Diffusion(Tensor(Imaging(Applica4ons(in(Neuropsychiatric(

Disorders(

Katherine(Narr(Ph.D.(

(Clinical(Research(Development(Seminars(Module(7:(

Neuroimaging:(A(Short(Course(on(Modern(Imaging(Modali4es(in(Clinical(Inves4ga4on(

(

Overview(

•  Brief(introduc4on(to(diffusion(imaging(and(the(tensor(model((

•  Local(tensor(derived(measures((

•  Tracts(and(tract(sta4s4cs((•  Applica4ons(in(schizophrenia(and(major(depression((

•  Applica4ons(in(other(clinical(disorders((

Introduc4on(to(Diffusion(Imaging(•  Water(diffusion(is(anisotropic(in(coherently(organized(fibers((muscle(and(

large(axon(bundles)((

•  Diffusivity( is( largest( parallel( to,( and( smallest( perpendicular( to( fiber(orienta4on(

•  To(describe(anisotropic(diffusion,(diffusivity*must(be(measured(in(more(than(one(direc4on(

Diagram shows the cellular elements that contribute to diffusion anisotropy

Hagmann P et al. Radiographics 2006;26:S205-S223

©2006 by Radiological Society of North America

Measuring(Diffusion(with(MRI(•  Diffusion(imaging(data(is(acquired(using(

echo( planar( imaging( (EPI)( pulse(sequences( sensi4ve( to( the( random((Brownian)( mo4on( of( water( molecules(in(4ssue(

•  Diffusion( along( the( direc4on( of( an(applied(magne4c(gradient(field(leads(to(a(signal(decrease(

•  By(applying( linear(gradients( in(different(axes,( diffusivity( may( be( measured( in(different(direc4ons(

•  A( 3D( volume( is( acquired( for( each((gradient(direc4on(

•  Reconstruc4on( methods( es4mate( local(diffusion(proper4es(

Image(from:(Chiang(M(et(al.((2009)(Gene4cs(of(Brain(Fiber(Architecture(and(Intellectual(Performance(J.(Neurosci.(29:2212\2224(

Purpose(of(Diffusion(Imaging(•  Water(diffuses(along(the(nerve(fibers(and(freely(in(fluid(filled(spaces(

•  Diffusion(proper4es(vary(according(to(the(local(structure(of(the(4ssue(being(imaged(

•  Proper4es(of(MR(diffusion(may(thus(reflect(the(integrity(and(geometric(proper4es(of(4ssue(microstructure(

(

Diffusion(weighted(image(of(a(human(brain(a_er(a(stroke.(The(bright(areas(indicate(areas(of(restricted(diffusion.(Image(courtesy(Noriko(Salamon,(MD,(PhD)(

•  Changes(in(diffusion(thus(indicate(microscopic(details(and(disrup4ons(in(4ssue(architecture(as(non+invasively(and(in*vivo*

Applica4ons(•  Quan4fy(microstructural(characteris4cs(of(4ssue–(par4cularly(of(white(

macer((WM)(where(the(loca0on,*orienta0on,(and(anisotropy(of(fiber(bundles(and(tracts(can(be(measured(

•  Important(clinical(relevance(–(localiza4on(and(characteriza4on(of(WM(abnormali4es(and(pathology(–(trauma4c(brain(injury,(tumors,(stroke,(neuropsychiatric(disorders,(neurodevelopmental(disorders,(AD(etc.((

•  Structural(connec4vity(–(Human(Connectome(Project((Sporns(2005;(Wedeen(2008;(Hagmann(2007)(

T2(weighted( MPRAGE(image( FA(map( Fiber(track(

•  In( the( mid( 1990�s,( the( diffusion* tensor* model( (Basser( et( al.,( 1994),( was(devised( to( describe( the( shape( and(orienta0on( of( anisotropic( diffusion( (the*diffusion*ellipsoid)((

•  By( applying( ≥6( gradient( direc4ons,( the( diffusion( tensor( provides( the( 3(principal( diffusivi4es( (eigenvalues)( and( 3( direc4ons( (eigenvectors)( to(es4mate( the(magnitude( and( preferred( direc4on( of(water( diffusion( in( each*voxel*

The(Tensor(Model(

DTI(Visualiza4on(

CSF(

White(macer( White(macer(

Gray(macer(

•  Fiber(direc4on(is(indicated(by(the(tensor’s(main(eigenvector.(This(vector(can(be(color\coded(to(map(the(posi4on(and(direc4on(of(a(white(macer(pathway((

DTI(Visualiza4on(

L/R(

A/P(

I/S(

DTI(Visualiza4on(Visualiza4on(using(the(diffusion(tensor(ellipsoid(

Spherical(shapes(indicate(isotropic(diffusion(

(

Elongated(shapes(indicate(direc4onality(

(

Flat(discs(are(sugges4ve(of(the(crossing(or(junc4on(of(nerve(fibers(

L/R(

A/P(

I/S(

•  DTI(provides(es4mates(of(the(principle(orienta4on(of(fibers(

Tracts(and(Tract(Sta4s4cs(

•  Notably,( scalar( measurements( derived(from( the( diffusion( tensor( also( provide(es4mates( of( other( biophysical( and(geometric(proper4es(of(brain(4ssue((

•  Frac%onal)anisotropy)(FA))(ellipsoid(eccentricity):(degree(of(anisotropy(in(a(given(voxel.(FA( is(greater( in(white(macer(and(smallest( in(unorganized(brain(4ssue(\(index*of*white*ma:er*integrity.((

•  Mean) diffusivity) (MD)) (average( ellipsoid( size):( rota4onally( invariant(magnitude(of(water(diffusion((trace/3).(MD(is(largest(in(CSF(and(smallest(in(organized(white(macer(\(can*reflect*brain*0ssue*atrophy*and*pathology(

Local(Tensor(Derived(Measures((

•  Axial)diffusivity)(AD):(AD(represents(the(largest(eigenvalue,(λ1( (also( termed( longitudinal( diffusivity),( and( measures(diffusion( parallel( to( the( axonal( fibers( –( can( reflect* axonal*integrity*

Local(Tensor(Derived(Measures((

•  Radial) diffusivity) (RD):) RD( is( the(average( of( diffusion( perpendicular( to(axonal(fibers* (λ2(and(λ3(\(also(termed(transverse( diffusivity)( –( can( reflect*integrity*of*myelin*

Tracts(and(Tract(Sta4s4cs(The(brain(is(connected(by(short(and(long(range(fiber(bundles.(Major(pathways(include:()Projec%on)fibers)(connect)cortex)with)subcor%cal)and)brainstem)regions):)• Corona(radiata((ant.*&*post.*limb*&*retrolen0cular*part*of*the*internal*capsule)(• Cor4cospinal(tract((Associa%on)fibers)(connect)regions)within)the)same)cerebral)hemisphere):)• Short(range(associa4on((or(U\fibers)(• Superior(longitudinal(fasciculus((SLF)(• Superior(fronto\occipital(fasciculus((SFO)(• Uncinate(fasciculus((UNC)(• Inferior(fronto\occipital(fasciculus((IFO)(• Inferior(longitudinal(fasciculus((ILF)(• Cingulum((CG)(• Fornix((FX)(((

Commissural)fibers)(connect)regions)across)hemispheres):)• Anterior(commissure(• Corpus(callosum((

(

Long(range(associa4on(fibers(15 Telencephalon: Neocortex 59515 Telencephalon: Neocortex 59515 Telencephalon: Neocortex 59515 Telencephalon: Neocortex 595

Fig. 15.46. Long association connections of the neocortex of the left hemisphere. The multimodal associationcortex in the superior temporal sulcus and the parieto-occipital sulcus is dotted

B Broca’s speech regionM1 primary motor areaMT Middle temporal visual association areaS1 primary sensory areaW Wernicke’s speech region

The(Human(Central(Nervous(System,(Nieuwenhuys,*4th(Edi4on.((

Long(associa4on(connec4ons(of(the(neocortex(of(the(le_(hemisphere.(The(mul4modal(associa4on(cortex(in(the(superior(temporal(sulcus(and(the(parieto\occipital(sulcus(is(do:ed*(

Short(range(associa4on(fibers(15 Telencephalon: Neocortex 59715 Telencephalon: Neocortex 59715 Telencephalon: Neocortex 59715 Telencephalon: Neocortex 597

Fig. 15.47A,B. Short association connections of the cerebral cortex. A Lateral view. The frontal and part ofthe parietal operculum has been removed; the temporal operculum is retracted. B Medial view. The primaryand secondary sensory areas (S1 and S2), the primary and secondary motor areas (M1 and M2), the primaryvisual and auditory cortices, the paralimbic association cortex and the insula, and the limbic cortex are indi-cated with different shadings. The multimodal cortex in the superior temporal sulcus and the parieto-occipi-tal sulcus is dotted

B Broca’s speech regionp.h. parahippocampal gyruspl.t. planum temporaleW Wernicke’s speech region

The(Human(Central(Nervous(System,(Nieuwenhuys,*4th(Edi4on.((

Short(associa4on(connec4ons(of(the(cerebral(cortex.((

Catani and Thiebaut de Schotten 2008

Downloaded from: StudentConsult (on 6 January 2012 07:29 PM) © 2005 Elsevier

Long)associa%on)tracts:)(

• SLF/arcuate:(temporofrontal(arching(pathway(((((((linking(posterior(&(anterior(language\related(regions(

• Cingulum:(connects(frontal,(parietal(&(parahippocampal(regions((limbic)(• Uncinate:(connects(temporal((hippocampus/amygdala)(&(orbitofrontal(regions((limbic)(• ILF:(connects(temporal(lobe(and(occipital(lobes(

• IFO:(connects(frontal(and(occipital(lobes(• Fornix:(connects(hippocampus(&(hypothalamus(

Changes(in(diffusion(metrics(can(be(analyzed(in(several(ways:(

•  By(comparing(regions(of(interest((

•  Voxel\based(analysis(

•  Tract\based( atlasing( approaches,( e.g.,( tract( based( spa4al( sta4s4cs((TBSS)(

•  Tractography(or(fiber(tracking(methods(

Tracts(and(Tract(Sta4s4cs(

!!!!ROI!!!!!!!!!!!!!!!!!!!!!!Voxel*based!!!!!!!!!!!!!!!!!Tractography!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!TBSS

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•  A( vast( body( of( neuroimaging( research( supports( that( psychiatric( disorders( are(

associated(with(abnormali4es(in(brain(structure(and(func4on(

•  The( biological( bases( of( these( disorders( may( be( acributed( to( disturbances( in(

specific(brain(regions(or(in(the(structural/func0onal*connec0ons*between(them(

•  Since( WM( appears( homogenous( in( structural( MRI( data,( DTI( provides( an(

opportunity(to(address(whether(altera4ons(in(WM(connec4vity(and/or(integrity(

contribute(to(disease(pathophysiology(in*vivo*

•  Schizophrenia(has(been(the(most(widely(studied(

(neuropsychiatric(disorder(with(imaging(methods(

•  Since(the(first(schizophrenia(DTI(publica4on(1998,((DTI(has(since(been(used(to(study(nearly(all(of(the((

major(psychiatric(disorders(

Applica4ons(in(Psychiatric(Disorders(

•  Schizophrenia( is( a( complex(mental( disorder( characterized(by( delusions( and(hallucina4ons,(cogni4ve( impairment,(and(blunted(affect,(with(a(peak(age(of(onset(in(early(adulthood(

•  Though( ROI\based(methods( are(more( labor( intensive( and( subjec4ve,( these(methods(may(reveal((local(changes(in(4ssue(structure(associated(with(disease(and(gene4c(vulnerability(in(schizophrenia(

•  For( example,( both( CSF( increases( and( regional( brain( 4ssue( reduc4ons( are(widely(observed(in(schizophrenia(and(are(reported(in(unaffected(rela4ves((

•  MD(is(greater(in(CSF(and(smaller(in(organized(brain(4ssue(and(may(thus(also(reflect(schizophrenia(related(neuropathology(

Schizophrenia:(ROI(Applica4ons(

First episode schizophrenia Chronic schizophrenia

Chronic schizophrenia: Family Study

Significant)ExtraLcor%cal)CSF)Increases)in)Schizophrenia)

•  Using( an( ROI( approach( to( compare( MD( in( pa4ents( their,( first\degree(unaffected(rela4ves(and(controls,(increases(in(temporal(regions(where(shown(as(a(biological(marker(for(schizophrenia(and(disease\related(gene4c(liability(

•  Although( MD( and( CSF( volume( are( correlated,( disease( and( gene4c( liability(effects(remained(a_er(removing(the(variance(associated(with(changes(in(CSF(

•  Thus,(MD(appears(to(be(a(sensi4ve(marker(of(disease(and(gene4c(liability(in(schizophrenia( that( characterizes( at( least( par4ally( dis4nct( aspects( of( brain(structural(integrity(

Schizophrenia:(ROI(Applica4ons(

r=.80,(p<0.0001(

N=132,*community*control*probands*and*rela0ves*(n=55),*pa0ent*rela0ves*(n=44),*schizophrenia*probands*(n=33)*(Narr(et(al.,(2007)(

(

•  Many( prior( DTI( studies( have( used( voxel\based( morphometry–type( (VBM)(analysis(approaches,(which(rely(on(the(registra4on(of(data(between(subjects(

•  Though(these(methods(are(fully(automated(and(cover(the(en4re(brain,(errors(in(registra4on(can(be(incorrectly(interpreted(as(changes(in(DTI(signal(

•  However,( voxel\based( studies( are( suited( for( hypothesis( free,( exploratory(analyses( and( are( useful( for( performing(meta\analy4c( studies( as( results( are(reported(in(a(common(stereotaxic(space(

Schizophrenia:(Voxel\based(Applica4ons(

Schizophrenia(((red)((&(gene4c(liability((blue)(effects(overlaid(

VBM(Gray(Macer((meta\analysis)( VBM(DTI(MD(VBM(DTI(MD(

•  Tract\based(atlasing(approaches(circumvent(poten4al(registra4on(confounds(by(using(linear(&(non\linear(registra4on(to(align(WM(pathways(

•  For(example,(FSL’s(TBSS(aligns(tracts(and(compares(FA(from(tract(centers(

•  While(TBSS(&(VBM(show( reduced(FA( in( the( callosum(&( fornix,(VBM(shows(spurious(result(in(thalamus(due(to(increased(ventricles(in(schizophrenia(

Schizophrenia:(Tract\based(Atlasing(

TBSS)) ) ))VBM )))))))mean)FA)(con.))))))mean)FA)(schiz.)(

Mackay(et(al,(n=(33(pa4ents(with(schizophrenia(and(n=36(controls(

•  Tract\based( altasing( performed( by( using( higher( order( (105( parameter)(nonlinear(warping(procedures(to(align(major(tracts(from(the(JHU(WM(atlas(to(each( subject’s( FA( image( also( demonstrate( significant( disease( and( gene4c(liability(effects(for(FA(in(schizophrenia(

Schizophrenia:(Tract\based(Atlasing(

JHU(white(macer(tractography(atlas((Hau(et(al.,(2010)(

Mean( FA( for( the( le_( and( right( inferior( fronto\occipital( fasciculus( (IFO);( le_( inferior(longitudinal( fasciculus( (ILF);( and( le_( temporal( component( of( the( superior( longitudinal(fasciculus( (fSLF)( showing( significant( effects( of( both( schizophrenia( and( gene4c( liability((Clark(et(al.,(2011)(

Schizophrenia:((Tract\based(Atlasing(

JHU(white(macer(tractography(atlas((Hau(et(al.,(2010)(

!

Schizophrenia:(Tractography(Applica4ons(•  DTI tractography allows the more precise mapping of tract anatomy

within and between subjects and may thus better localize disruptions of connectivity in particular tracts and networks(

Narr(et(al.(

!

Tractography(

•  Once(we(know(the(orienta4on(of(fibers(at(each(voxel,(the(preferred(diffusion(in(adjacent(voxels(can(be(es4mated(to(reconstruct(en4re(pathways(and(hence(brain(connec4ons(

•  For(streamline(or(determinis4c(tractography,(the(preferred(direc4on(of(diffusion(is(mapped(between(two(seed(points(

Preferred(diffusion(direc4ons( are( shown(as( the( long(axes(of(diffusion(ellipsoids.(The(white( line(shows(the(streamline(obtained(by(connec4ng(up(a(set(of(pixels(based(on(their(preferred(direc4ons(

•  Scalar(metrics,(fiber(number,(length(may(be(measured(from(each(tract(without(registra4on(

•  Streamline( tractography( used( to( examine(tracts( that( connect( lateral( and( medial(temporal( lobe( regions( (AF,* ILF* and* UF)* show(significant(reduc4ons(of(FA(in(schizophrenia(

•  These( abnormali4es( are( related( to( thinking(disorder(and(withdrawal(cluster(scores(

30(dir(DTI(data,(n=(23(schizophrenia(pa4ents,(n=(22(controls,((Phillips(et(al.,(2009)(

Schizophrenia:(Tractography(Applica4ons(

•  Short\range( associa4on( (U\fibers)( and( intra\cor4cal( axons( (termed(superficial( white( macer,( SWM)( are( cri4cal( for( the( integra4on( of(informa4on(between(proximal(cor4cal(regions(

•  Since(cor4cal( thickness( reduc4ons(are(widely( reported( in( schizophrenia,(the(structural(integrity(cor4o\cor4cal(connec4ons(may(also(contribute(to(disease(processes(and(represent(gene4c(predisposi4on(for(the(illness(

•  Since( SWM(connec4ons( have( less( defined( trajectories( and( the( cortex( is(highly( variable,( more( refined( cor4cal( pacern( matching( methods( have(been(used(to(map(SWM(structural(connec4vity(

Cor4co\cor4cal(connec4vity((

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Significant)Reduc%ons)of)Gray)MaTer)Thickness)in)Schizophrenia)

Mapping(SWM(microstructure(

Cor4co\cor4cal(connec4vity((

•  Microstructural( changes( in(SWM(occur(in(distributed(lobar(regions(and(may(cons4tute(a(mechanism(for( the( func4onal( disturbances(associated(with(schizophrenia(

•  SWM( FA( reduc4ons( in( rela4ves(of( pa4ents( suggest( that( gene4c(factors,( though( to( a( lesser(extent,( disrupt(WM( connec4vity(across(a(variety(of(networks(

Cor4co\cor4cal(connec4vity((

•  Understanding(how(changes(in(WM(microstructure(relate(to(normal(brain(func4on( may( determine( how( altered( structural( connec4vity( relates( to(clinical(symptoms(or(specific(cogni4ve(deficits(in(schizophrenia(

•  The(arcuate(fasciculus((AF)(connects(cor4cal(regions(important(in(language(processing(

•  AF(WM(fiber(coherence(and(organiza4on(is(shown(to(relate(to(gray(macer(macrostructure(and(aspects(of(language(func4on((Phillips(et(al.,(2011)((

Rela4onships(with(Cogni4on(and(Symptoms(

Rela4onships(between(arcuate(FA(and(cor4cal(thickness( (show(highly(significant(associa4ons(between(FA(and(cor4cal(thickness(along(the(trajectory(of(the(AF(encompassing(Broca’s(area((BA(44,(45)(and(proximal(prefrontal(cortex((BA(6),(Wernicke’s(area((BA(22),(and(inferior(parietal((BA(39(and(40),(superior(and(middle(temporal((BA(41,(42)(and(inferior(temporal(cor4ces((BA(37).(

•  A( recent( tractography( study( has(further( shown( that( pa4ents( with(schizophrenia( demonstrate( bilateral(reduc4ons( of( FA( arcuate( fasciculus(compared(to(controls(

•  Reduc4ons( of( FA( were( highest,( and(bilateral,( in( pa4ents( with( auditory(v e r b a l( h a l l u c i n a4on s( ( AVH )(compared( to( pa4ents( without( AVH(and(controls(

Differences(between(pa4ents(with(schizophrenia((SCZ)(without(auditory( verbal( hallucina4ons( (AVH−),( pa4ents( with( auditory(verbal( hallucina4ons( (AVH+),( and( healthy( controls( in( three(segments(of(the(arcuate(fasciculus.(*Differences(are(significant(at(p(=(.011(versus(healthy(controls.(†Differences(are(significant(at(p(=( .009(versus(healthy(controls.(°Differences(are(significant(at(p(=( .008(versus(healthy(controls.(P(values(are(corrected( for(mul4ple(comparisons.(L,(le_;(R,(right.(

Rela4onships(with(Cogni4on(and(Symptoms(

Catani(et(al.,(Biol(Psychiatry(2011;(70:1143–1150(

•  Several( recent( studies( have( employed( mul4\modal( imaging( to( clarify(rela4onships( between( func4onal( and( structural( disconnec4vity( in(schizophrenia.(

•  For(example,(reduced(func4onal(connec4vity(in(medial(frontal(regions(has(been(shown(associated(with(reduced(anatomical(connec4vity( in(adjacent(WM(((

Structural(and(Func4onal(Connec4vity(

Overlap(between(altered(res4ng(state(DMN(connec4vity(and(TBSS(FA(reduc4ons(in(medial(prefrontal(cortex(

Camchong(et(al.,(2009(

•  More( sophis4cated( network\based( sta4s4cal(methods( that( combine( the(tractography,( parcella4on( schemes( to( divide( the( cortex( into( nodes( and(graph\theory( based( analysis( approaches( have( been( applied( to( es4mate(anatomical(network(connec4vity(in(schizophrenia(

Network(Connec4vity(

Figure(1.(Overview(of(methodology((Zalesky(et(al.,(Biological(Psychiatry(Volume(69,(2011,(80(–(89)((

Network(Connec4vity(

Schema4c( of( the( frontal\parietal/occipital( network(that(was(impaired(in(schizophrenia((p(=(.021(±(.004,(corrected).( Each( connec4on( comprising( this(network(was(impaired(in(pa4ents(but(not(in(control(subjects.( Le_:( uniquely( colored( nodes( and(streamline( representa4on( of( interconnec4ng( fiber(bundles.(Anterior\posterior(fibers:(green;( le_–right:(red;(and(superior\inferior:(blue.(Right:(planar(graph(representa4on,( where( each( node( is( depicted( as( a(circle(posi4oned(at(its(node's(center(of(gravity.((

•  Impaired( connec4vity( was(found( to( involve( a( distributed(network( of( nodes( comprising(medial( frontal,( parietal/occipital,(and(the(le_(temporal(lobe(in(schizophrenia(

•  The(cortex(was(interconnected(more( sparsely( and( up( to( 20%(less(efficiently(in(pa4ents(

Zalesky(et(al.,(Biological(Psychiatry(Volume(69,(2011,(80(–(89(

•  Fiber(tracking(in(T1(image(space(

•  ROI\wise(connec4vity(analysis(

Network(Connec4vity(

Shacuck(et(al.,(Brainsuite(so_ware(is(available(online(at:(hcp://brainsuite.loni.ucla.edu/((

Network(Connec4vity(

Shacuck(et(al.,(Brainsuite(so_ware(is(available(online(at:(hcp://brainsuite.loni.ucla.edu/((

Network(Connec4vity(

Shacuck(et(al.,(Brainsuite(so_ware(is(available(online(at:(hcp://brainsuite.loni.ucla.edu/((

•  WM(abnormali4es,(typically(reduced(FA,(have(been(shown(in(most(all(major(associa4on(and(projec4on(pathways(and(the(callosum(in(schizophrenia(

•  Recent( reviews( and( meta\analyses( of( voxel\based( studies( suggest( fronto\temporal(WM(disturbances(are(more(closely(linked(with(the(disorder(

•  Such( WM( abnormali4es( occur( in( pa4ents( with( recent( onset( and( with( no(an4psycho4c(medica4on(exposure(sugges4ng(they(predate(illness(onset(

•  Changes( in( WM( integrity( are( shown( to( associate( with( specific( cogni4ve(deficits( (verbal( and( spa4al( working( memory)( as( well( as( psychopathology((posi4ve(more(than(nega4ve(symptoms)(

Synthesis(of(Schizophrenia(DTI(Findings(

Major(brain( regions( implicated( in(first( episode( schizophrenia(based(on(DTI( studies.(A(parasagical( sec4on(of( the( cerebrum(shows( the(major( brain( regions( and(white(macer( tracts,( i.e.,(temporal( lobe( (highlighted( dark( grey),( occipital( lobe((highlighted( light( grey),( corpus( callosum,( inferior( (straight(lines)( and( superior( longitudinal( fasciculi( (doced( lines)((Kuswanto(et(al.,(2012).(

•  Schizophrenia( is( known( to( have( a( high( heritability,( while( recent( evidence(shows(that(varia4ons(in(DTI(metrics(are(also(heritable(

•  DTI( indices(are(shown(to(indicate(a(gene4c(liability(for(schizophrenia,(which(may(be( important( for( iden4fying( specific( gene4c( risk( factors( such( as(NRG1(and(ErbB4((oligodendrocyte/myelin\related)(genes(implicated(in(the(disorder(

Graph(showing(propor4on(of(papers(that(reported(either(an(increase,(a(decrease,(an(or(no(difference(in((a)(func4onal(connec4vity(and((b)(structural(connec4vity(between(pa4ent(group(versus(HCs.(William((Pecersson\Yeo(et(al.,(2010(

Synthesis(of(Schizophrenia(DTI(Findings(

•  Though( major( depression( is( also( considered( a( network( disorder( involving(mood(regula4ng(circuits,( fewer(studies(have(used(DTI(to( inves4gate(altered(WM(integrity(in(the(disorder(

•  A( consensus( is( star4ng( to( emerge( to( suggest( altered( WM( integrity( in(prefrontal(and(parietal(networks(and(striatal(and(paralimbic(areas(

•  Further,( WM( microstructure( is( shown( to( vary( with( illness( severity( and( in(pa4ents(unresponsive(to(an4depressant(medica4ons(

•  For( example,( a( recent( voxel\based( and( tract( of( interest( study( showed(rela4onships(between(illness(severity(and(thalamic(connec4ons(

DTI(in(Major(Depression(

Posi4ve(correla4on(of(FA(with(HAMD(score(

Group(analysis(for(subcor4cal(tracts(of(interest(

Tract(of(interest(

(Osoba(et(al.,(2013)(

(

•  Few( longitudinal( studies( have( addressed( whether( altera4ons( in( WM(integrity(relate(to(or(predict(treatment(response(in(major(depression(

•  Our(recent(findings(show(greater(MD(and(RD(in(commissural((forceps(major)(and(associa4on((ILF(and(IFO)(fibers(forming(temporo\(and(parietal\occipital(projec4ons(in(pa4ents(with(major(depression(compared(to(controls(

Major(Depression:(Applica4ons(

•  Pa4ents(followed(prospec4vely(while(receiving( electroconvulsive( therapy((ECT)( show( treatment( related(increases( in(AD(sugges4ng( increases(in( fiber( coherence( that( act( to(normalize( disease\related( WM(deficits(

Significant(effects(of(MDD(for(MD(and(RD((top(two(panels)(and(significant(effects(of(ECT( for(AD(es4mated(using(FSL’s(Tract\Based( Spa4al( Sta4s4cs,( red( and( blue:( t( >( 2,( p<.05,(cluster(corrected).(n=13(MDD(pa4ents,(n=20(controls.(

•  Deep( brain( s4mula4on( (DBS)( is( another( neuromodulatory( technique( that(has(emerged(as(a(treatment(op4on(for(pa4ents(with(major(depression(that(have(not(responded(to(other(therapies(

•  Though( different( targets( have( been( inves4gated,( the( subgenual( cingulate((Cg25)((Mayberg(et(al.(2005)(,(which(includes(strong(WM(connec4ons(with(limbic( and( prefrontal( structures,( appears( to( most( effec4ve( s4mula4on(target(

Major(Depression:(Applica4ons(

WM( connec4ons( to( the( subgenual( cingulum.( Seeding( of( the(subgenual( cingulum( demonstrates( tracts( linking( with( the(ventromedial(prefrontal(cortex,(hypothalamus,(and(amygdala((via(the(stria(terminalis(and(the(uncinate(fasciculus)((Bha4a(et(al.(2012)(

•  Recent( evidence( suggests( that(stereotac4c( target( selec4on( using( T2(MR( sequences,( is( improved(using(DTI(tractography( to( map(WM( tracts( that(cross( in( Cg25( ( (Johansen\Berg( et( al.,(2008;(Bha4a(et(al.,(2012)(

•  DTI( has( been( used( to( characterize( the( neurobiological( underpinnings( of(many( other( disorders( such( as( anxiety* disorders,* obsessive+compulsive*disorder,*a:en0on*deficit*disorder*and*au0sm*

•  DTI(has(also(led(to(clinical(applica4ons(for(determining(brain(pathology,(such(as( cerebral* ischemia,* trauma,* MS,* presumed* AD,* epilepsy,* brain* tumors,*metabolic*disorders*and*congenital*brain*malforma0ons*

Applica4ons(in(other(Clinical(Disorders((

DTI(of(HGPSS.((A)(and((B)(show(DTI(color(maps(of(the(middle(and(superior(pons,( respec4vely,( and( demonstrate( the( absence( of( normal( decussa4ng(pon4ne(fibers( (A)( and(SCP( (B)( in(HGPPS( compared(with( control( subjects.(Red( arrows( indicate( the( MCP( (A)( and( SCP( (B);( yellow( arrows( indicate(normal(decussa4ng(fibers( in(control(subjects.(Bocom(panel(displays(fiber(tractography( of( cor4cospinal( tracts( (C,D)( and( corpus( callosum( (E)( in( an(HGPPS( subject( (In(Wahl( and(Mukherjee,( 2009( \( from( Sicoce( et( al.,( 2006(and(Haller(et(al.,(2008)(

•  DTI( demonstrates( a( lack( of( normal( crossing(of( SCP( pathways,( pon4ne( fibers( and( the(cor4cospinal( tract( in( horizontal* gaze* palsy*with* progressive* scoliosis* (HGPPS),( caused(by(of(muta4ons(in(the(ROBO3(gene(

Non\(tensor(based(models(\(HARDI(•  The(diffusion(tensor(model(performs(well(in(

regions(with(only(one(fiber(popula4on(

•  However,(it(fails(in(regions(with(several(fiber(popula4ons(along(intersec4ng(axes((crossing(fibers)(because(it(cannot(map(several(diffusion(maxima(at(the(same(4me((

•  In(such(areas,(imaging(techniques(that(provide(higher(angular(resolu4on(are(needed(to(provide(a(more(complete(picture(of(the(diffusion(pacern(

•  Examples(include(Diffusion(Spectrum(and(faster(Q\Ball(imaging(

(

Image(from(Shacuck(et(al.((2008)(Visualiza4on(Tools(for(High(Angular(Resolu4on(Diffusion(Imaging,(Medical*Image*Compu0ng*and*Computer*Assisted*Interven0on*(MICCAI)*2008(

Comparison(between(diffusion(tensor(and(diffusion(spectrum(imaging(in(regions(that(contain(fiber(crossings.((Hagmann P et al. Radiographics 2006;26:S205-S223

©2006 by Radiological Society of North America

High(Angular(Resolu4on(Diffusion(Imaging((HARDI)(

Takahashi et al., 2011

Cats DSI ex vivo

Weeden et al.

Human in vivo