enticed our investigation of the DBS response pattern and potential alternative working mechanisms described in the next chapter.In chapter 4 we investigated the response pattern of DBS. We found that when the stimulation was discontinued for 7 days, mood, anxiety and obsessive-compulsive symptoms deteriorated to pre-DBS levels. Mood and anxiety symptoms even seemed to show a rebound effect during DBS-discontinuation as symptoms increased to levels beyond pre-DBS levels, similar to what was previously reported in a study by Ooms et al. (2015). Although we hypothesized to find a sequential response pattern, DBS-R resulted in an simultaneous and rapid (30-120 minutes) decrease of more than 50% in depression, anxiety and obsessive-compulsive symptoms in 8 out of 10 initial DBS responders. The discrepancy between this gradual and sequential symptom improvement after initial DBS activation versus the immediate and simultaneous symptom


improvement after DBS-R in DBS-responders generated 2 clinically relevant questions: 1) First of all, these findings may imply shortening the DBS optimization phase. Currently, each optimization-step of DBS parameter settings (voltage, frequency, pulsewidth) requires a 2-week evaluation interval, based on the hypothesis of delayed improvement of OCD symptoms. However, this hypothesis is largely based on general clinical observations, with no study having specifically investigated the response pattern in the DBS optimization phase. The reported sequential improvement in the study of Denys et al. (2010) was partly derived from mean symptom changes (HAM-D, HAM-A and Y-BOCS) with a relatively large time-interval between clinical symptom measures. Therefore, this could overshadow a potential simultaneous improvement of individual patients. If our findings of rapid and simultaneous symptom improvement following DBS-R do reflect the optimal DBS response in the optimization phase, this may suggest drastically shortening the time-intervals between each optimization step and search for this optimal response pattern in a relatively short time-span, reducing the prolonged burden of long optimization phases for OCD patients.Nevertheless, we can’t exclude the pronounced effects of DBS-R being (partially) based on the sense of expectancy or the recognition of symptom improvement, and future studies should first measure the rapid response pattern in the optimization phase in more detail in order to elucidate this clinically relevant hypothesis. 2) Second, the discrepant response pattern could suggest that prolonged DBS for OCD induces neuroplasticity. The relatively slow and sequential initial improvement of symptoms after finding optimal DBS parameter settings in the optimization phase, as opposed to the immediate and simultaneous improvement of affective and obsessive-compulsive symptoms after reactivation of the DBS, may hint at stimulation-induced neuroplasticity. DBS-induced neuroplasticity is supported by similar findings in dystonia patients who are treated with DBS of the Globus Pallidus Interna (GPi). A study by


Ruge et al. (2011) showed retention of clinical benefits when DBS was stopped after at least 5 years, thereby suggesting that neuronal plasticity has occurred during chronic stimulation. This effect, however, seemed to be time-dependent, as cessation after 6 months of stimulation resulted in an immediate increase of symptoms, almost back to the levels seen prior to DBS surgery (Tisch et al., 2007). Several case-reports of GPi DBS for dystonia describe a similar maintenance of effect after DBS cessation (Hebb et al., 2007; Hung et al., 2007), hinting at the challenging possibility that DBS may have the capacity to induce neuronal plastic changes that diminish or obviate the need for further treatment in susceptible patients. To date, it remains unclear if DBS for OCD may be able to generate neuronal plasticity at the area of stimulation or in upstream or downstream neural circuits. Evidence suggests that DBS is able to induce neuronal plasticity, since long-term depression (LTD) and long-term potentiation (LTP), reflecting local synaptic changes, was found after high-frequency stimulation in experimental models of learning, memory, and epilepsy, as well as in excised human cortex and hippocampal tissue (Cooke et al., 2006; Disterhof et al., 2006). Furthermore, nucleus accumbens DBS increased the length of apical and basilar dendrites in pyramidal neurons of the prefrontal cortex in mice? (Faloswki et al., 2011). Finally, post-mortem brain tissue of Parkinson patients treated with DBS revealed significantly greater numbers of proliferating cells expressing markers of the cell cycle, plasticity, and neural precursor cells in the tissue around the implanted leads compared with brain tissue derived from healthy individuals or tissue from PD patients not treated with DBS (Vedam-Mai et al., 2014). Together, these studies strongly suggest that DBS is capable of increasing cellular plasticity in the brain, possibly with more widespread effects beyond the electrode location. Although these neuroplastic events are of unknown clinical relevance, they could fit with our observations of immediate symptom improvement after DBS-reactivation. This hypothesis raises the question if DBS for OCD needs to be continued permanently or if newly formed pathways will remain after DBS cessation in a subpopulation of optimal responders.


Evidence for sustained response of DBS for psychiatric disorders has been reported in a DBS study of the subcallosal cingulate gyrus in treatment-resistant depressive patients who achieved full remission after continuous DBS (Puigdemont et al., 2015), They reported 2 out of 5 participants did not relapse following 3 months sham DBS, thereby suggesting the existence of long-lasting therapeutic effects of DBS in some depressed patients.To date no DBS for OCD studies have investigated possible neuroplastic changes by testing the possibility of sustained symptom response after tapering off the stimulation in a subgroup of optimal DBS responders long-term DBS for OCD patients.

HOW DOES DBS AFFECT THE NEUROENDOCRINE SYSTEM?

We showed long-term DBS decreases HPA-axis activity as we found lower 24-hour urinary cortisol levels during >1 year DBS ON compared to 1-week DBS cessation. These changes were in strong association with obsessive-compulsive and depressive symptom changes measured with the Y-BOCS and HAM-D, hereby enticing its use for possible DBS response prediction (chapter 3) Our finding that OCD symptom improvement following long-term DBS is strongly correlated with decreased HPA-axis activity is in accordance with human OCD studies, suggesting HPA-axis dysregulation is a hallmark of OCD (Kluge et al., 2007; Fluitman et al., 2010; Lord et al., 2011). This assumption is underlined by clinical observations reporting psychosocial stressors frequently precede onset or exacerbations of OCD symptoms. Abnormal serotonergic neurotransmission is hypothesized to underlie OCD, based on the results of various neuroimaging studies (Hesse et al., 2005; Reinold et al., 2007; Zitterl et al., 2007) and pharmacological (challenge) studies reporting selective symptom improvement with serotonergic agonists (Denys et al., 2006). HPA-axis activity may alter serotonergic (5-HTT) neurotransmission as animal studies showed decreased 5-HTT levels following cortisol application (Slotkin et al., 1997) and human study of patients suffering from negative mood


states reported an association between stress response, thalamic 5-HTT levels and anxiety (Reimold et al., 2011). Alternatively, HPA-axis activity is suggested to regulate dopamine efflux through glucocorticoid receptors being present on dopaminergic neurons, which are highly expressed throughout the cortical-striatal circuit (Butts et al., 2011). Neuroimaging and pharmacological studies also strongly link dopamine with the pathophysiology of OCD (Denys et al., 2013). Because effective DBS is associated with a massive decrease of psychiatric symptoms and our results suggest DBS normalizes HPA-axis activity in association with psychiatric symptoms, this may imply that DBS is capable of altering serotonergic and dopaminergic neurotransmission (partly) through regulation of the HPA-axis. To date no other human study investigated the effect of DBS on serotonergic or dopaminergic neurotransmission. However, two DBS animal studies in freely moving rats investigated the effect of bilateral DBS of the ventral striatum (nucleus accumbens core (Nac)) for 5 resp. 2 hours on serotonin and dopamine levels in the ventral striatum, the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC), (van Dijk et al., 2011; van Dijk et al., 2012). Although they reported no changes in serotonin or dopamine release in the area surrounding the electrodes they did report a rapid increase in the release of serotonin and dopamine to a maximum 127% and 177%, respectively, in the mPFC. Thereby providing evidence for distal effects of DBS, potentially regulated in part through glucocorticoids.In order to further investigate the role of the HPA-axis in the underlying working mechanism of DBS for OCD future studies could measure rapid clinical symptoms in comparison to repeated saliva cortisol levels using a blinded DBS OFF/ON design. In order to investigate the possible use of cortisol for early response prediction similar designs could be implemented in the DBS optimization phase around every new adjustment of DBS parameter settings. Interestingly, our findings may imply that DBS enhances psychosocial stress resilience. Although DBS for OCD studies with a follow-up time of >2 years are lacking, based on our extensive clinical expertise in 55 DBS for OCD patients we suggest that effective DBS reduces the exacerbation risk of


OCD symptoms following confrontation with psychosocial-stressors. Future studies could investigate the hypothesis of DBS inducing stress resilience by performing a trier social stress test (TSST) in a DBS ON/OFF comparison study using 2 groups of effective DBS patients, as the TSST is the most useful and appropriate standardized protocol for studies of stress hormone reactivity (Kirschbaum et al., 1993; Dickerson et al., 2004). Besides investigating the psychological stress response, it would be interesting to perform a cold-stressor test using a blinded DBS ON/OFF design in order to investigate the effect of DBS on the physiological stress response.In Chapter 4 we focussed on the long-term, as well as rapid clinical effects of DBS and various other neuroendocrine parameter changes. Contrary to a decrease in urinary cortisol we found other hypothalamic-pituitary neuroendocrine parameters (prolactin/TSH) increased following long-term DBS.The simultaneous mean 50% improvement of anxiety, depression and obsessive-compulsive symptoms was inversely-associated with changes in plasma TSH and prolactin levels, both following DBS OFF as well as already 30 min after DBS-R. Subsequently we hypothesize that rapid and simultaneous increase in TSH and prolactin is likely to result from stimulation of hypothalamic thyrotropin-releasing hormone (TRH), which may underlie the commonly observed transient mood elevation following DBS. The clinical relevance of the aforementioned findings was questioned by the fact that also 3 out of 5 non-responders showed a 50% simultaneous decrease of clinical symptoms after DBS-R, suggesting DBS is capable of inducing rapid,symptom changes through an alternative or additional underlying mechanism. In parallel with the acute clinical effects of DBS-R, discontinuation of DBS resulted in neuroendocrine changes that reversed acutely after DBS-R. TSH and prolactin decreased after switching off the DBS and increased again within 30 minutes after DBS-R. This suggests that DBS changes are mediated, at least in part, via the hypothalamus, as both TSH and prolactin secretion are stimulated by hypothalamic thyrotropin-releasing hormone (TRH) and inhibited


by dopamine released from neuroendocrine neurons projecting to the median eminence of the hypothalamus (Fliers et al., 2006; Freeman et al., 2000). The strong negative association between HVA and prolactin levels in our study suggests involvement of dopamine in the DBS changes, which is in agreement with our demonstration of DBS–induced dopamine release described in chapter 6 (Figee et al., 2014). However, a stimulatory effect of TRH on TSH and prolactin by DBS cannot be excluded at present especially since we found no association of TSH with HVA levels. Interestingly, a significant body of preclinical and human data indicates that intravenous or intrathecal TRH administration has mood enhancing effects, with some studies even reporting a mean HAM-D decrease of >50% (Marangell et al., 1997 / Szuba et al., 2005). Although responses to TRH administration were rapid and clinically robust, they only lasted for several days. In the study by Marangell et al. (1997) mood elevation coincided with a rapid increase of both plasma prolactin and TSH after intrathecal TRH administration. TRH-induced transient mood elevation is especially interesting as stimulation initiation in DBS for OCD is associated with mood elevation and hypomanic symptoms, also lasting for several days (Denys et al., 2010 / Luigjes et al., in press). In conclusion, we hypothesize that TRH secretion may be a major determinant of the transient mood changes during DBS for the treatment of OCD. As a result this reduces the likelihood that rapid mood alterations following DBS activation are a clinical response predictor. Moreover, as participants were aware of their stimulation settings, we cannot exclude the pronounced effects of DBS-R being (partially) based on the sense of expectancy or the recognition of symptom improvement. Despite these limitations, the findings of the present study may stimulate further research on neuroendocrine changes of DBS, especially with a focus on TRH as a potential initiator in the mechanism of rapid symptom improvement and transient mood elevation or TSH/Prolactin level changes to be a response predictor for DBS, feasible for use in the optimization phase. In order to clarify the role of TRH in the transient mood elevation in DBS for OCD future studies should investigate the rapidity of mood improvement during the initial DBS


optimization phase while measuring TSH and prolactin before and after each DBS parameter change. However, this would still not differentiate between TRH or dopamine regulated neuroendocrine changes. As TRH concentrations can be measured in cerebrospinal fluid (Roy et al., 1994), future studies could measure TRH in CSF just before and shortly after DBS-R in order to further investigate the role of TRH in the transient mood improvement of DBS for OCD. As TSH and prolactin changes were seen in both responders and non-responders these peripheral measures are probably not eligible for clinical response prediction.

HOW DOES DBS ALTER THE IMMUNE SYSTEM

In chapter 5 we showed that DBS has long-term and rapid pro-inflammatory effects that correlate with OCD symptom improvement. We hypothesized that the correlation between immune and clinical symptom changes, together with the rapidity of these changes, hints at DBS inducing a local immune response capable of directly communicating with the cortico-striatal network. Astrocytes and microglia involvement is suspected as (i) they are known regulators of neuronal synaptic networks, (ii) they both secrete various cytokines/chemokines and (iii) can be activated by high frequency electrical stimulation (DBS) (Vedam-Mai et al., 2012). However, at this moment we can not rule out that the local or peripheral immune response is solely a non-clinically relevant pathway, e.g. by DBS inducing an inflammatory response of the glial cells surrounding the electrodes or a rapid peripheral response mediated by the SNS. In order to differentiate local vs peripheral immune responses future DBS for OCD studies could first measure various immune mediators in cerebrospinal fluid (CSF). To date no DBS for OCD study investigated neuroimmune alterations in CSF and only 1 neuroimmune CSF study was performed in OCD patients that solely investigated IL-6 CSF levels and showed negative results (Carpenter et al., 2002).Provided that DBS induces a local immune response, a next step would be


performing a DBS immune study that compares the effective DBS contact-points with the non-effective contact-points using a similar DBS ON/OFF design. This way we could differentiate non-clinically relevant from clinically relevant local immune alterations that could further help elucidate possible neuroimmune involvement (astrocytes or microglia) in the underlying working mechanism of DBS for OCD. To date no studies investigated the role of astrocytes or microglia in OCD, despite the OCD mouse model demonstrating a role for Hoxb8-expressing microglia in modulating OCD-like behavior (Chen et al., 2010).There have been few postmortem studies in OCD, and none described to date have investigated microglial activation. Therefore, we suggest future studies to perform histopathological studies, investigating astrocyte & microglia morphology, in post-mortem brain tissues from OCD patients. Furthermore, Microglia express the 18kDa translocator protein (TSPO), which can be quantified by the positron emission tomography (PET) ligand [(11)C]PK11195 (Owen et al., 2011). Therefore it would be very interesting to to assess microglia activation with [(11)C]PK11195 PET pre-surgery, as well as pre- and post-DBS activation. The pre-surgery scan would be necessary in order to control for the potential long-lasting activation of microglia following the surgical implantation of the electrodes. In conclusion our results imply a causal relationship between DBS, immune modulation and OCD, which warrants further mechanistic investigation.

HOW DOES EFFECTIVE DBS MODULATE DOPAMINE RELEASE?

We showed that effective DBS for OCD induced striatal dopamine release as was demonstrated by lower dopaminergic D2/3 receptor availability in the putamen and increased plasma levels of HVA (chapter 6). As we used a dopaminergic neurotracer with affinity to D2 receptors, our results likely reflect DBS effects on indirect corticostriatal D2 expressing pathways only. In these indirect D2 pathways, excitatory glutaminergic cortical input into the striatum is assumed to result in net GABA-ergic inhibition of output structures resulting in


indirect pathways. Our findings of DBS-induced dopamine release in indirect D2 pathways may thus reflect inhibitor striatal output on excessive cortical activity, resulting in improved control of obsessive-compulsive symptoms. It would be interesting for future studies to investigate if DBS-induced dopamine release in indirect D2 pathways is accompanied by decreases in direct D1 expressing pathways, e.g. using the D1 receptor tracer [11C]-SCH23390. Moreover, further studies are needed to discern whether this inhibitory output caused by dopamine release, is accompanied by GABA-ergic increases and glutaminergic decreases. GABA-ergic and glutamatergic changes could be measured with 1H magnetic resonance spectroscopy, though it is currently unknown if this technique can be safely applied in DBS-implanted patients. Finally, imaging studies should also apply serotonergic neurotracers to clarify whether stimulatory dopamine release in this group of therapy-refractory OCD patients primarily compensates dopaminergic or serotonergic deficits.

METHODOLOGICAL CONSIDERATIONS

First of all our study design was very demanding for our participants as they had to endure a significant increase of their clinical symptoms during a 8 day period of DBS discontinuation in order to create sufficient time between the DBS ON and OFF measures in order to exclude any lagging of the stimulation effects. One of the participants dropped out after experiencing severe anxiety following DBS cessation. Also, the relatively small sample size (total N=16) created some limitations, which is, however, common for DBS studies. Furthermore, the rather difficult self-assessment of 24-hour urine samples on two consecutive days was a burden for patients and resulted in an incorrect collection in 5 participants that subsequently had to be excluded for analysis in the DBS-cortisol study (chapter 3). In the SPECT study (chapter 6) we analyzed changes in pre-defined regions of interests (ROIs), namely the putamen and caudate as our study was underpowered for whole-brain analysis with appropriate correction for multiple comparisons. In contrast to the clear reflection of dopaminergic changes by [123]IBZM receptor binding in


Figure 1. Overview of various hypothesized pathways underlying the rapid working mechanism of DBS for OCD.

1. DBS-induced urinary cortisol changes are associated with mood and OCD symptom changes2: DBS-induced TSH and prolactin plasma level increases may underlie transient mood elevation following DBS 3: DBS induces a rapid inflammatory response in parallel with clinical symptom changes4: DBS-induced dopamine changes alter the cortical-striatal circuit DBS deep brain stimulation, vALIC ventral part of the anterior limb of the internal capsule, OCD obsessive-compulsive disorder, TSH thyroid-stimulating hormone. HPA-axis Hypothalamic-Pituitary-Adrenal-axis


our SPECT study, the origin of the peripheral measures of HVA is debated. There is evidence that plasma HVA is primarily produced by brain dopamine neurons, but to a lesser extent also by central noradrenergic and peripheral dopaminergic neurons (Davis et al., 1991). However, as we compare plasma HVA changes related to a central intervention (DBS), peripheral effects are likely to be minimal in our study as well. Finally, the DBS cessation condition of 8 days that we used for the design of all our studies may not be a correct baseline pre-treatment measure for comparison with stimulation conditions. The results of a study by Ooms et al. (2015) suggest discontinuation in this group may even induce some rebound effects. Future studies in general should obtain baseline neurobiological and imaging measures before implantation.

CONCLUSION

Our results suggest that following 1-week of DBS discontinuation, DBS-R results in a rapid and simultaneous improvement of symptoms, which may have clinical implications of reducing the follow-up time in the optimization phase or hint at prolonged effective DBS inducing neuroplasticity in the corticostriatal circuit. As DBS altered immune and neuroendocrine system activity, in part associated with clinical symptom response, we hypothesized immune and neuroendocrine communication with the cortical-striatal circuit as well as with possible alternative mechanisms capable of inducing transient mood improvement. Furthermore, our findings of DBS-induced dopamine release in indirect D2 pathways may reflect inhibitor striatal output on excessive cortical activity, thereby resulting in improved control of obsessive-compulsive symptoms. We suggest future studies to further investigate these potential underlying working mechanisms of DBS for OCD using CSF measures or PET. As we performed 4 largely hypothesis-generating studies this thesis may provide a platform of further exploring these questions in order to optimize the procedure as well as elucidate the underlying working mechanism in DBS for OCD


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Slotkin TA, McCook EC, Ritchie JC, Caroll BJ, Seidler FJ. Serotonin transporter expression in rat brain regions and blood platelets: aging and glucorticoid effects. Biol Psychiatry. 1997;41:172–183.

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Butts KA, Weinberg J, Young AH et al.. Glucocorticoid receptors in the prefrontal cortex regulate stress-evoked dopamine efflux and aspects of executive function. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18459-64.


Denys D, de Vries F, Cath D et al.. Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder. Eur Neuropsychopharmacol. 2013 Nov;23(11):1423-31.van Dijk A, Mason O, Klompmakers AA et al.. Unilateral deep brain stimulation in the nucleus accumbens core does not affect local monoamine release. J Neurosci Methods. 2011 Nov 15;202(2):113-8. van Dijk A, Klompmakers AA, Feenstra MG et al.. Deep brain stimulation of the accumbens increases dopamine, serotonin, and noradrenaline in the prefrontal cortex. J Neurochem. 2012 Dec;123(6):897-903.

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Part VIAppendix

Nederlandse samenvatting en

conclusie

Nederlandse samenvatting en conclusie | 157

NEDERLANDSE SAMENVATTING EN CONCLUSIE

SAMENVATTING

In de introductie beschreef ik het buitengewone effect van diepe hersenstimulatie (DBS) bij mw. V. Mijn patiënte mw. V., leed op dat moment ernstig onder haar terugval in angst, stemming en obsessieve-compulsieve symptomen nadat haar DBS tijdelijk was uitgezet. Het opnieuw aanzetten van de DBS verloste haar echter binnen enkele seconden van haar bijna ondraaglijke symptomen. De opvallend snelle klinische verbetering van mw. V. wakkerde mijn interesse aan om het onderliggende werkingsmechanisme van diepe hersenstimulatie bij patiënten met een obsessieve-compulsieve stoornis (OCS) verder te onderzoeken. Het belangrijkste doel van mijn proefschrift behelst daarom het onderzoeken van de snelheid symptoomverandering door DBS, evenals het exploreren van mogelijke onderliggende werkingsmechanismen. Hiervoor gebruikten we gevalideerde vragenlijsten om psychiatrische symptomen te meten, welke door de behandelaar of door patiënt zelf ingevuld diende te worden. Ook bepaalden we de activiteit van de HPA-as (stress systeem) en andere neuroendocriene en immunologische parameters in het bloed en in de urine. Als laatste onderzochten we de effecten van DBS op dopamine in het striatum met behulp van Single Photon Emission Computed Tomography (SPECT) scans. Aangezien de onderzoeken grotendeels hypothese genererend van aard waren, was het primaire doel van de onderzoeken om de onderliggende mechanismen te karakteriseren. Daarbij onderzochten we ook of er eventuele onderlinge verbanden waren en/of er relatie bestond tussen de onderzochte mechanismen, klinische symptoom verandering en het corticale-striatale hersencircuit, welke sterk geassocieerd is met OCS.


DBS IS EEN EFFECTIEVE, VEILIGE EN SNELLE BEHANDELING VOOR PATIËNTEN MET THERAPIE-REFRACTAIRE OCS.

In het eerste deel van het proefschrift geef ik een uiteenzetting van de effectiviteit en mogelijke bijwerkingen van DBS voor OCS van alle tot op heden gebruikte hersengebieden. In een overzichtsartikel beschrijf ik de resultaten van negen open “case-studies” en zeven gerandomiseerde onderzoeken met in totaal 63 patienten (hoofdstuk 2). Ik toonde aan dat 54% van alle patiënten respondeerden op de behandeling (response = 35% afname van OCS symptomen, gemeten middels de Y-BOCS). Er traden weinig bijwerkingen op, waarbij het optreden van voorbijgaande hypomane symptomen, direct na het aanzetten van de stimulatie, meest frequent werd gerapporteerd. Ernstige bijwerkingen ten gevolgde van de operatie waren zeldzaam en eventueel optredende bijwerkingen ten gevolge van de stimulatie verbleekten door het aanpassen of uitzetten van de stimulator. In hoofdstuk 4 vergeleek ik de klinische effecten van langer durende DBS met een periode dat de DBS 1-week had uitgestaan. Vervolgens onderzocht ik de klinische effecten van het opnieuw aanzetten van de DBS. Ik vond dat angst, stemming en obsessieve-compulsieve symptomen 1 week na het uitzetten van de DBS allen significant waren toegenomen. Het opnieuw aanzetten van de DBS zorgde er echter voor dat alle symptomen na 30 minuten al met ±50% verbeterden.

UITGEBREIDE NEURO-ENDOCRIENE VERANDERINGEN DOOR DBS

In hoofdstuk 3 beschreef ik dat langdurige DBS (>1jaar actieve stimulatie) geassocieerd is met een verlaging van vrij cortisol, gemeten in 24-uurs urine, en dat deze cortisol verandering sterk geassocieerd is met veranderingen in obsessieve-compulsieve (Y-BOCS) en depressieve symptomen (HAM-D). We vonden geen veranderingen in adrenaline en noradrenaline waarden, gemeten in 24-uurs urine.In hoofdstuk 4 onderzocht ik het effect van DBS op andere neuroendocriene parameters. We toonden aan dat klinische symptoom verandering negatief


geassocieerd was met veranderingen in plasma thyroid-stimulating hormone (TSH) en prolactine. Dit effect was zichtbaar tijdens de 1-week durende DBS-UIT fase, evenals reeds 30 minuten na het reactiveren van de stimulatie. Onze hypothese was dat de snelle en gelijktijdige TSH en prolactine veranderingen een gevolg zijn van stimulatie van thyrotropin-releasing hormone (TRH) uit de hypothalamus. Deze TRH stimulatie zou op zijn beurt weer de voorbijgaande stemmingsverbetering kunnen verklaren welke frequent optreedt na het aanzetten van de DBS.

DBS ZORGT VOOR SNELLE VERANDERINGEN VAN HET IMMUUNSYSTEEM

In hoofdstuk 5 onderzocht ik de effecten van DBS op het immuunsysteem. Onze resultaten wijzen op een pro-inflammatoir effect van DBS welke geassocieerd zijn met veranderingen in obsessive-compulsieve symptomen (Y-BOCS). De snelle stijging van inflammatoire mediatoren na het activeren van de stimulatie duidt op een causale relatie tussen DBS, modulatie van het immuunsysteem en OCS, welke mogelijk gereguleerd is door astrocyten en microglia.

DBS ZORGT VOOR HET VRIJKOMEN VAN DOPAMINE IN HET STRIATUM

In hoofdstuk 6 toonden we aan dat de centrale en perifere dopamine veranderingen erop duiden dat DBS zorgt voor het vrijkomen van dopamine in het striatum. Hierbij vonden we dat patienten met langdurige actieve DBS verbeterde OCS symptomen hadden, evenals een lagere beschikbaarheid van de SPECT radioactieve tracer [123] iodobenzamide, welke bindt aan striatale D2/3 receptoren. Daarbij vonden we ook dat langdurige actieve DBS zorgde voor verhoogde plasma waarden van de dopamine/noradrenaline metaboliet “homovanillic acid”


CONCLUSIE

Onze resultaten tonen aan dat het opnieuw aanzetten van de DBS, nadat deze 1 week uit heeft gestaan, zorgt voor een opvallend snelle en tegelijkertijd optredende verbetering van angst, depressie en obsessieve-compulsieve symptomen. Wij veronderstellen dat deze bevindingen suggereren dat (i) het mogelijk is om de opvolgtijd tijdens de DBS optimalisatiefase te verkorten (ii) langdurige effectieve DBS kan zorgen voor neuroplasticiteit in het corticostriatale circuit. Omdat we aantoonden dat DBS effect had op de activiteit van het neuroendocriene- en immuunsysteem, en deze gedeeltelijk in associatie waren met veranderingen in klinische symptomen, veronderstellen wij dat deze systemen in contact staan met het cortico-striatale circuit, evenals met mogelijke alternatieve mechanismen welke de voorbijgaande stemmingsverbetering kunnen veroorzaken. Toekomstige studies zouden de door ons onderzochte en veronderstelde mechanismen nader kunnen onderzoeken, gebruik makende van een verbeterde studie opzet en nieuwe onderzoekstechnieken zoals metingen in hersenvocht of het gebruik van positron emissie tomografie (PET)-scans. Aangezien we grotendeels hypothese-genererende studies hebben verricht kan dit proefschrift als platform dienen voor verder onderzoek naar dergelijke vragen om zodoende het onderliggende werkingsmechanisme te verhelderen en de DBS procedure te optimaliseren.

List of publications

List of publications | 165

LIST OF PUBLICATIONS

de Koning PP, Figee M, Endert E, van den Munckhof P, Schuurman PR, Storosum JG, Denys D, Fliers E. Rapid effects of deep brain stimulation reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorder. Transl Psychiatry. 2016 Jan 26;6:e722.

Figee M, de Koning P, Klaassen S, Vulink N, Mantione M, van den Munckhof P, Schuurman R, van Wingen G, van Amelsvoort T, Booij J, Denys D. Deep brain stimulation induces striatal dopamine release in obsessive-compulsive disorder. Biol Psychiatry. 2014 Apr 15;75(8):647-52.

Smolders R, Mazaheri A, van Wingen G, Figee M, de Koning PP, Denys D. Deep brain stimulation targeted at the nucleus accumbens decreases the potential for pathologic network communication. Biol Psychiatry. 2013 Nov 15;74(10):e27-8.

Polak AR, Witteveen AB, Mantione M, Figee M, de Koning P, Olff M, van den Munckhof P, Schuurman PR, Denys D. Deep brain stimulation for obsessive-compulsive disorder affects language: a case report. Neurosurgery. 2013 Nov;73(5):E907-10; discussion E910.

Luigjes J, de Kwaasteniet BP, de Koning PP, Oudijn MS, van den Munckhof P, Schuurman PR, Denys D. Surgery for psychiatric disorders. World Neurosurg. 2013 Sep-Oct;80(3-4):S31.e17-28.

de Koning PP, Figee M, Endert E, Storosum JG, Fliers E, Denys D. Deep brain stimulation for obsessive-compulsive disorder is associated with cortisol changes. Psychoneuroendocrinology. 2013 Aug;38(8):1455-9.


Overbeek JM, de Koning P, Luigjes J, van den Munckhof P, Schuurman PR, Denys D. Deep brain stimulation for psychiatric disorders. Ned Tijdschr Geneeskd. 2013;157(52):A7015.

Figee M, Luigjes J, Smolders R, Valencia-Alfonso CE, van Wingen G, de Kwaasteniet B, Mantione M, Ooms P, de Koning P, Vulink N, Levar N, Droge L, van den Munckhof P, Schuurman PR, Nederveen A, van den Brink W, Mazaheri A, Vink M, Denys D. Deep brain stimulation restores frontostriatal network activity in obsessive-compulsive disorder. Nat Neurosci. 2013 Apr;16(4):386-7.

Pelle P. de Koning, Pepijn van den Munckhof, Martijn Figee, Rick Schuurman, Damiaan Denys.Deep Brain Stimulation in Obsessive–Compulsive Disorder Targeted at the Nucleus Accumbens. Deep Brain Stimulation. A New Frontier in Psychiatry. Berlin; Heidelberg: Springer; 2012., p. 43 Polak AR, van der Paardt JW, Figee M, Vulink N, de Koning P, Olff M, Denys D.Compulsive carnival song whistling following cardiac arrest: a case study.BMC Psychiatry. 2012 Jul 3;12:75.

de Koning PP, Figee M, van den Munckhof P, Schuurman PR, Denys D.Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Curr Psychiatry Rep. 2011 Aug;13(4):274-82.

Peters BD, de Koning P, Dingemans P, Becker H, Linszen DH, de Haan L.Subjective effects of cannabis before the first psychotic episode.Aust N Z J Psychiatry. 2009 Dec;43(12):1155-62.

List of publications | 167

Curriculum Vitae

Curriculum Vitae | 171

CURRICULUM VITAEPelle de Koning was born on the 30th of September 1976. After finishing secondary school he studied medical microbiology from 1996-1997 at the University of Amsterdam (UvA). In 1997 he switched studies and started Medical School at the Academic Medical Center (AMC, UvA). In 2006 he finished his clinical rotations in the AMC following an elective clinical rotation at Mentrum (Amsterdam). From October 2006 until March 2007 he worked at the Psychiatric Crisis Team and Home-Treatment Team of Mentrum (Amsterdam). In April 2007 Pelle de Koning started his psychiatry residency program at the AMC under supervision of Prof. dr. Aart Schene and Guido Nabarro. His last year of training he completed at the department of anxiety disorders at the AMC were he joined the deep brain stimulation (DBS) team. After finishing his residency in October 2011 he continued working at the department of anxiety disorders as a psychiatrist ever since. In 2010 Pelle de Koning started his PhD on the neuroendocrine and neuroimmunological effects of DBS under the supervision of Prof. dr. Damiaan Denys. Since 2015 he holds the function of associate program director for the psychiatry residency program. Pelle de Koning is happily engaged to Juliette Klaver and they have 1 child, Fabe.

Dankwoord

Dankwoord | 175

DANKWOORD PROMOTIEMijn dank en respect gaan uit naar de deelnemers aan dit DBS-onderzoek, voor hun getoonde betrokkenheid, nieuwsgierigheid en enthousiasme, evenals voor het doorzettingsvermogen op de moeilijke momenten wanneer de DBS uit stond. Prof. dr. D.A.J.P. Denys, mijn promotor. Je gaf mij het vertrouwen om als jonge psychiater en onderzoeker op de afdeling angststoornissen te komen werken en gaf mij hierbij de ruimte om eigen keuzes te maken, terwijl je altijd messcherp bleef op de uitvoering. Je doceerde passief de kracht van het weglaten en ik raakte en bleef geïnspireerd door je nimmer aflatende focus, behoud van overzicht en je spreek- en schrijfbehendigheid. Jitschak Storosum, mijn copromotor en collega psychiater. Dat jij voor mij zo belangrijk en dichtbij bent geworden, na onze wat stroeve start tijdens mijn coschap psychiatrie in 2004, is mij dierbaar. Als copromotor was je zeer betrokken, punctueel en vaak confronterend. Daarbij was je de schakel in de soepele samenwerking met andere betrokken medische disciplines gedurende het onderzoek. Als collega psychiater en opleider leer en geniet ik van je nimmer aflatende kritisch-ironische houding, waarbij de wekelijkse ironie aangaande de beklagenswaardige prestaties van onze grootstedelijke voetbalclub mijn dag vaak maken.Martijn Figee, mijn copromotor en collega psychiater op de afdeling angststoornissen. Ik ken niemand die zo bevlogen zijn klinische en onderzoek werkzaamheden weet te combineren met alle overige moois dat het persoonlijke, stadse, culinaire en klinische leven een mens kan bieden. Samen hebben we de opzet en uitvoering van het DBS onderzoek intensief doorlopen en altijd bleef je naar mij en mede-onderzoekers een onderzoek-enthousiasmeerder van de eerste orde met een onuitputtelijke energie. De leden van de promotiecommissie, Prof. dr. J.A. Swinkels, Prof. dr. E. Fliers, Prof. dr. T. Van der Poll, Prof. dr. H.A. Drexhage en dr. C.H. Vinckers wil ik bedanken voor het beoordelen van mijn proefschrift. Prof. dr. J.M. Menchón,


thank you for reviewing my thesis and for participating in the PhD ceremony.Prof. dr. A. Fischer en dr. I. Willuhn dank voor jullie optreden als gastopponent.Nienke, collega afdelingspsychiater, energieke duizendpoot en rots in de afdelings-branding. Ik bewonder je organisatietalent en vasthoudendheid en ben je dankbaar voor het frequent geboden luisterend oor en advies. Dank Pieter, Belg en veelzijdige doorpakker van de afdeling. Dank voor het delen van wetenschapssmart en het bieden van dagelijks ontladende humor. Mariska, de Italiaanse DBS dame van het AMC. Schoenen.. en de patiënt altijd centraal. Sinds 2016 gemist door vertrek naar het UMC Utrecht. Ron: DBS-expert van het eerste uur. “Wat zie je er goed uit”.Dan zeer veel dank voor alle overige collega’s van de afdeling angststoornissen bij wie ik altijd enthousiast, uitgeput, klagend of op zoek naar een lach kon binnenvallen. Het is een groot plezier om met jullie te mogen werken. Charlotte, wanneer iemand als parasiet mag teren op de potentiele wetenschaps-tegenspoed van de ander, dan zit het goed. Arnoud, Marthe, Carla, Sylvia, Annemieke, Janine, en Danielle dank voor de diverse ondersteuning tijdens de actieve onderzoeksfase, Dank collega’s van de afdelingen stemmingsstoornissen, vroege psychose, acute stoornissen en de MPU voor het weten te combineren van zoveel expertise met voldoende luchtigheid op de werkvloer. Het secretariaat van het AMC bedankt voor het oplossen van mijn onmogelijke last-minute agenda aanpassingen. Jullie waren onmisbaar! Daarvoor in het bijzonder dank aan Barbara, Ditte, Ellen en Lara.Erik Endert dank voor hartelijke introductie in het laboratorium endocrinologie en de getoonde betrokkenheid bij mijn onderzoeken de afgelopen jaren. Rene Lutter, dank voor het zo vele malen verhelderen van mijn immunologische vraagstukken evenals voor je nimmer aflatende enthousiasme voor gevonden resultaten. Jörg Hamann, dank voor de razendsnelle en inhoudelijk scherpe formuleringen, tijdens de laatste fase van mijn promotie.Anja Lok, mijn Geneeskunde studie maatje en collega psychiater in het AMC bij de afdeling stemmingsstoornissen. Wat ben ik trots op wat jij in de drukte van het bestaan de afgelopen jaren op persoonlijk, klinisch en wetenschappelijk

Dankwoord | 177

niveau allemaal bereikt hebt. Dank voor je immer getoonde betrokkenheid en vertrouwen in en revisies van mijn onderzoek.Arjen Sutterland, mijn collega psychiater en enthousiasmeerder van psychoneuroimmunologisch onderzoek. Dat PNI-congres in het AMC dat gaat er komen… Marloes Oudijn, collega psychiater. Dank voor je kritische reflecties als mede DBS-pionier. En collega psychiaters Hiske, Lieuwe, Ellen, Martine, Dominique, en Herman wat voel ik me vertrouwd bij jullie. Dank voor de kritische beschouwingen, inspiratie, overname van werkzaamheden en het kunnen delen van individuele expertises en memorabele ski-ervaringen.Dank collega’s van het NIN voor jullie verbredende visie op de psychiatrie en Matthijs Feenstra, dank voor het delen van je encyclopedische kennis van de hersenstructuren en verwijzende literatuur.Dank Isidor, Judy en Melisse voor het samen ontwikkelen en delen van zoveel DBS expertise en Arjan Versluis, als student was jouw opgewektheid en toewijding tijdens de DBS onderzoeksperiode van essentieel belang voor de betrokken patiënten en mede-onderzoekers. Dank Rick en Pepijn, onze neurochirurgen voor het mogelijk maken van dit onderzoek en de verhelderende uitleg tijdens het bijwonen van de DBS operaties.Maarten Koeter †, dank voor de deur die altijd open stond ter noodzakelijke verheldering van complexe statistiek. Dank Guido voor het altijd kunnen simplificeren van moeilijke vraagstukken, Jasper, aanstaande collega, voor je hulp bij neurofysiologische metingen en Prof. dr. M. Olff voor de ondersteuning en feedback tijdens mijn exploratie van het stress-systeem. Mirjam, Roel en Jessie, dank voor het kunnen binnenvallen voor neuroendocriene of onderzoek-logistieke vraagstukken.Renske, Odette en Judith, dank voor de nimmer aflatende ondersteuning, vooral rondom naderende deadlines. Judith dank voor je drop-pot.Mijn dierbare intervisieleden Jasper, Kim, Maaike, Asker, Margje en Floris, dank voor de maandelijkse geboden raad, het kunnen relativeren/ageren, maar vooral de lach, welke onze professie zo nodig heeft.En dank aan alle andere collega’s en mede-onderzoekers die ik onverhoopt


vergeten ben te noemen.

Al mijn vrienden en familie, dank voor jullie nimmer aflatende enthousiasme over mijn onderzoek, maar vooral voor het maken van zoveel warme herinneringen en het bieden van (ont)spanning op velerlei gebied…Lieve schoonfamilie, dank voor de warme band en veelvuldige gastronomische ontspanning. En Jan; “alles voor de wetenschap…”Lieve Eelco en Nellieke, grote broer en zus. Vroeger al zoveel wegen geplaveid, skisporen getrokken en voorbeeldrollen vervuld. Wat vind ik het dierbaar en ben ik vereerd dat jullie tijdens dit grote avontuur mijn paranimfen willen zijn. Lieve pap en mam, dank voor jullie liefde en vertrouwen. Jullie zijn een baken van rust en steun in mijn/ons leven. En dank voor het aan de basis staan van mijn blijvende verwondering en nieuwsgierigheid naar de psyche van de mens.

Lieve Fabe, grote kleine man, die mijn hart gestolen heeft en toenemende promotiespanningen met een blik kan doen vervagen.

Maar vooral Juliette, liefde van mijn leven. Dank voor het hebben mogen meeliften op jouw ongekende arbeidsethos, je scherpzinnigheid, je verhelderende vragen en je speelse avontuurlijkheid die mijn hoofd weer leeg kon maken. Dank voor het geven van ruimte en voor het beschermen van “samen” bij dreigend tekort. Dank voor je nuchterheid, het samen sportief ontladen op land of op zee en het me keer op keer laten verbazen over je elegantie en schoonheid. Dank voor je interesse en het doorvragen. Maar vooral dank voor je liefde, voor mij en voor Fabe.

Dankwoord | 179

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