White Matter Deficits: New TMS Treatment Targets in Depression?

Xin-Min Li, MD, PhD, FRCPCProfessor and Chair, Department of PsychiatryCapital Health Chair in Mental Health ResearchSpecial Advisor on China Research Initiatives, 

University of Alberta, Canada   

Department of Psychiatry

White Matter Deficits: New TMS Treatment Targets in Depression?

Without emotion, man would be nothing but a biological computer. Love, joy, sorrow, fear, apprehension, anger, satisfaction, and discontent provide the meaning of human existence.

------------Arnold M. Ludwig (1980)

Samuel Clemens(Mark Twain)

Ernest Hemingway

Peter Tchaikovsky Robert Schumann Kurt Cobain

Alexander Pushkin

Vincent Van Gogh

Virginia Woolf

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Adapted from Health Statistics and Informatics 2004

Ten leading causes of burden of disease World, 2004 and 2030

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Lifetime risk: 1 in 6 individuals in the United States, 1 in 10 in Canada

Core symptoms:Depressed mood, anhedonia, irritability, difficulties in concentrating, and abnormalities in appetite and sleep

High mortality associated with suicide

Treatment: Psychotherapy (cognitive therapy, interpersonal therapy)

Social supports (family and friends et al)

Antidepressants treatment 

Brain stimulations (ECT, rTMS, DBS et al) 

Alternative Therapy (Light therapy, herbal et al)

Quick facts of depression

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In the limbic (emotional) regions of the brain, that are primarily responsible for depression, there is a relative deficit in:

Noradrenaline (NA),Serotonin (5-HT)Possibly dopamine (DA)(Leonard and Healy, 1999)

Acute action of antidepressants that were available resulted in the “monoamine hypothesis”

Monoamine Hypothesis of Depression

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Serotonin and Norepinephrine in the brain

Limbic System

Locus Ceruleus (NE Source)

Prefrontal Cortex

Raphe Nuclei  (5-HT source)

Cooper JR, Bloom FE. The Biochemical Basis of Neuropharmacology. 1996.

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Two sides to the neurotransmitter theory

Sex

Appetite

Aggression

Concentration

Interest

Motivation

Depressed Mood

Anxiety

Irritability

Thought  process

References:1. Adapted from: Stahl SM. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications: 2nd ed. Cambridge University Press 2000.

2. Blier P, et al. J Psychiatry Neurosci. 2001;26(1):37-43.3. Doraiswamy PM. J Clin Psychiatry. 2001;62(suppl 12):30-35.4. Verma S, et al. Int Rev Psychiatry. 2000;12:103-114.

Norepinephrine (NE)

• Both serotonin and norepinephrine mediate a broad spectrum of depressive symptoms

Serotonin (5-HT)

Vague Aches and pain

Functional domains of Serotonin and Norepinephrine1-4

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2-3 week lag period for therapeutic responseMonoamine depletion does not produce depressive symptoms in healthy individualsPET studies fail to show the reduced receptor and transporter numbersGenetic association analyses shows no evidence of monoaminergic gene involvement in depressionThe chronic effects of antidepressantsNeurotrophic and neurogenesis hypothesis

Challenges to traditional theories

Am J Psychiatry 167:11, 2010

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The brain is a dynamic system that derives its structural and functional capacity from the interaction of genes and environmental factors.Neuroplasticity describes the ability of the brain to undergo functioning-relevant adaptations to external or internal stimuli.Depression occurs when the processes involved in maintaining structural plasticity are impaired (e.g., changes in neurotransmitter concentrations, receptor activity, synaptic cascades).

Depression is a disorder of neuroplasticity

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Depression, in part, results from a loss of neurotrophic support that leads to:

atrophyloss of neurons in the brain

Suggests that the etiology and treatment of depression will involve alterations in:

structureneurochemicals

Antidepressants act, in part, by inducingneurotrophic effects that reverse structural changes that have occurred.

Neurotrophic hypothesis

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Hippocampal volume is decreased in patients with depression • is related to duration of depression*• antidepressant treatment partially blocks or reverses 

the hippocampal volume reduction**

In depressed patients, volumes are decreased in:• amygdala core nuclei †• subgenual prefrontal cortex ††

Structural alterations in depression

*Sheline et al., Proc Natl Acad Sci. USA 996;93:3908  Sheline et al., J Neurosci. 1999;19:5034   MacQueen et al., 2003

 ** Sheline et al., Am J Psych. 2003;160(8):1 Vermetten et al.,  Biol Psych. 2003;54:693  † Sheline et al.,  Neuroreport.  1998;9:2023†† Drevets et al., Nature  1997;386:824

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Sheline YI et al., J Neurosci. 1999;19:5034-5043

Hippocampus and Depression

0 500 1000 1500 2000 2500 3000 3500 4000

Tota

l Hip

poca

mpa

l Vol

ume,

mm

3

5800

5300

4800

4300

3800

3300

2800

Time Depressed, Days

Correlation between duration of depression and hippocampal volume

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• In adult animals, new neurons are formed continuously from progenitor cells located in the subgranular zone (SGV)• Those neurons differentiate and become incorporated into neuronal circuits in the dentate gyrus

Hippocampal Neurogenesis

Warner-Schmidt and Duman (2006) Hippocampus 16: 239

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Antidepressant treatment increases neurogenesis

Santarelli et al. 2003 Science 301(5634): 805-809.

Dranovsky and Hen 2006 Biological Psychiatry 59(12): 1136-1143.

Antidepressants induce the Expression of BDNF and FGF in cortical and Hippocampal Neurons

Reviewed by Turner, Akil et al. 2006 Biological Psychiatry 59(12): 1128-1135. 

Reviewed by Tardito, Perez et al. 2006 Pharmacol Rev 58(1): 115-134.

Stress and Neurogenesis

Biological Psychiatry (2006), 59. 1116-1127 

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Biologicalrisks

Stressors

Limbic-cortical circuits

Depressiveepisode

Treatment

Homeostasis

Phenotype Dimensional characteristics?

Categorical subtypes? 

Environment Early abuse Life events Medical illness

Gender Family history Temperament HPA reactivity Specific genes

Conceptual Model of Depression

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White matter hyperintensities (WMHs) are areas of increased signal intensity on T2 weighted MRIs. 

A higher rate and severity of WMHs in individuals with late life depression compared with healthy elderly controls.

WMHs also found in early onset depression recently

WMHs are due to three major causes: dilated perivascular spaces, oligemic demyelination and ischemic demyelination. 

Oligodendrocyte dysfunctions in MDD

review in Journal of Neurology, Neurosurgery, and Psychiatry (2008);79:619-624. Ann N Y Acad Sci. (2002) Nov;977:333-9. Biological Psychiatry. (2001), 50:179-183.

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Forest plots of cross-sectional analyses comparing (A) overall white matter hyperintensities (WMH), (B) deep WMH, and (C) periventricular WMH on depression.

Journal of Psychiatric Research, Volume 56, 2014, 56–64

White Matter Hyperintensities on Depression

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Journal of Psychiatric Research, Volume 56, 2014, 56–64

White Matter Hyperintensities on Depression

Forest plots of longitudinal (A) and cross-sectional (B) studies comparing volumetric assessment of overall white matter hyperintensities and depression. 

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(A) Lateral view of the cortical surface of the brain, showing the dorsolateral prefrontal cortex (dlPFC), ventrolateral PFC (vlPFC), orbitofrontal cortex (OFC), and insular cortex (ins). (B) Mid‐sagittal view of the brain, showing the medial PFC (mPFC), anterior cingulate cortex (subgenual (sgACC), rostral (rACC), dorsal (dACC)), striatum (stria), amygdala (Am), and hippocampus (Hp). 

Brain Regions Implicated as Potential Illness and Treatment Biomarkers in MDD

Annals of the New York Academy of Sciences (2015) Volume 1344, Issue 1, pages 50-65. 

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Expression of CNPase protein in ventral prefrontal white matter from 14 matched pairs of subjects with major depressive disorder (MDD) and control subjects. Mean values (with S.E.M.) of the normalized optical density for each group are presented.

Journal of Psychiatric Research, Volume 65, 2015, 53–62

Oligodendrocyte Morphometry and Expression of Myelin – Related mRNA in Ventral Prefrontal White Matter in MDD

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Oligodendrocyte Dysfunctions in MDD

Molecular Psychiatry (2005) 10, 309–322.

Major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendrocyte and synaptic function.

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Reduced oligodendrocyte are found in various brain areas in MDD

Oligodendrocyte Dysfunctions in MDD

Biological Psychiatry (2004) 55, 563-569Schizophrenia Research (2007) 94, 273-280Neuroscience (1999) 91, 1247-1255

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Psychiatry Research (2007)151: 179-188

(A) Normal control subject(B) Normal control subject(C) Schizophrenic subject(D) Bipolar disorder subject(E) Major depression subject

A       C       D       E

The density and size of oligodendrocytes reduced in patients with SCZ and depression

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Depression is the commonest psychiatric comorbidity in Multiple Sclerosis (MS) patients– Point prevalence rates for major depressive syndromes in MS clinic populations are in the range of 14%

– Lifetime risk for MDD in the MS population may be as high as 50%

– Almost all comparison studies have reported higher rates of depression among MS patient cohorts than among those with other chronic illnesses, including other neurologic disorders

Medical intervention may increase depression– Corticosteroids, beta interferons

Depression in Multiple Sclerosis

Mult Scler Relat Disord. 2016 Jan;5:12-26; Multiple Sclerosis (2005) 11: 328-337

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Antidepressant treatment partially blocks or reverses the memory impairment and  hippocampal volume reduction

Antidepressants and Structural Alterations in Depression

Sheline et al., Am J Psych. 2003;160(8):1;  Vermetten et al.,  Biol Psych. 2003;54:693 

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* Malberg et al., J Neurosci. 2000;20:9104** Manev et al., Eur J Pharmacol. 

2001;411:67

Studies from several laboratories have reported increased neurogenesis in adults treated with

SSRI, SNRI, MAOI, ECT*SSRI and atypical antidepressants**SSRI and tricyclic antidepressants†

Atypical antipsychotics ††

Antidepressant Treatment Increases Neurogenesis

 †  Santarelli et al., Science 2003;302:805-809 †† Madsen et al., Biol Psychiatry 2000;47:1043

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Do oligodendrocyte dysfunctions play their roles in Depression pathogenesis?

Contributions to the disease onset and development

Interaction between stress and oligodendrocyte dysfunction 

Will interventions work on depression influence the function of oligodendrocyte cells?

Questions

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Therapeutic Potential on White Matter Deficits in The Treatment of MDD-

preclinical Studies

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• Cuprizonecopper chelator produces copper deficiency in mice        demyelinationcan be added to feed

• Cuprizone administrationdemyelination and apoptosis  of oligodendrocytescessation of cuprizone results in remyelination within 3-4 weeks demyelination and remyelination can be manipulated 

• dose of cuprizone • duration of administration

Cuprizone

Animal Model – Cuprizone-induced Demyelination

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(Brain Pathol., 2003; 13:329-339)

Two-way ANOVA & Newman-Keuls Test **p< 0.01 vs. Con; +p<0.05 ++p< 0.01 vs. cup

Y-maze results

• Quetiapine protects from cuprizone-inducedSpatial working memory impairment in mice

Department of Psychiatry

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Magnification: 10x

LFB-PAS staining Corpus Callosum MBP staining Cerebral CortexNormal

• Protects Mice from Cuprizone-Induced Demyelinationdecreased LFB-PAS in corpus callosumdecreased MBP staining in cortex

Quetiapine (10mg/kg/day)

Cuprizone (0.2%w/w) Cuprizone+quetiapine

Normal Quetiapine (10mg/kg/day)

Cuprizone (0.2%w/w) Cuprizone+quetiapine

Quetiapine Prevents Demyelination

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Zhang,  et al., 2008 

Two-way ANOVA & Newman-Keuls Test  **P< 0.01 vs. Control; ++P< 0.01 vs. Cuprizone

• Cuprizone causes enlargement of lateral ventricles• Quetiapine prevented the enlargement of lateral ventricle

Quetiapine (10mg/kg/day)Normal

Cuprizone (0.2%w/w) Cuprizone+quetiapine

Quetiapine prevents ventricle enlargement

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PhotomicrographsA: Control B: DM-12w C: DM-12w -- RM-2w (W) D: DM-12w -- RM-2w (Q)E: DM-12w -- RM-3w (W) F: DM-12w -- RM-3w (Q) G: DM-12w -- RM-4w (W) H: DM-12w -- RM-4w (Q) W: water Q: quetiapine Bar: 200μm

Quetiapine Promotes MBP Expression in Cerebral Cortex of Demyelinated Brain

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Zhang, et al 2012

*P < 0.05; **P < 0.01, vs. controls

• Quetipine in normal micestimulates oligodendrocytesdecreases proportion of astrocytes

Quetiapine Increases Oligodendrocytes

Xiao, et al., Molecular psychiatry,2008* 17/3/2017

Initialization of myelination

Myelin lamella Myelinated axon

• Quetiapine facilitates myelination in aggregating neocortical cell cultures

Quetiapine in Neocortical Cell Cultures

Xiao, et al., 2008

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The Effects of Transcranial Magnetic Stimulation (rTMS)

on White Matter Deficits

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rTMS is a procedure in which cerebral electrical activity is influenced by a pulsed magnetic field

Transcranial magnetic stimulation (TMS)*

Major depression, Schizophrenia, Addition, Stroke Parkinson’s Disease

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Mechanisms to treat depression are still not fully clearAn hypothesis is that the effects of rTMS on the brain are long-term depression (LTD)-or long-term potentiation (LTP)-like, as the duration of the effects seems to  implicate the changes in synaptic plasticity.

Mechanisms may exist in:

Regulating the endocrinological response of the HPA axis

Effects on neurotransmitter systems in major depression

Affecting neurotrophic factors in the brain 

inducing neurogenesis in the brain

Mechanism of rTMS

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Hypothesis

White Matter Dysfunction

MDD

rTMS ?

rTMS may improve the function of white matter and oligodendrocytes in the brain of MDD patient

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Cuprizone

Animal Model – Cuprizone-induced Demyelination

Co-treatment with cuprizone and rTMS for 3-6 weeks  Behavioural tests  White matter pathology Genetic and molecular reactions to rTMS treatment Fourier transform infrared (FT-IR) microspectroscopy for white matter repair and molecular reformation 

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Effect of HF-rTMS on CPZ-induced Y-Maze Spontaneous Alteration

Effect of HF-rTMS on CPZ-induced Y-Maze spontaneous alteration. (A): Experimental 1 (acute phase); (C): Experimental 2 (recovery phase); Experimental 3 (chronic phase) Results are expressed as mean ± SEM of 16 mice in each group. #P<0.05 vs. Sham group;*P<0.05 vs. CPZ group

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rTMS Improves Social Interactions

The effect of HF-rTMS on CPZ-induced social interaction behavior. (A): Experimental tracking chart; (B): Experiment 1 (acute phase) (a): Session 1; (b): Session 2; (C): Experiment 2 (recovery phase) (c): Session 1; (d): Session 2; (D) Experiment 3 (chronic phase) (e): Session 1; (f): Session 2. Results are expressed as mean ± SEM of the 16 mice in each group. Session 1:#P<0.05 vs. empty cup;*P<0.05 vs. strange1; Session 2: $P<0.05 vs.strange1; %P<0.05 vs.strange2;

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rTMS Alleviates Demyelination

(A) Luxol fast blue and periodic acid Schiff (LFB-PSA) staining for phospholipid of myelin sheaths from Bregma 0.86mm - 0.38mm [A.(1)] and [A.(2),(3)] are shown using low and high magnification (4X and 20X) respectively. Myelination score of ec and cp areas are represented in A (4), (5).

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rTMS Alleviates Demyelination(B) MBP immunostaining in cortical area Bregma 0.86mm - 0.38mm. [B. (1)] and [B. (2)] are shown using low and high magnification (4X and 20X) respectively. MBP western blotting in cortical area B. (3); (C) MBP immunostaining in hippocampus area from Bregma -1.46mm -2.18mm.[C.(1)] and [B.(2)] are shown using low and high magnification (4X and 20X) respectively. MBP western blotting in hippocampus area C.(3); Results are expressed as mean ± SEM of 8 mice in each group. #P<0.05 vs.Sham group;*P<0.05 vs. CPZ group. 1: Sham; 2: CPZ; 3: Sham + rTMS; 4: CPZ + rTMS; cg: cingulum; ec: external capsule; cp: caudate putamen (striatum) LV: lateral ventricle; ctx: cortex; DG: dentate gyrus; 

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Effect of HF-rTMS on PDGFαexpression in prefrontal cortex and hippocampus after 6 weeks of CPZ

(A) PDGFα-immunostaining in ec (A.1), cg (A.2), and DG (A.3) areas. Western blotting in prefrontal cortex (B) and hippocampus (C). Results are expressed as mean ± SEM of 8 mice in each group. #P<0.05 vs.Sham group; *P<0.05vs. CPZ group.1: Sham; 2: CPZ; 3: Sham+rTMS; 4: CPZ+rTMS; cg: cingulum; ec:external capsule; DG: dentate gyrus

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The Effect of HF-rTMS on GFPA and CD11b Expression in Cortex and Hippocampus after 6 Weeks of CPZ

(A):immunofluorescent  staining  for  GFAP  inBregma0.86mm-0.38mm[A.(1)]and  [A.(3)]  are represented the 4×,and 20× magnificationrespectively. [A.(2)] are represented the DG area. Western blotting of GFAP, CD-11b in cortex and hippocampus (B, C).Results are expressed as  mean±  SEM  of  8mice  in  each  group.  1:  Sham;  2:  CPZ;  3:  Sham+rTMS;  4: CPZ+rTMS;#P<0.05 vs.Sham group;*P<0.05vs. CPZ group.

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Myelination, Oligodendrocytes, and Serious Mental Illness

Haroutunian, et al., 2015

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Involvement of oligodendrocyte degeneration in pathophysiology of MDD

decrease in white matter volume• loss of oligodendrocytes• down-regulation of myelin genes• lesions in the white matter may be treatment resistant MDD 

Quetiapine and rTMS• increases oligodendrocytes and reduces astrocytes in normal 

mice• prevents demyelination caused by cuprizone• prevents behaviour impairments• The oligodendrocyte genesis as a potential target in the 

treatment of MDD 

Summary

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Bench & Bedside White matter deficits and environmental interactions through disease progress

Impact of pharmacological and non-pharmacological treatments on white matter deficits in patient

Apply preclinical study to demyelinating diseases

White matter deficits Vs. neurogenesis theory

White matter deficit in pharmacogenomic and neuroimaging

New treatment focusing on white matter in future?

In Future……

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Department of Psychiatry

CIHR, CPRF, MHRC, Schizophrenia Society, NSFC,中国科技部中加科技合作项目(CIHR-MOST)CollaboratorsDrs. Yanbo Zhang, Jiming Kong, Jue He, Haiyun Xu, Lan Xiao, Dai Zhang, Qingrong Tan, Zhijun Zhang, Qingjun Huang

Postdoctoral Fellows and StudentsDrs., Kelly Hartle, Handi Zhang, Junhui Wang, Shufang Feng, Shenghua Zhu

Acknowledgements

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