White matter and cognitive function in schizophrenia

White matter and cognitive functionin schizophrenia

Andrew J. Dwork1,2,3, Branislav Mancevski1,2 and Gorazd Rosoklija1,2,41 Department of Neuroscience, New York State Psychiatric Institute, New York, NY, USA

Departments of 2 Psychiatry and 3 Pathology, College of Physicians and Surgeons of Columbia University, New York, NY, USA4 Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia

Abstract

Abnormalities of cerebral white matter, oligodendrocytes, and myelin have been observed in schizo-

phrenia with in-vivo imaging and post-mortem biochemistry. White-matter abnormalities are also fre-

quently associated with cognitive impairment in both healthy and diseased individuals, and cognitive

dysfunction is an important component of schizophrenia. While many studies have documented these

associations, only a handful have examined the role of white matter in cognitive function in schizophrenia.

In this paper, we explore what is known about white-matter deficits in relation to schizophrenia, cognitive

deficits, or both together, in order to generate a theoretical model for the role that compromise of white

matter might play in producing cognitive impairment in schizophrenia.

Received 30 August 2006; Reviewed 12 October 2006; Revised 15 January 2006; Accepted 18 January 2006;

First published online 21 February 2007

Key words : Cognition, myelin, neuropathology, oligodendrocyte, schizophrenia.

Introduction

Abnormalities of cerebral white matter, myelin, and

oligodendrocytes have been reported in schizophrenia

(reviewed in Davis et al., 2003; Sullivan and

Pfefferbaum, 2003; Walterfang et al., 2006). White-

matter abnormalities are also a common feature of

dementia, particularly, but not exclusively, when of

vascular origin (Bronge, 2002; Chin and Goldman,

1996; Hachinski, 1990). Cognitive impairment is now

recognized as a core feature of schizophrenia. In

young individuals with schizophrenia, cognitive defi-

cits are often detectable on psychological testing

(Goldberg andWeinberger, 1988; Green et al., 2004). In

the majority of elderly individuals with schizophrenia,

cognitive impairments are of a severity that would be

characterized as dementia in individuals without

schizophrenia (Arnold et al., 1995; Davidson et al.,

1995; Dwork et al., 1998).

The neuropathological substrates of cognitive im-

pairment in schizophrenia are unknown. In elderly

individuals with schizophrenia, there is no increase in

Alzheimer-type changes (Arnold et al., 1998; Dwork

et al., 1998; Purohit et al., 1998), and the cholinergic

deficits found in Alzheimer’s disease are not present

(Haroutunian et al., 1994). Although diminished cog-

nitive reserve in schizophrenia may increase suscep-

tibility to the cognitive effects of mild Alzheimer-type

changes that commonly occur with age, many elderly

individuals with schizophrenia and severe cognitive

impairment lack such changes (Dwork et al., 1998;

Ortakov et al., 1999). Two neuropathological processes,

however, are common to dementia and schizophrenia.

The first is a loss of presynaptic and post-synaptic

elements in cerebral cortex (Bigio et al., 2001;

Browning et al., 1993; Davidsson et al., 1999; Dawson

and Hallenbeck, 1996; DeKosky and Scheff, 1990;

Eastwood et al., 1995; Eastwood and Harrison, 1995,

1999; Gabriel et al., 1997; Garey et al., 1998; Glantz

and Lewis, 1997, 2000; Goto and Hirano, 1990; Hamos

et al., 1989; Harrison, 1999; Honer et al., 1992, 1997;

Honer and Young, 2004; Karson et al., 1999; Law et al.,

2004; Masliah et al., 1989, 1991; Perdahl et al., 1984;

Perrone-Bizzozero et al., 1996; Regeur et al., 1994;

Rosoklija et al., 2000; Tcherepanov and Sokolov,

1997; Terry et al., 1991; Vawter et al., 1999). The

second, which is the focus of this study, is an alter-

ation of cerebral white matter.

Although white-matter changes appear to be less

severe in schizophrenia than in many forms of

dementia, they could nonetheless be an intrinsic com-

ponent of schizophrenia that contributes eventually

Address for correspondence: Dr A. J. Dwork, 1051 Riverside Dr.,

Unit 62, New York, NY 10032, USA.

Tel. : 212-543-5563 Fax : 212-543-6017

E-mail : [email protected]

International Journal of Neuropsychopharmacology (2007), 10, 513–536. Copyright f 2007 CINPdoi:10.1017/S1461145707007638

SPECIAL SECTION

CINP

to dementia. In addition, normal or pathological vari-

ation in white matter that is not related to schizo-

phrenia could have cognitive consequences that are

exaggerated in individuals with schizophrenia. One

such consequence might be a lessening of cognitive

reserve, or the capacity to resist the cognitive manifes-

tations of normal ageing processes or age-associated

degenerative changes (Stern, 2006). The concept of

cognitive reserve comprises both anatomical capacity

(e.g. size of brain or neurons) and the ability to recruit

neuronal activity. Both types of reserve are probably

impaired in schizophrenia. Pre-existing impairment

may predispose to the development of schizophrenia

and may worsen its prognosis, and schizophrenia may

progressively impair cognitive reserve (Barnett et al.,

2006). Myelin integrity correlates with cognitive pro-

cessing speed (Liston et al., 2006), and might thus

contribute to cognitive reserve. On the other hand,

factors conventionally associated with cognitive

reserve, such as education or physical activity, ap-

pear to protect against loss of processing speed in

conditions associated with myelin loss, e.g. ageing

(Dik et al., 2003), infection with human immuno-

deficiency virus (Stern et al., 1996), or white-matter

hyperintensities on magnetic resonance imaging

(MRI) (Nebes et al., 2006). It thus seems likely that

early-life myelination is relatively resistant to ageing

and contributes to cognitive reserve, while the various

components of cognitive reserve impart resistance to

the cognitive effects of pathological or age-related loss

of myelin.

White-matter abnormalities in schizophrenia

The majority of studies implicating white-matter

alterations in schizophrenia employ in-vivo imaging.

T2-weighted signal intensity is largely determined

by water content, and therefore serves as a sensitive

indicator of demyelination, oedema, or inflammation.

Early studies, looking for regions of T2 hyperintensity,

gave mixed results, but white-matter hyperintensities

were certainly not consistently present (Brown et al.,

1992, 1995; Hulshoff Pol et al., 2000; Keshavan et al.,

1996; Lane et al., 1996; Rivkin et al., 2000; Symonds

et al., 1997). Brown et al. (1995) concluded that T2 hy-

perintensities in schizophrenia were associated with

stroke or hypertension and were no more common

than in non-psychiatric subjects. Thus, the abnormali-

ties uncovered by more sensitive MRI techniques must

be considered relatively subtle, which is consistent

with the failure of conventional neuropathological

studies of schizophrenia to note any excess of white-

matter lesions.

Volumetric studies of white matter (reviewed in

Walterfang et al., 2006) give conflicting results, par-

ticularly with regard to the size and shape of the cor-

pus callosum. The more consistent findings include

reduction in volume of the left uncinate fasciculus and

the anterior limb of the internal capsule. These struc-

tures contain fibres connecting the thalamus with

frontal and cingulate cortices, and frontal cortex with

rostral temporal cortex, respectively. In general, simi-

lar decrements in schizophrenia are reported for grey-

matter volumes and white-matter volumes, suggest-

ing that the latter may simply reflect the former.

However, this interpretation should be viewed with

caution; with the possible exception of the medial

dorsal nucleus of the thalamus (Byne et al., 2002;

Dorph-Petersen et al., 2004; Pakkenberg, 1992; Young

et al., 2000) there is little replicated evidence for neu-

ronal loss in schizophrenia (reviewed in Dwork, 1997;

Harrison, 1999; Heckers, 1997). Therefore, white-

matter deficits probably cannot be simply explained

by deficits in neurons giving rise to axons.

Magnetic resonance spectroscopy (MRS) exploits

the magnetic resonance spectra of specific organic

compounds to localize and quantify these compounds

in vivo. Commonly analysed compounds include

N-acetylaspartate (NAA), which is believed to be un-

ique to neurons and is generally accepted as a measure

of density or viability of neurons and axons. NAA is

quantified either in absolute terms or relative to cre-

atine, a relatively stable component of neurons and

glia (Hammen et al., 2003). MRS has demonstrated

decreased NAA, increased creatine or a decreased

NAA/creatine ratio in right prefrontal white matter

(Choe et al., 1994), white matter in general (Lim et al.,

1998), and parietal white matter (Auer et al., 2001) in

schizophrenia. Bartha et al. (1999), finding no change

in NAA signal in a medial temporal region of interest

designed to include predominantly grey matter, con-

cluded that previously reported decreases in NAA

probably reflected a loss in white matter. Reductions

of NAA in prefrontal white matter reported by Steel

et al. (2001) were not statistically significant.

The studies pointing most frequently to abnormali-

ties of white matter in schizophrenia employed dif-

fusion tensor imaging (DTI). DTI applies several

magnetic gradients in various orientations in order to

obtain a set of diffusion-weighted images, from which

is derived a tensor corresponding to the apparent rate

of diffusion of water in three orthogonal dimensions

within each voxel (typically several mm in each di-

mension). For each voxel, several indices are obtained

from this procedure, including (a) trace or mean dif-

fusivity (D=trace/3), measures of average diffusivity,

514 A. J. Dwork et al.

independent of direction, (b) fractional anisotropy

(FA) or relative anisotropy (RA), measures of the de-

gree of directionality of apparent diffusion (these em-

ploy different formulas, but both range theoretically

from 0 with equal diffusion in all directions to 1 with

diffusion confined to one direction), (c) lk, or axial

diffusivity, the apparent diffusion constant in the di-

rection of maximal apparent diffusivity, and (d) l?, or

radial diffusivity, the mean rate of diffusion in the

perpendicular dimensions (Basser and Jones, 2002;

Basser and Pierpaoli, 1996; Kingsley and Monahan,

2005). Comparison of diffusion tensors in adjacent

voxels is employed for fibre tract tracing (diffusion

tractography, e.g. Pierpaoli et al., 2001) who point out

the danger of artefactual construction of non-existent

tracts) or measures of intervoxel coherence, the aver-

age angle between the vector of maximum diffusivity

in a given voxel and those of its neighbours (Pierpaoli

and Basser, 1996).

In complex systems, such as cerebral white matter,

the arrangement of fibres must obviously contribute to

anisotropy (see, e.g. Pierpaoli et al., 2001). In tissues

such as peripheral or optic nerve, where most of the

fibres are oriented in parallel, lk is the apparent dif-

fusion constant in the direction of fibre orientation;

however, even in isolated preparations of such tissue,

the anatomical factors contributing to the tensor are

complex (reviewed in Beaulieu, 2002). In healthy

nerve, lk is nearly equal to the diffusion of free water,

while l? is several times smaller. Myelin probably

contributes to anisotropy by reducing l?, but it is not

required for anisotropic diffusion, which is readily

observed in normally unmyelinated nerves or in gen-

etically myelin-deficient rat spinal cords. The latter

show increased lk and somewhat greater increases in

l?. With Wallerian degeneration, in which axons and

myelin disintegrate distal to an injury of peripheral

nerve, lk decreases and l? increases ; anisotropy

eventually returns to normal with regeneration, al-

though regenerated peripheral nerves typically have

thinner myelin sheaths than previously. While atten-

tion is frequently focused on diffusion of water within

axons, diffusion in the extracellular space should also

have important effects on anisotropy.

In pathological conditions of the nervous system,

axonal damage, myelin loss, and reactive processes

tend to occur in unison. Thus, it is very difficult to

determine, even with histological examination and

DTI of the same piece of tissue, how an individual

component of tissue damage affects various indices of

diffusion. One exception is the shiverer mouse, in

which a mutation of the gene for myelin basic protein

(MBP) results in myelin sheaths that are thin, loosely

wrapped, or absent, without evidence of axonal injury

or tissue reaction. In major cerebral white-matter tracts

of live shiverer mice, Song et al. (2002) found decreases

in RA (y20%), with lk unchanged, but l? increased

by y20%. Thus, a relatively pure deficit in myelin re-

sulted in a modest increase in radial diffusivity, with

no effect on axial diffusivity and preservation of a

considerable degree of anisotropy. This is essentially

consistent with the conclusion of Beaulieu (2002) that

the axolemma forms the principal boundary to radial

diffusion, with the myelin sheath playing a mod-

ulatory role. It is also notable that, while axonal pack-

ing density was unchanged in the shiverer mice of

Song et al. (2002), the illustrations show an increase in

water-accessible space between adjacent myelin

sheaths and between layers of individual myelin

sheaths. One difficulty in interpreting such studies is

that tissue can change during fixation and histological

preparation. In white matter of fixed shiverer brains,

soaked in the contrast-enhancing agent gadoteridol, lkand l? were both increased, with a 10–20% decrease

in FA and a slightly larger increase trace, compared

with wild-type mice (Tyszka et al., 2006).

In more complex pathological models [retinal

ischaemia (Song et al., 2003; Sun et al., 2006a),

b-amyloid overexpression (Song et al., 2004; Sun et al.,

2005), experimental allergic encephalomyelitis (Kim

et al., 2006) cuprizone toxicity (Song et al., 2005; Sun

et al., 2006b)], increases in l? and decreases in lk,

were interpreted as damage to myelin and axons,

respectively, but as noted by the authors, other inter-

pretations are plausible.

Another refinement of MRI is the measurement of

magnetization transfer (MT), simplistically, the sup-

pression of the T2 signal of water by the transfer of

proton spin from adjacent, immobilized macro-

molecules. Presumably, loss of macromolecules, such

as myelin lipids, results in decreased MT, which is

distinguishable from a simple increase in water con-

tent (Grossman et al., 1994).

Of at least 39 DTI or MT studies of schizophrenia

(Table 1), only four were entirely negative (Begre et al.,

2003; Foong et al., 2002; Price et al., 2005; Wang et al.,

2003) ; only one of these four (Foong et al., 2002) sur-

veyed all regions of cerebral white matter, and that

study imposed stringent criteria for statistical signifi-

cance. The remaining studies, while all showing de-

creased FA somewhere in the white matter, are not

entirely consistent about where such loss is located. In

prefrontal white matter, the results suggest a pre-

dominance of ventral abnormalities (Ardekani et al.,

2003; Buchsbaum et al., 1998, 2006a,b; Hao et al., 2003;

Kumra et al., 2004). Some studies found generalized

White matter and cognition 515

Table 1. Studies of schizophrenia by diffusion tensor or magnetization transfer imaging (diffusion measures other than FA, when available, appear in italics)

Study

Regions of white matter with decreased

fractional anisotropy or decreased

magnetization transfer

Regions without decreased fractional

anisotropy or magnetization

transfer

Schizophrenia

sample

Non-psychiatric

sample

Age

(av, S.D.)

(range) M/F

Age

(av, S.D.)

(range) M/F

Buchsbaum et al. (1998) Prefrontal WM (ventral more than dorsal) All other regions 34, 7 3/2 46, 13 3/3

Lim et al. (1999) Widespread in both hemispheres, from

frontal to occipital

48, 8 10/0 42, 8 10/0

32–64 30–57

Foong et al. (2000a) Right and left temporal regions (by

magnetization transfer imaging)

Frontal, parietal, occipital, corpus callosum. 37 19/6 35 22/8

25–46 25–49No correlation of temporal lobe anisotropy

with age, duration of illness, or symptoms

Foong et al. (2000b) Splenium of corpus callosum. D increased Genu of corpus callosum. D unchanged 38 15/5 34 16/9

Agartz et al. (2001) Splenium of corpus callosum and adjacent

occipital WM

All other regions 38, 8 11/9 42, 7 15/9

23–49 23–55

Foong et al. (2001) WM of middle temporal gyri (by magnetization

transfer). Lower MT in splenium of corpus

callosum correlated with negative symptoms

37, 7 19/6 35, 7 22/8

25–46 25–49

Hoptman et al. (2002) In schizophrenia, impulsivity correlated with

decreased FA in right ventromedial prefrontal

WM, aggression and assaultiveness with increased

trace

41, 8 14/0

31–60

Kubicki et al. (2002) Uncinate fasciculus: Schizophrenia associated

with loss of L >R asymmetry and with

correlations to cognitive test scores

Uncinate fasciculus: no difference between

groups in magnitude

43, 7 15/0 43, 6 18/0

17–55 17–55

Foong et al. (2002) All WM. D unchanged 39 11/3 35 12/7

Ardekani et al. (2003) Bilateral deep frontal perigenual region, left

superior temporal gyrus, bilateral middle

temporal gyri, bilateral parahipocampal gyri,

bilateral inferior parietal lobules, bilateral

medial occipital lobes, corpus callosum

All other regions 31, 9 11/3 34, 11 11/3

20–55 20–55

Bagary et al. (2003) Uncinate fasciculus (by magnetization transfer) Most other abnormalities were in grey matter 27, 7 19/11 29, 6 18/12

18–47 21–49

Begre et al. (2003) Bilateral hippocampi in first-episode

schizophrenia

23 6/1 23 6/1

16–30 16–30

Burns et al. (2003) Left uncinate fasciculus, left arcuate fasciculus Bilateral anterior cingulate gyri, right uncinate

fasciculus, right arcuate fasciculus

36, 11 15/15 36, 12 15/15

516A.J.

Dwork

etal.

Kubicki et al. (2003) Cingulum bundle. D unchanged 43, 7 16/0 43, 6 18/0

18–55 18–55

Minami et al. (2003) All WM regions bilaterally 41, 9 10

Sun et al. (2003) Anterior cingulate gyrus All other regions 27, 8 18/12 26, 8 12/7

Wang et al. (2003) Superior and middle cerebellar peduncles.

D unchanged

28, 7 29/0 26, 6 20/0

Wolkin et al. (2003) Inferior frontal WM anisotropy inversely

proportional to SANS score in schizophrenia

cases. No comparison group

41, 9 10/0

Kumra et al. (2004) Bilateral frontal WM in plane of anterior and

posterior commissures (i.e. ventral), right

occipital WM in same plane

Bilateral dorsal frontal WM, left occipital WM in

plane of anterior and posterior commissures, genu

of corpus callosum, splenium of corpus callosum

17, 2 9/3 16, 2 6/3

15–19 12–16

Hoptman et al. (2004) In schizophrenia, impulsivity correlated with

decreased FA in some areas, including right

ventromedial prefrontal WM, and increased FA

in other areas

39, 7 25/0

24–51

Hubl et al. (2004) Arcuate fasciculus, uncinate fasciculus, inferior

longitudinal fasciculus, corpus callosum

Temporoparietal arcuate fasciculus and anterior

left corpus callosum greater in schizophrenia

subjects with auditory hallucinations than in

controls

32, 9 16/10 32, 8 8/5

Nestor et al. (2004) Uncinate fasciculus: FA correlates with memory

performance in schizophrenia only

41, 7 14/0 42, 7 14/0

17–55 17–55

Cingulate bundle: FA correlates with WCST errors

in schizophrenia only

Okugawa et al. (2004) Middle cerebellar peduncles. D unchanged Less difference in subjects on higher dosage

of neuroleptics

30, 7 12/13 30, 4 11/10

Park et al. (2004) Normal L>R asymmetry absent in uncinate

fasciculus and anterior limb of internal capsule,

reduced in anterior corpus callosum

43, 7 23/0 44, 6 32/0

28–53 30–55

Wang et al. (2004b) Bilateral cingulum bundle, especially left Posterior cingulum bundle 29, 6 21/0 26, 6 20/0

Jones et al. (2005) Right superior temporal gyrus, left cerebellum.

D unchanged

All other areas. D unchanged 34 14/0 34 14/0

22–53 19–57

Kubicki et al. (2005) FA: anterior and middle cingulum bilaterally,

anterior and posterior superior occipito-frontal

fasciculus, internal capsule bilaterally, fornix,

corpus callosum, right inferior occipito-frontal

fasciculus, left arcuate fasciculus

All other regions 21/0 21/018–55 18–55

MT: corpus callosum, fornix, right internal capsule,

anterior superior occipito-frontal fasciculus

Okugawa et al. (2005) Middle cerebellar peduncle. D unchanged 30, 7 12/13 29, 4 11/10

[continues overleaf

White

matter

andcogn

ition517

Table 1. (cont.)

Study

Regions of white matter with decreased

fractional anisotropy or decreased

magnetization transfer

Regions without decreased fractional

anisotropy or magnetization

transfer

Schizophrenia

sample

Non-psychiatric

sample

Age

(av, S.D.)

(range) M/F

Age

(av, S.D.)

(range) M/F

Price et al. (2005) Genu and splenium of corpus callosum in first

episode patients. D unchanged

25 14/6 28 11/18

18–49 20–40

Szeszko et al. (2005) Left internal capsule, left middle frontal gyrus WM

and left superior temporal gyrus WM

All other regions 27, 5 6/4 29, 6 7/6

Brambilla et al. (2005) Increased diffusivity throughout corpus callosum. 41, 12 42/25 40, 11 37/33

Correlates with positive symptoms rostrally

Kitamura et al. (2005) Frontal WM. l? and lk increased Parietal WM. l? and lk unchanged 31, 5 6/0 32, 4 6/0

24–38 26–36

Jones et al. (2006) Left superior longitudinal fasciculus. Greater

difference at younger age. D unchanged

Right cingulum, right uncinate. Other

nonsignificant differences difficult to interpret

because of age effects

34, 9 14/0 34, 10 14/0

22–53 19–57

Kuroki et al. (2006) Fornix. D increased 40, 9 24/0 41, 9 31/0

24–52 23–54

Hao et al. (2006) Multiple, including ventral prefrontal bilaterally

and right middle frontal gyrus WM. First episode

with f6 wk antipsychotic exposure

Multiple, including left dorsal prefrontal 24, 5 12/9 25, 5 10/11

18–42 19–33

Buchsbaum et al.

(2006a)

Frontal WM (ventral>dorsal, under age

60 yr>over age 60 yr), rostral corpus callosum,

cingulate grey and WM, superior longitudinal

fasciculus

Most other regions 42, 13 44/19 42, 20 32/23

20–73 18–80

Buchsbaum et al.

(2006b)

Shorter frontal thalamocrtical projections by

diffusion tractography, lower anisotropy in

ventral tracts

No difference in length of ventral tracts on

right side. No difference in anisotropy of dorsal

tracts

43, 12 83/20 44, 15 28/13

Federspiel et al. (2006) Decreased intervoxel coherence in deep WM,

mostly prefrontal and temporal, left anterior

limb of internal capsule

Increased intervoxel coherence in right anterior

thalamic peduncle, right optic radiation, and

left posterior external capsule. No differences

in superficial WM

23, 3 8/4 23, 3 8/4

18–29 18–29

Lim et al. (2006) Multiple correlations of FA in different regions

with different cognitive domains in schizophrenia

36, 10 22/3

WM, White matter; FA, fractional anisotropy; SANS, Scale for the Assessment of Negative Symptoms; WCST, Wisconsin Card Sorting Test ; MT, magnetization transfer.

518A.J.

Dwork

etal.

decreases that included dorsal prefrontal white matter

(Federspiel et al., 2006; Lim et al., 1999; Minami et al.,

2003), underlying a cortical region implicated in func-

tional imaging studies of cognition in schizophrenia

(Callicott et al., 2003; Weinberger et al., 1986). None of

the DTI studies of schizophrenia involved elderly

subjects, except for the large study by Buchsbaum

et al. (2006a), who reported that decreases in frontal

anisotropy were enhanced when subjects aged>60 yr

were removed from the sample. According to

Jones et al. (2006), by middle age, differences in FA

between schizophrenia and comparison subjects start

to become less evident with age.

As noted above, decreases in FA may be the result

of alterations in myelin. A subtle axonopathy, e.g. as

part of a slow dying-back process, might be consistent

with the reported loss of anisotropy and with the loss

of NAA signal in white matter, with relative preser-

vation of normal histology (see below). For example, it

appears that in amyotrophic lateral sclerosis, DTI may

be more sensitive than histological examination for

detecting abnormalities in the suprabulbar portions of

the corticospinal tracts (Toosy et al., 2003), which

usually appear normal on myelin stains.

Although a number of studies describe decreased

anisotropy in the uncinate fasciculus, or in ventral

frontal white matter, where it terminates, Highley et al.

(2002) report normal size and axon number in the un-

cinate fasciculus at autopsy. The methodology did not

allow myelin changes to be ruled out, but the discre-

pancy between normal axonal number and decreased

anisotropy could also be explained by disorganization

of the fasciculus. This possibility is supported by

tractography evidence of shorter frontal fibre bundles,

which could indicate dispersion of fibre tracts before

they reach their targets (Buchsbaum et al., 2006b).

Resolution of these issues will require stereological

studies of axonal orientation and, in plastic-embedded

tissue, of axonal diameter and thickness of myelin

sheaths.

Few of the DTI studies report diffusion measures

other than FA (Table 1). In four studies, decreased FA

was associated with increased D ; in five studies it was

not. Only one study reports l? and lk, which were

both increased where FA was decreased, leading the

authors to attribute the changes to expansion of the

extracellular space in frontal white matter (Kitamura

et al., 2005).

Only a few post-mortem studies have specifically

evaluated white matter in schizophrenia (Table 2).

Hof et al. (2002, 2003), in small groups of aged,

chronically institutionalized subjects, found, using

Cresyl Violet stains, a 15–20% decrease in density of

oligodendrocytes in the white matter underlying

Brodmann’s area (BA) 9, and a 28% decrease when

oligodendrocytes were identified by immunoreac-

tivity for 2k,3k-cyclic nucleotide-3k-phosphodiesterase(CNPase). However, in the younger sample from the

Stanley Consortium, Uranova et al. (2004) found an

effect of schizophrenia on density of oligodendroglia

in this region only in the cortex, not in the white

matter. Marner and Pakkenberg (2003), comparing

eight schizophrenia subjects and nine controls with a

mean age of 60 yr, found no difference in the total

length of myelinated axons in the prefrontal white

matter, nor in the diameters of these axons. In a large

series of elderly, chronically institutionalized schizo-

phrenia subjects, we performed detailed histological

evaluations of Verhoeff myelin stains in the white

matter of the dorsal prefrontal region and found no

difference from non-psychiatric subjects (Dwork et al.,

2005). Falkai et al. (1999) found no evidence for astro-

cytosis in the white matter of the premotor cortex or

the subventricular zone of the third ventricle, which

suggests that, at least in these regions, a demyelinating

process is unlikely.

Highley et al. (2002) reported normal size and axon

number in an autopsy study of the uncinate fasciculus

in elderly subjects with schizophrenia. In the same

sample, the anterior commissure was of normal size,

but there was a 31% decrease in fibre density in the

female schizophrenia subjects compared with con-

trols, while there was no effect of diagnosis among the

males (Highley et al., 1999b). In the corpus callosum,

fibre density was decreased among females with

schizophrenia but not among males (Highley et al.,

1999a). In the fornix, there was a 32% increase in fibre

density on the left side in males with schizophrenia

(Chance et al., 1999). These studies found a loss of

fibres with age in most subregions of the corpus cal-

losum, but not in the uncinate fasciculus, anterior

commissure, or fornix. In other studies of the corpus

callosum of middle-aged (Casanova et al., 1989) and

elderly (Nasrallah et al., 1983) subjects, schizophrenia

was not associated with a loss of fibre density.

Ultrastructural studies of white matter in schizo-

phrenia are lacking, but there are several reports on

oligodendroglial and myelin morphology in frontal

cortical area BA 10. An electron microscopic study

of BA 10 biopsies found lipofuscin deposits in oligo-

dendroglial cytoplasm and increased numbers of

electron-dense granules in neuronal cytoplasm, axon–

oligodendrocyte interfaces, and myelin sheaths

(Miyakawa et al., 1972). An electron microscopic study

of autopsy material (Uranova et al., 2001) purported to

show subtle abnormalities in oligodendroglia and

White matter and cognition 519

Table 2. Post-mortem studies of cerebral white matter

Study Regions investigated Findings in schizophrenia

Schizophrenia

sample

Non-psychiatric

sample

Age

(av, S.D.)

(range) M/F

Age

(av, S.D.)

(range) M/F

Nasrallah et al. (1983) Corpus callosum No difference in density of axons or glia in anterior or

posterior portions

69, y11 n=18 64, 11 n=11

Casanova et al. (1989) Corpus callosum No difference in fibre density in anterior, middle, or

posterior portions

15, 12 10/1 50, 16 10/3

30–73 30–84

Falkai et al. (1999) Grey matter (entorhinal cortex and

subiculum) and WM (premotor cortex,

subventricular zone of the third ventricle

and next to inferior horn)

No evidence for astrocytosis 54, y8 14/19 53, 12 13/13

Highley et al. (1999a) Corpus callosum Normal size 67, y16 15/11 70, y15 15/14

Decrease fibre density among females with schizophrenia 74 0/10 64 0/11

No difference in fibre density among the males 65 10/0 64 10/0

Highley et al. (1999b) Anterior commissure Normal size 67, y16 15/11 70, y15 15/14

31% decrease in fibre density in the female

schizophrenia subjects compared with controls

72, 18 0/8 73, 14 0/10

No difference in fibre density among the males 67, 13 9/0 64, 17 10/0

Chance et al. (1999) Fornix 32% increase of fibre density on the left side among males

with schizophrenia, no difference in total number of fibres

62,15 16/0 67,13 19/0

No difference in density or total number of fibres among females 78, 12 0/13 72,13 0/14

Highley et al. (2002) Uncinate fasciculus Normal size and axon number 64, y20 9/8 72, y13 10/11

Hof et al. (2002) BA 9 cortex and WM Decrease in density of oligodendrocytes in cortical layer III and WM 80, 3 2/2 80, 4 2/2

Hof et al. (2003) BA 9 cortex and WM Decrease in number and density of oligodendrocytes in

cortical layer III and WM

77, 6 3/4 79, 6 4/3

66–82 69–85

Marner and Pakkenberg

(2003)

Prefrontal WM No difference in the total length of myelinated axons nor

in the diameters of the axons

60, 14 8/0 60, 14) 9/0

41–78 40–8

Uranova et al. (2004) BA 9 cortex and WM Decrease density of oligodendrocytes in cortical layer VI,

but not in the WM

45, 13 9/6 48, 11 9/6

25–62 29–68

Dwork et al. (2005) Dorsal prefrontal WM No difference from nonpsychiatric subjects in myelin histology 79, 11 52/40 62, 12 12/16

46–103 43–87

McCullumsmith et al. (2007) Anterior cingulate WM Decreased mRNA for MAG; CNPase; QKI; and transferrin 75, 12 29/12 79, 12 13/21

Mancevski et al. (2006) Dorsal prefrontal WM Correlation of myelin histology with cognitive function

in schizophrenia subjects

79, 12 46/35

46–103

Beasley et al. (in press) Anterior cingulate WM Decreased mRNA for MAG; MBP; and CNPase; decreased

levels of MBP protein but not CNPase

51, 14 18/20 52, 14 18/20

24–80 23–75

WM, White matter; MAG, myelin-associated glycoprotein; CNPase, 2k,3k-cyclic nucleotide-3k-phosphodiesterase; QKI, quaking homologue; MBP, myelin basic protein.

520A.J.

Dwork

etal.

myelin sheaths of cortical layer VI of BA 10 and the

caudate nucleus in schizophrenia. These included de-

creased cross-sectional areas of nuclei and decreased

fraction of cytoplasmic volume occupied by mito-

chondria, but not the electron-dense granules or lipo-

fuscin described in the biopsies (Miyakawa et al.,

1972). The non-specific findings of these studies are

somewhat compromised by a failure to note whether

the examiners were masked to diagnosis. None of

these studies described evidence of demyelination,

and none measured the thicknesses of myelin sheaths,

which could be reduced in the case of remyelination or

altered by aberrant regulation of myelination (e.g. as

hypothesized in the case of an abnormality or insuf-

ficiency of neuregulin 1; see below).

In the only reported study of mRNA in white matter

(McCullumsmith et al., 2007), expression of myelin-

associated glycoprotein [MAG; transmembrane glyco-

protein of oligodendrocytes, largely localized to the

periaxonal collar and believed to be involved in signal

transduction between the axon and myelin sheath

(Schachner and Bartsch, 2000)], CNPase (cytoplasmic

protein of oligodendrocytes, with unknown function),

quaking homologue [QKI, regulates alternative spli-

cing of several myelin-related genes (Aberg et al.,

2006a; Wu et al., 2002)], and transferrin (iron transport

protein expressed by oligodendrocytes) were down-

regulated in the anterior cingulate white matter of 41

elderly, medicated and unmedicated schizophrenia

subjects, compared with 34 elderly non-psychiatric

subjects. Similarly, in a small, middle-aged sample, we

found decreased mRNA for MAG, MBP, and CNPase,

and decreased levels of MBP protein, but not CNPase,

in anterior cingulate white matter (Beasley et al., in

press).

Studies of myelin- and oligodendrocyte-related

proteins and mRNA levels in grey matter are more

numerous (Table 3). Flynn et al. (2003) found sub-

stantial decreases in immunoreactivity for CNPase

and MAG in prefrontal cortex. Hakak et al. (2001)

demonstrated down-regulation of mRNA for CNPase,

MAG, myelin and lymphocyte protein, gelsolin, and

transferrin, all of which are expressed predominantly

in oligodendrocytes, and for ErbB3, a receptor for

neuregulin (see below) in BA 46 of elderly schizo-

phrenia subjects. Similar results were obtained in BA 9

in a younger sample (Tkachev et al., 2003). Aberg et al.

(2006a) demonstrated down-regulation of mRNA for

proteolipid protein 1, MAG, and transferrin in frontal

cortex, and proposed that this was regulated by ex-

pression of the QKI 7-kb splice variant, which is also

down-regulated (Aberg et al., 2006b). Dracheva et al.

(2006) found, in an elderly sample, that mRNA for

MAG, CNPase, SRY (sex determining region Y)-box 10

(SOX10; oligodendroglial transcription regulator),

claudin11 (CLDN11, essential for the formation of

myelin tight junctions), and peripheral myelin protein

22 (PMP22) was reduced in the hippocampus and an-

terior cingulate cortex but not in the putamen of pa-

tients with schizophrenia, while transcripts for MBP

and myelin-associated oligodendrocyte basic protein

(MOBP), both involved in compaction of the myelin

sheath, were unaffected. Expression of CNPase, the

only protein examined in this study, was decreased in

the hippocampus but not in the putamen.

The aforementioned abnormalities of myelin-

related proteins and mRNA, although studied in grey

matter, have undoubtedly contributed to assumptions

or speculation that the decreases in FA and MT, ob-

served in MRI studies, are the result of abnormalities

in myelin. This line of thought is further supported by

genetic studies.Myelination-related geneswhose poly-

morphisms have been associated with schizophrenia

include Nrg1 (Harrison and Weinberger, 2005), which

is involved (at least in peripheral nerve) in regulating

the extent of wrapping of the myelin sheath around

the axon (Michailov et al., 2004). Although previous

reports involved non-coding regions, association of

psychosis with a missense mutation of the Nrg1 gene

was recently discovered (Walss-Bass et al., 2006).

Studies of white matter in these individuals have not

yet been reported. A genetic association of schizo-

phrenia was found with an exonic polymorphism of

CNPase, an allele that is less expressed than its

counterpart allele in the cerebral cortex of normal

heterozygous individuals (Peirce et al., 2006). Schizo-

phrenia has also been associated with a specific hap-

lotype in the region of the QKI gene and, in a different

population of schizophrenia patients, with altered pat-

terns of expression of QKI splice variants. Expression

of all QKI splice variants was elevated in subjects

treated with typical neuroleptics (Aberg et al., 2006b).

While the biology of oligodendrocytes in grey mat-

ter appears to be similar to that of oligodendrocytes in

white matter, there may be differences that are poorly

understood; for example, Graeber et al. (2002) refer to

the satellite oligodendrocytes that surround neurons

as an ‘enigma’ (p. 150). Thus, while white-matter

myelin may be abnormal in schizophrenia, direct evi-

dence for this is very limited, and such an abnormality

may or may not underlie the loss of anisotropy seen

with DTI. It should also be remembered that axonal

abnormalities, such as the slow dying-back of amyo-

trophic lateral sclerosis (motor neuron disease)

(Coleman and Ribchester, 2004), are associated with

loss of myelin, and demyelinating diseases, such as

White matter and cognition 521

Table 3. Post-mortem studies of oligodendrocytes and myelin in cerebral grey matter

Study Regions investigated Findings in schizophrenia Schizophrenia sample Non-psychiatric sample

Miyakawa et al. (1972) BA 10 No abnormalities by light microscopy. Lipofuscin deposits and

other, subtle abnormalities by electron microscopy (see text)

25–45 3/2 n=4

Uranova et al. (2001) Cortical layer VI of BA

10 and caudate nucleus

Subtle abnormalities in oligodendroglia and myelin sheaths by

electron microscopy

60, 15 9/13 60, 13 9/7

Flynn et al. (2003) Prefrontal cortex Decreased immunoreactivity for CNPase and MAG 31, 10 28/2 37, 12 23/4

Hakak et al. (2001) BA 46 Decreased mRNA for CNPase, MAG, myelin and lymphocyte

protein, gelsolin, transferrin, and ErbB3

72, 12 9/3 79, 14 4/8

Tkachev et al. (2003) BA 9 Down-regulation of mRNA for PLP1, CLDN11, MOG,

ErbB3, transferrin, OLIG1, OLIG2, SOX10, and some MBP

transcripts. No difference for NRG1 or markers of immature

oligodendrocytes

44 9/6 48 9/6

25–62 29–68

Aberg et al. (2006a,b) Frontal cortex Down-regulation of mRNA for proteolipid protein 1, MAG,

transferrin and QKI splice variants 7 kb and 7 kbB

55, 17 32/23 59, 18 32/23

Dracheva et al. (2006) Hippocampus Reduced mRNA for MAG, CNPase, SOX10, CLDN11, PMP22 76, 10 13/11 80, 11 8/13

No changes in mRNA for MBP and MOBP

CNPase protein reduced

Anterior cingulate cortex Reduced mRNA for MAG, CNPase, SOX10, CLDN11, PMP22 77, 10 18/12 82, 12 9/16

Caudate Reduced mRNA for MAG, CNPase, SOX10, CLDN11, PMP22 76, 10 13/10 79, 11 8/12

Putamen No changes in gene or protein expression 76, 10 13/11 79, 11 7/12

CNPase, 2k,3k-cyclic nucleotide-3k-phosphodiesterase; MAG, myelin-associated glycoprotein; PLP1, proteolipid protein 1; CLDN11, claudin 11; MOG, myelin oligodendrocyte

glycoprotein; OLIG 1, 2, oligodendrocyte transcription factor 1, 2; SOX10, sex-determining region Y-box 10 transcription factor; NRG1, neuregulin 1; QKI, quaking homologue;

MBP, myelin basic protein; MOBP, myelin-associated oligodendrocyte basic protein.

522A.J.

Dwork

etal.

multiple sclerosis, result in axonal damage and loss

(Craner et al., 2004). It may ultimately prove diffi-

cult to determine whether myelin abnormalities in

schizophrenia are primary or secondary to neuronal

abnormalities. Furthermore, as we discuss below, re-

myelination can result in increased density of oligo-

dendrocytes and related mRNA, so lower levels of

mRNA for myelin-related proteins in schizophrenia

could represent either an abnormal increase in myelin

stability, or absence of repair of normally occurring

(e.g. age-related) demyelination.

Ageing, myelin, and ApoE genotype

Myelination of the human brain continues into adult-

hood (Yakovlev and Lecours, 1967), and by late middle

age there begins a process of demyelination (Marner

et al., 2003; Tang et al., 1997). In rhesus monkeys, age-

related demyelination is accompanied by evidence

of remyelination, at least in cerebral cortex, where

numerical densities of oligodendrocytes (Peters et al.,

1991; Peters and Sethares, 2004), grouping of oligo-

dendrocytes (Peters, 1996), and frequency of paranodal

profiles, short internodes, and thinly myelinated inter-

nodes (Peters and Sethares, 2003) all increase with age.

Some of these changes, as well as a loss of axons, are

also observed in the anterior commissure (Sandell and

Peters, 2003), corpus callosum (Peters and Sethares,

2002), and optic nerve (Sandell and Peters, 2002) of

elderly rhesus monkeys. Sloane et al. (2003) found in-

creasing calpain activation with age in rhesus white

matter, accompanied by increased levels of intact and

degraded CNPase but decreased levels of MAG [poss-

ibly explaining observations by Peters and colleagues

of impaired adherence of myelin sheaths to axons, a

process in partmediated byMAG (Kursula, 2001)] ; this

pattern of protein expression may be common to early

demyelination of various aetiologies (Aboul-Enein

et al., 2003). An interesting question is why these

monkeys, like humans (Marner et al., 2003; Tang et al.,

1997), undergo a loss of axons in white matter, while

axonal numbers are maintained in the simian cortex.

Sandell and Peters (2003) suggest a dying-back process

that affects distal axons in white matter but not proxi-

mal axons in cortex. This explanation is quite plausible ;

equally plausible is the possibility that axonal damage

is secondary to primary demyelination. White-matter

oligodendrocytes could be more vulnerable than cor-

tical ones to age-related stressors, or distal axons could

be more vulnerable than proximal ones to damage

secondary to demyelination.

In humans, imaging (reviewed in Bartzokis, 2004;

Bartzokis et al., 2006) and post-mortem studies (Ansari

and Loch, 1975; Berlet and Volk, 1980; Chia et al.,

1983; Marner et al., 2003; Meier-Ruge et al., 1992;

Miller et al., 1980; Svennerholm et al., 1991, 1997; Tang

et al., 1997; Wender et al., 1991; Wiggins et al., 1988;

Yakovlev and Lecours, 1967) indicate a loss of white

matter and its myelin content with ageing. Lintl and

Braak (1983) demonstrated an age-associated increase

in intra-cortical myelin (in the stria of Gennari) in the

first three decades, followed by a linear decrease with

age over the next seven decades, consistent with the

predictions of Yakovlev and Lecours (1967) that the

end-point of cortical myelination would be pathologi-

cal or senile demyelination. Kemper (1994), reviewing

data from the atlas of Kaes (1907), found pronounced

senile loss of myelin in association cortices, but not

in primary sensory or motor cortices. Presumably, re-

myelination also increases with age, as in rhesus

monkeys, but this remains to be proven histologically.

Preliminary data from the anterior nucleus of the

thalamus indicate an increase in oligodendrocytes

with normal ageing that is not seen in schizophrenia

(W. Byne, personal communication), suggesting that a

normal process of demyelination and remyelination

may be disrupted by schizophrenia.

It is frequently stated (e.g. Bartzokis, 2004) that the

latest axons to be myelinated are the first to be de-

myelinated. The evidence is consistent with this as-

sumption, but it is not conclusive. The most specific

statement that can be made about the effect of ageing

on white matter, based on quantitative histology, is

that there is a significant loss of myelinated fibres,

preferentially affecting those of small calibre (Marner

et al., 2003; Pakkenberg et al., 2003; Tang et al., 1997).

According to Yakovlev and Lecours (1967) and their

citations of Flechsig (1920), the latest white-matter

fibres to be myelinated are the connections between

thalamus and association cortex, long cortical associ-

ation fibres, and commissural fibres, with myelination

of the corpus callosum gradually extending from the

splenium rostrally. Kemper (1994) was of the opinion

that the material in Yakovlev’s collection showed age-

related pallor confined to corticocortical fibres. Among

the commissures of the rhesus monkey, the greatest

proportion of small-diameter fibres is in the genu of

the corpus callosum, connecting frontal association

areas (Lamantia and Rakic, 1990). DTI shows that

in normal human ageing, reduced anisotropy in the

corpus callosum is primarily in the genu (Head et al.,

2004), or at least spares the splenium (Ota et al., 2006).

Salat et al. (2005) found age-related decreases in ani-

sotropy in frontal white matter and the genu of the

corpus callosum, but also in the posterior limb of the

internal capsule [with differences between young and

White matter and cognition 523

middle-aged adults ; similarly Schneiderman et al. (in

press) found a decrease in anisotropy of the posterior

limb between adolescence and adulthood]. The pos-

terior limb of the internal capsule, containing mostly

corticospinal fibres and general somatic projections

from thalamus to postcentral gyrus, completes myeli-

nation in the first few years of life (Yakovlev and

Lecours, 1967), and reaches a plateau of anisotropy at

5–18 months of age (Morriss et al., 1999), with no fur-

ther increase between childhood and early adulthood

(Suzuki et al., 2003).

Myelination, demyelination, and remyelination are

probably all affected by genotype for apolipoprotein E

(apoE). In young adults, the e4 allele is associated with

an abnormal pattern of cortical activation during a

recall task, without deficits in performance of the task

(Scarmeas et al., 2005). Some studies find impaired

cognitive function in middle-aged and older adults

possessing an e4 allele, while others do not, and there

is controversy over whether such abnormalities rep-

resent early Alzheimer’s disease (AD) (reviewed in

Savitz et al., 2006). Presence of an e4 allele is associated

with increased risk and earlier onset of AD. In a sam-

ple of 29 cognitively normal adults with a mean age

of 65 yr, the presence of an e4 allele was associated

with a localized decrease in white-matter anisotropy

in the ventral parahippocampal region, but not 5 mm

or 10 mm dorsal to this (Nierenberg et al., 2005). The

localized effect in an age group at risk for AD suggests

that this white-matter change may reflect senile de-

generation in the entorhinal and transentorhinal cor-

tex [Braak stages I–II (Braak and Braak, 1991)], rather

than a generalized effect of the e4 allele on myelin.

Kalus et al. (2006) found localized loss of intervoxel

coherence in this region in subjects with mild cogni-

tive impairment (mean age 76 yr), presumably inde-

pendent of genotype. On the other hand, using T2

relaxation time as a measure of myelin integrity,

Bartzokis et al. (2006) found that the apoE e4 allele was

associated with decreased integrity and an exagger-

ated correlation of decreased integrity with age in

frontal white matter and genu of corpus callosum (re-

gions without apparent vulnerability in early AD)

among normal adults aged 55–75 yr, while an e2 allele

was protective.

Homozygosity for e4 is associated with AD-related

white-matter abnormalities on MRI (Bronge, 2002),

and with a mean age of onset for schizophrenia that

is 10 yr earlier than with other genotypes (Kampman

et al., 2004). As noted by Bartzokis et al. (2004), the

essential role of apoE in the recycling of lipids and

cholesterol could be crucial to myelin repair, and the

influence of genotype on this process could explain its

influence on the clinical course of a variety of brain

insults.

Onset of schizophrenia and the natural course of

myelination

Benes and colleagues have noted that the molecular

layer of the subiculum and pre- and parasubiculum is

myelinated in the second and third decades of life

(Benes, 1989; Benes et al., 1994), and they suggest that

maturation of the connections subserved by these

fibres is required for the onset of schizophrenia (Benes,

1989, 2004; Benes et al., 1994). In a slightly different

interpretation of this phenomenon, Bartzokis (2002)

suggests that schizophrenia may result from inter-

ference withmyelination at this time. In schizophrenia,

subicular apical dendrites, which extend into the

molecular layer, have decreased densities of dendritic

spines (Rosoklija et al., 2000) and decreased im-

munoreactivity for microtubule-associated proteins

2 and 5 (Arnold et al., 1991; Rosoklija et al., 2005).

mRNA for spinophilin is reduced in these neurons

(Law et al., 2004). These findings suggest that the

afferent axons may also be abnormal. However, the

question is unresolved, with only one relevant study

published. Chambers and Perrone-Bizzozero (2004)

compared optical density of MBP immunoreactivity in

16 schizophrenia subjects (10 males, mean age 52 yr;

6 females, mean age 70 yr) and 14 non-psychiatric

subjects (9 males, mean age 51 yr; 5 females, mean

age 70 yr). Among the females, optical density was

significantly lower in the schizophrenia group, while

among the males, there was no significant difference

between groups. Unfortunately, this study cannot

provide a definitive conclusion about the state of

myelination of the subicular/presubicular molecular

layer, since the number of subjects is small, and optical

density of MBP immunoreactivity is not a sensitive

method for evaluating the status of myelin [which

perhaps explains the small variance that these in-

vestigators report, while Benes et al. (1994) illustrate

considerable variability among control subjects, even

within a given age group].

DTI reveals widespread areas of white-matter

change between adolescence and adulthood

(Schneiderman et al., in press), any of which could be

a candidate for a developmental abnormality of

myelination in schizophrenia. Indeed, extension of

these studies to schizophrenia has revealed complex

patterns of differences in effects of age on FA

(Schneiderman et al., 2006, and personal communi-

cation). These important studies are somewhat limited

by cross-sectional design and modest sample size;

524 A. J. Dwork et al.

longitudinal follow-up to demonstrate maturational

changes in individuals would be invaluable.

The various presentations of metachromatic leuko-

dystrophy, an autosomal recessive defect in aryl sul-

fatase A that results in widespread demyelination,

suggests that brain functions in the process of devel-

opment may be particularly vulnerable to disruption

by demyelination. The late infantile form of meta-

chromatic leukodystrophy presents in the first 2 yr of

life with motor difficulties. The juvenile form presents

between ages 4 yr and 12 yr with behavioural and

speech difficulties, while the adult form presents after

puberty with psychiatric symptoms that are fre-

quently mistaken initially for schizophrenia. The

psychotic presentation of the adult-onset form is fre-

quently cited as evidence for a role of myelin pathol-

ogy in the aetiology of schizophrenia (e.g. Bartzokis,

2002; Hyde et al., 1992). However, we would caution

against over-interpretation of this clinical phenom-

enon. The adult onset form of globoid cell leukody-

strophy, a sphingolipidosis with similar gross

pathology (due to a defect in the next step of sphin-

golipid metabolism), presents with motor difficulties.

Both diseases, while characterized by loss of myelin,

are caused by enzymatic deficiencies that also have

other effects.

Myelin integrity and cognitive function in healthy

humans and monkeys

The relationship between cognitive function and

myelin integrity has been studied histologically in the

rhesus monkey. Demyelination and axonal degener-

ation in the anterior commissure increase with

age. Both processes presumably lead to a loss of mye-

linated axons, and the number of myelinated axons

was significantly correlated with cognitive function

between ages 5 and 20 yr. In older monkeys, aged

25–35 yr, the number of myelinated fibres was uni-

formly decreased to the minimum level found in the

younger group, and there was no correlation with

cognitive function, which was well-preserved in some

of the older animals (Sandell and Peters, 2003). How-

ever, degenerative changes of cortical myelin in frontal

area 46 (Peters and Sethares, 2002) and primary visual

cortex (Peters et al., 2000) were correlated with cogni-

tive impairment at all ages, although at least in the

visual cortex, there was no loss of fibres (Nielsen and

Peters, 2000).

In a study of 47 children, aged 5–18 yr, there was

a significant correlation between IQ and FA in

several brain areas, including frontal, parietal,

occipito-temporo-parietal, and corticospinal tracts

(Schmithorst et al., 2005). In a series of 23 children,

working memory was significantly correlated with FA

in dorsal left fronto-parietal, ventral left frontal, and

left temporo-occipital white matter and in rostral cor-

pus callosum, while reading correlated with FA in left

temporal white matter (Nagy et al., 2004). In both

studies, anisotropy in these regions also correlated

with age, suggesting that deficits were the result of

failed or delayed development. Young and middle-

aged adults with dyslexia also show decreased FA in

left temporal white matter (Klingberg et al., 2000),

suggesting persistence of a developmental deficit in-

volving temporal white matter that can still be de-

tected years later by DTI. An even more striking

example of developmental variability comes from two

studies of healthy Scottish subjects (Deary et al., 2006;

Shenkin et al., 2003) who had received IQ tests (Moray

House Test) in 1932, at age 11 yr. A total of 69 healthy

subjects were examined at ages 80 or 83 yr. Current FA

in the centrum semiovale was significantly correlated

with IQ at age 11 yr, as well as with current measures

of cognitive function and reading ability. (The cen-

trum semiovale is a large region, dorsal to the entire

body of the lateral ventricle. More detailed localization

would be of great interest.) The remarkable feature

of these studies is that normal correlates of cognitive

functional abilities are detectable by DTI years after

these abilities are established, and indeed, years after

they were measured. Long-term longitudinal studies

of DTI are not yet available. While the studies cited

would suggest that early variations persist, especially

in the case of those related to reading ability (generally

believed to be among the most stable of cognitive

functions), we would point out that this is not necess-

arily the case, and that the histological basis of a deficit

of FA might change. Theoretically, for instance, neu-

ronal pathology could first give rise to a functional

deficit without any structural abnormality in white

matter. Subsequently, this abnormality could lead to

decreased FA due to structural changes in the distal

axon, as part of a dying-back axonopathy that

eventually might result in loss of myelin.

Significant correlations have been reported between

cognitive decline in normal ageing and decreased FA

in all levels of centrum semiovale (Charlton et al.,

2006) and in rostral corpus callosum (Persson et al.,

2006b). However, Shenkin et al. (2005), in a study of

105 non-demented individuals aged 76–82 yr, found

no significant correlations of FA in frontal white

matter or centrum semiovale with any cognitive

measure, including reading ability. Studies that did

not include measures of cognitive decline found a

significant, negative correlation between age and FA

White matter and cognition 525

in frontal white matter or rostral corpus callosum, but

not in posterior regions (Head et al., 2004; Ota et al.,

2006; Pfefferbaum et al., 2005; Salat et al., 2005)

whereas posterior deficits in FA have been associated

with early-stage dementia (Head et al., 2004), and with

an apoE e4 allele in a sample of non-demented in-

dividuals aged 50–79 yr (Persson et al., 2006a).

[Presumably, these posterior deficits in white matter

are related to the posterior cortical deficits in resting

metabolism and activation that have long been re-

cognized in Alzheimer’s disease (Ingvar et al., 1975).]

Since cognitive function and frontal and rostral callo-

sal FA are all correlated with ageing, it is difficult

to determine whether age-related decline in anterior

FA is independently related to cognitive decline. After

Charlton et al. (2006) controlled for age and reading

ability, the only significant correlation that remained

was between working memory and FA in middle and

posterior centrum semiovale. It seems plausible that

a developmental component of frontal FA contributes

to a static component of cognitive function, while age-

related loss of frontal FA has little relationship with

cognitive function.

In a small autopsy study of elderly subjects with

no cognitive impairment, mild cognitive impairment,

or AD (Wang et al., 2004a), there was a significant

negative correlation between cognitive impairment

and immunoreactivity for MBP in white-matter homo-

genates from the middle frontal gyrus, and a negative

correlation of MBP with age among the unimpaired

subjects.

Myelin integrity and cognitive function in

schizophrenia

A few studies have examined the relationship between

white-matter integrity and cognitive function or

symptomatology and schizophrenia. In an autopsy

study of elderly, chronically institutionalized schizo-

phrenia subjects, dorsal prefrontal myelin ratings

(from left or right hemisphere, selected randomly)

were associated with severity of cognitive dysfunction

[evaluated by review of medical records (Ortakov

et al., 1999)] at the onset of schizophrenia (typically

y50 yr before death) and during the last years of

life, but not with the intervening change (Mancevski

et al., 2006). Age at death and neuropathological evi-

dence for vasculopathy, infarction or AD were all as-

sociated with lower myelin ratings, greater cognitive

impairment at the end of life, and greater progression

of cognitive impairment over the course of illness,

but not with severity of cognitive impairment at the

onset of illness. Thus, as suggested above for healthy

subjects, normal variability early in life may contri-

bute to a deficit of white-matter integrity and a static

component of cognitive deficit, or decreased cognitive

reserve. Whereas in healthy individuals this may

correspond only to a few points of IQ, in schizo-

phrenia it is manifested by mild but clinically evident

deficits on most items of the adapted Clinical

Dementia Rating scale (Ortakov et al., 1999).

Several DTI studies of younger (see Table 1 for ages)

schizophrenia subjects found correlations between

anisotropy and cognitive measures. Hoptman et al.

(2002) found, in a group of male schizophrenia sub-

jects, that in right ventral frontal white matter, but

not right dorsal or left, impulsiveness correlated with

decreased FA. In a subsequent voxelwise study, the

correlation with impulsiveness was confirmed, and

other regions were also involved (Hoptman et al.,

2004). These two studies did not include healthy sub-

jects, but the result is generally consistent with normal

involvement of ventral prefrontal cortex in impul-

siveness. Kubicki et al. (2002) found that in patients,

but not in comparison subjects, FA of the right uncin-

ate fasciculus at the level of the anterior commissure

correlated inversely with measures of attention and

verbal abstraction, and FA of the left with immediate

recall, but neither side was correlated with perform-

ance on the Wisconsin Card Sorting Test (WCST).

Nestor et al. (2004) found that in patients but not

comparison subjects, WCST performance was in-

versely correlated with FA in the left cingulum

bundle, while FA in the uncinate fasciculi was related

to memory functions and general intelligence. Lim

et al. (2006), in a whole-brain voxelwise study, found

significant correlations (r2o0.41), between three cog-

nitive dimensions and FA in various regions of white

matter. Verbal declarative memory was positively

correlated with FA in both hippocampi. Attention was

positively correlated with FA bilaterally in anterior

cingulate and prefrontal regions and white matter

adjacent to the caudate nucleus. Executive function

was positively correlated with FA in the anterior

cingulate region bilaterally, the corpus callosum, and

widespread areas in the left hemisphere. This sum-

mary of the findings is not exhaustive. Correlations

were found in the expected regions, as well as others,

possibly reflecting correlations among performances

in a number of cognitive domains. On all of the tests

in all of these studies there were significant positive

correlations with frontal FA, except for the WCST.

However, in the studies that employed the WCST,

the frontal region of interest was limited to the uncin-

ate fasciculus, which is situated far ventrally, while

functional imaging demonstrates activation of the

526 A. J. Dwork et al.

dorsolateral prefrontal cortex during this task

(Callicott et al., 2003; Weinberger et al., 1986).

Although correlations of cognitive performance

with FA in the uncinate fasciculus and cingulum

bundle could be explained by the neuroanatomical lo-

calization of the specific tasks in healthy people, these

correlations were found only in the schizophrenia

subjects, in whom mean values of FA in these regions

were depressed. This is apparently not a measurement

issue; performance was impaired in schizophrenia,

but variance in performance was very similar among

schizophrenia and healthy comparison subjects

(Nestor et al., 2004). This raises the possibility that,

rather than a static, developmental element of dimin-

ished cognitive reserve, the components of FA in these

two regions that correlate with specific cognitive tasks

are caused by processes related to schizophrenia itself.

A theoretical model

Characterization of white-matter abnormalities in

schizophrenia is a formidable undertaking that is still

in its early stages. While many imaging studies indi-

cate the presence of abnormalities, only a handful have

examined correlations with cognitive function. There

are no studies of the longitudinal course of FA, and

there is none of elderly subjects with schizophrenia.

There are only a few autopsy studies, and most are

small. Thus, the findings that must be explained by a

model will undoubtedly change over the next few

years.

For now, we believe that a model should explain the

following phenomena:

(1) There are deficits of white-matter integrity that are

specifically related to schizophrenia.

(2) Schizophrenia-specific white-matter deficits be-

come less prominent with advancing age.

(3) Schizophrenia-specific white-matter deficits are

related to schizophrenia-specific cognitive deficits

that are permanent and progressive, often result-

ing in dementia.

(4) There is normal developmental variability in

white-matter integrity that contributes a static

component of cognitive variability both to in-

dividuals who remain healthy and to those who

develop schizophrenia.

(5) Myelin integrity normally declines with age

through a process of demyelination and re-

myelination.

(6) Oligodendrocyte density in some areas of grey

matter increases with age in healthy humans and

monkeys.

We propose a model (Figure 1) in which a deficit of

myelin in schizophrenia arises from a partial or com-

plete failure of myelination in late adolescence and

early adulthood. The concept of ‘ last myelinated, first

demyelinated’ would predict that the fibres that fail to

myelinate in schizophrenia would be the first to de-

myelinate with age in healthy individuals, while

schizophrenia subjects would have less of this myelin

to lose at the same age. Healthy ageing individuals,

undergoing more demyelination than ageing in-

dividuals with schizophrenia, would respond with

more remyelination; hence, shorter internodes re-

quiring more oligodendrocytes. (Remyelination could

also be pathologically impaired in schizophrenia,

but in our proposed model, the efficacy of normal re-

myelination or its decrement in schizophrenia would

be insufficient to amount to a significant contribution

Age

Myelin

~18 ~25 (onset of schizophrenia) ~60

Schizophrenia

Normal

Lowdevelopmentalendowment

Highdevelopmentalendowment

Devel

opm

enta

l mye

linde

ficit

Schizophrenia-relatedmyelin deficit

Figure 1. Hypothetical model of myelination in development

and schizophrenia. In this model, normal myelination

(red lines) progresses into adulthood, and then regresses.

Differences occurring early in life (solid red line vs. dashed

red line) remain constant (shaded blue area). Myelination in

individuals who will develop schizophrenia (blue lines)

starts off normally, with similar variations among individuals

(dashed blue line vs. dotted blue line). Some time during late

adolescence, several years before the onset of schizophrenia,

myelination is interrupted, depriving affected individuals of

much (shown here as all) of the myelin normally acquired in

adulthood. For simplicity, the schizophrenia-related deficit

is indicated, by diagonal shading, only for individuals with

initially high levels of myelination. In middle age, healthy

individuals begin to lose myelin acquired in adulthood, while

individuals with schizophrenia have less (shown here as

none) such myelin to lose, so levels of myelination in healthy

individuals decline to the level seen in schizophrenia. At

older ages still (shown here as y60 yr), there may be a

loss of myelin acquired prior to late adolescence, whose

initial acquisition and senescent loss are independent of

schizophrenia.

White matter and cognition 527

to the myelin deficit.) The adverse consequences of

failed myelination in schizophrenia could be myriad,

including greater vulnerability of the axon to injury,

greater metabolic requirements of the neuron, im-

paired transport of neurotrophic factors, and trans-

synaptic effects on axonal targets. These effects could

already be manifest at the onset of clinical disease,

which may follow several years of failing myelination,

and they would become more severe over time, but

they would not necessarily entail further deficits of

myelin. A normal, earlier-developing, stable varia-

bility in white-matter integrity, corresponding to a

component of variability among individuals in natural

cognitive endowment, would be superimposed on this

process.

Acknowledgements

This work was supported by Supported by MH60877,

MH64168, the National Alliance for Research on

Schizophrenia and Depression, and the Lieber Center

for Schizophrenia Research at the Department of

Psychiatry, College of Physicians and Surgeons of

Columbia University. We thank Dr Jasmine Chen and

Dr Cheryl Corcoran for thoughtful review of the

manuscript, and Dr Ana Sotrel for helpful discussions.

Statement of Interest

None.

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