Cerebral hemispheres
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established: there is speculation that it is involved in activities such as Middle longitudinal fasciculus
semantic language processing, face recognition and visual perception.
The middle longitudinal fasciculus runs in the white matter within the
Inferior fronto-occipital fasciculus
superior temporal gyrus, connecting the angular gyrus (area 39) with
the superior temporal gyrus (area 22) up to the temporal pole (area 38)
The inferior fronto-occipital fasciculus runs mostly along the temporal (Makris and Pandya 2009) (Fig. 25.38). It lies medial and ventral to
lobe and connects the dorsolateral aspects of the frontal and occipital segment II of the superior longitudinal fasciculus and the arcuate fas-
lobes (Forkel et al 2014, Sarubbo et al 2013) (see Figs 25.35–25.36). ciculus; lateral and superior to the inferior fronto-occipital fasciculus;
Two components of the inferior fronto-occipital fasciculus have been and dorsal to the inferior longitudinal fasciculus. Posteriorly, it is close
described in postmortem brains dissected using the Klingler fibre dis- to the inferior longitudinal fasciculus in the sagittal stratum. Its func-
section technique. A superficial, dorsal part connects the frontal lobe, tion is unknown: initial speculation that it is essential for language
superior parietal lobule and the posterior portions of the superior and function has not been supported by electrostimulation mapping in
middle occipital gyri. A deep, ventral subpart connects the frontal lobe glioma patients during surgical resection (De Witt Hamer et al 2011).
with the posterior portion of the inferior occipital gyrus and the poste-
rior temporobasal area. Anteriorly, the fasciculus is intermingled with Cingulum
other association fasciculi and with the most anterior fibres of the
external capsule, the latter consisting mainly of claustrocortical fibres.
The cingulum lies within the depth of the cingulate and parahippo-
Inferiorly, the fibres of the inferior fronto-occipital fasciculus cross the


campal gyri, starting below the rostrum of the corpus callosum within
anteroinferior portion of the external capsule and claustrum in order
the paraolfactory gyri. It contains fibres of different length; the longest
to join the temporal stem, underneath the anterior aspect of the inferior
run from the anterior temporal gyrus to the orbitofrontal cortex, while
limiting sulcus of the insula and just behind the limen insulae and the
short U-shaped fibres connect the medial frontal, parietal, occipital and
uncinate fasciculus. While the uncinate fasciculus corresponds to the
temporal lobes and different portions of the cingulate cortex. The cin-
anterior one-third of the temporal stem, the inferior fronto-occipital
gulum receives fibres of the anterior thalamic nuclei, superior frontal
fasciculus corresponds to its posterior two-thirds, reaching the level of
gyrus, paracentral lobule and precuneus along its curved course, which
the lateral geniculate body underneath the inferior limiting sulcus
enlarge it significantly. The cingulum ends within the presubiculum and
(Martino et al 2010a, Martino et al 2010b). Within the temporal lobe,
entorhinal cortex of the parahippocampal gyrus.
the inferior fronto-occipital fasciculus joins the sagittal stratum covering
the temporal horn and the atrium superiorly and laterally, running just
Fornix
superior to the optic radiation and inferior to the auditory radiation
(Türe et al 2000). According to the findings of studies based on subcor-
tical brain mapping by intraoperative electrostimulation, the superior The fornix is the largest single pathway linking the hippocampus with
longitudinal fasciculus is related to phonological aspects of language, distal brain sites. It contains many different hippocampal connections:
whereas the inferior fronto-occipital fasciculus is more related to its some appear to be exclusively efferent, e.g. from the hippocampus to
semantic aspect (Duffau 2008). the anterior thalamic nuclei (anterior medial, anterior ventral and ante-
rior dorsal thalamic nuclei), mammillary bodies, ventral striatum and


Uncinate fasciculus prefrontal cortex; some are reciprocal e.g. with the medial septum and
nucleus reuniens; some are exclusively afferent to the hippocampus, e.g.
from the supramammillary and raphe nuclei and the locus coeruleus
The uncinate fasciculus is a hook-shaped bundle that connects the
(Aggleton et al 2010, Jang and Kwon 2013, Jang and Kwon 2014). As a
anteromedial temporal lobe (superior, middle and inferior temporal
midline white matter tract, the fornix is particularly susceptible to
gyri, cortical nuclei of the amygdala) with the orbitofrontal region
involvement by tumours that favour this route of spread, e.g. glioblas-
(medial and posterior orbital cortex, gyrus rectus and subcallosal area)
toma multiforme, and to rotational shearing injuries responsible for
see Figs 25.35–25.36). The ventromedial part originates in the mesial
diffuse axonal injury (Thomas et al 2011). The topography of the fornix
temporal lobe and is connected to the medial frontal areas. The dorso-
is described with the hippocampal formation (Fig. 25.39).
lateral part originates from the superior and middle temporal gyri and
reaches the orbital gyri (Wang et al 2011). Its fibres constitute a well-
Temporoparietal fibre intersection area
defined tract along the temporal stem, where it occupies its anterior
one-third, immediately posterior to the limen insulae and anterior to
the inferior fronto-occipital fasciculus, underneath the most anterior The temporoparietal fibre intersection area has been described as a
aspect of the inferior limiting sulcus of the insula. Both the uncinate critical neural crossroads involving millions of axons (Martino et al
fasciculus and the inferior fronto-occipital fasciculus intermingle with 2013). Located deep to the angular gyrus and the posterior portions of
the most ventral fibres of the extreme and external capsules (Fernández- the supramarginal, superior, middle and inferior temporal gyri, the
Miranda et al 2008b). temporoparietal fibre intersection area is traversed by the superior


Fig. 25.38 A diffusion tensor imaging tractography
reconstruction of the middle longitudinal fasciculus
(1) and inferior longitudinal fasciculus (2). (With
permission from Martino J, De Lucas EM.
Subcortical anatomy of the lateral association
fascicles of the brain: a review. Clin Anat 2014
May;27(4):563–9.)
1
2


White matter of the cerebral hemispheres
393
52
reTpahC
fasciolaris curve up to the splenium. The crus continues forwards
Corpus callosum Body of fornix on the inferior surface of the callosal trunk, but the gyrus fasciolaris
Crus of fornix skirts above the splenium, then rapidly diminishes into the indusium
griseum.
Columns
A superior and an inferior layer of tela choroidea advance below the
of fornix
splenium through the transverse fissure, forming the velum interposi-
Thalamus tum cistern within the roof of the third ventricle and between the
Precommissural thalami, just below the bodies of the fornices; it contains the distal
ATN LD
fornix branches of the medial posterior choroidal arteries and the internal
Prefrontal
cortex MTT cerebral veins. The internal cerebral veins join together distally giving
RE rise to the great cerebral vein (of Galen), which runs upwards around
NAcc AC
Septum SUM Midbrain the posterior aspect of the splenium to join the straight sinus located
MB nuclei (e.g. LC) along the junction between the falx and the tentorium cerebelli.
Diagonal Hypoth
Axons of the corpus callosum radiate into the white matter core of
band
Hippocampus
each hemisphere, thereafter dispersing to the cerebral cortex. Commis-
Postcommissural fornix subiculum sural fibres forming the rostrum extend laterally, below the anterior
Entorhinal horn of the lateral ventricle, connecting the orbital surfaces of the
Fig. 25.39 The location of the fornix and its divisions. The blue arrows frontal lobes. Fibres in the genu curve forwards, as the forceps minor,
show fornical connections that are solely efferent from the hippocampal to connect the lateral and medial surfaces of the frontal lobes (Fig.
formation, the green arrows show fornical connections that are solely 25.40). Fibres of the trunk pass laterally, intersecting with the projection
afferent to the hippocampal formation, and the red arrows show fibres of the corona radiata to connect wide neocortical areas of the


reciprocal connections within the fornix. Abbreviations: AC, anterior hemispheres. Fibres of the trunk and splenium, which form the roof
commissure; ATN, anterior thalamic nuclei; Hypoth, hypothalamus; LC, and lateral wall of the atrium and the lateral wall of the inferior horn
locus coeruleus; LD, thalamic nucleus lateralis dorsalis; MB, mammillary of the lateral ventricle, constitute the tapetum, which runs underneath
bodies; MTT, mammillothalamic tract; NAcc, nucleus accumbens; RE, the optic radiation within the sagittal stratum. The remaining fibres of
nucleus reuniens; SUM, supramammillary nucleus. (With permission from the splenium curve back into the occipital lobes as the forceps major.
Aggleton JP, O’Mara SM, Vann SD et al, Hippocampal-anterior thalamic Interhemispheric connections through the corpus callosum do not
pathways for memory: uncovering a network of direct and indirect all represent a simple linking of loci in one hemisphere with the same
actions, Eur J Neurosci 2010 Jun;31(12):2292–307.)
loci in the other. In areas containing a clear representation of a contra-
lateral sensorium (e.g. body surface, visual field), only those areas that
are functionally related to midline representation are linked to the
longitudinal fasciculus (horizontal portion and arcuate fasciculus), contralateral hemisphere. This is most clearly seen for the visual areas,
middle longitudinal fasciculus, inferior longitudinal fasciculus, inferior where the cortex containing the representation of each midline retinal
fronto-occipital fasciculus, optic radiations and tapetum. Given the zone is linked to its counterpart on the contralateral side. A similar
organizational complexity of the area, a lesion within the temporo- arrangement is seen in somatic areas, where the trunk representation is
parietal fibre intersection area is likely to produce disconnections callosally linked, but the peripheral limb areas (hand and foot) are not.
involving more than one fasciculus. Connections that link the same, or similar, areas on each side are
termed homotopic connections. The corpus callosum also intercon-


nects heterogeneous cortical areas on the two sides (heterotopic
COMMISSURAL FIBRES
connections). These may serve to connect functionally similar, but
anatomically different, loci in the two hemispheres, and/or to connect
Corpus callosum
functional areas in one hemisphere with regions that are specialized for
a unilaterally confined function in the other.
The corpus callosum contains 150–200 million fibres and is the largest
fibre pathway of the brain. It forms an anteroposterior midline arch
Anterior commissure
approximately 10 cm long and divided into four portions for descrip-
tive purposes, namely: rostrum, genu, trunk and splenium (see Fig.
25.3). The genu corresponds to the anterior wall of the frontal horn of The anterior commissure is a compact bundle, about 4 mm in diameter,
the lateral ventricle; the rostrum corresponds to its floor. containing approximately 3.5 million myelinated axons (Peltier et al
The genu is the most anterior portion, and is located approximately 2011). It runs within the basal forebrain and fans out laterally within
4 cm from the frontal poles. The ventral aspect of the genu curves pos- the temporal lobe. It is believed to connect areas that include the olfac-
teroinferiorly in front of the septum pellucidum, then diminishes tory bulb and anterior olfactory nucleus; the anterior perforated sub-
rapidly in thickness and is prolonged to the upper end of the lamina stance, olfactory tubercle and diagonal band of Broca; the prepiriform
terminalis as the rostrum. Posterior to the genu, the trunk of the corpus cortex; the entorhinal area and adjacent parts of the parahippocampal
callosum arches backwards, convex above, and ends posteriorly in the gyrus; part of the amygdaloid complex (especially the nucleus of the
expanded splenium. This is the thickest part of the corpus callosum and lateral olfactory stria); the bed nucleus of the stria terminalis and the
is located approximately 6 cm from the occipital poles. Superiorly, the nucleus accumbens; and the anterior regions of the middle and inferior
median region of the trunk of the corpus callosum forms the floor of temporal gyri.


the longitudinal fissure, supporting the anterior cerebral arteries and The anterior commissure has the shape of a classic bicycle handlebar.
lying underneath the lower border of the falx cerebri, which may contact It crosses the midline just ventral to the supraoptic recess of the third
it behind. On each side, the trunk is overlapped by the cingulate gyrus, ventricle, immediately anterior to the major component of the column
from which it is separated by the callosal sulcus. The inferior surface of of the fornix that projects to the mammillary body, and posterior to the
the corpus callosum is concave in its long axis, and attached to the smaller components of the fornix that project to the septal nuclei (see
septum pellucidum along the trunk, genu and rostrum. It is fused with Figs 25.27A, 25.28). At this point, the anterior commissure bulges
the crura of the fornix and with the commissure of the fornix under- inside the third ventricle, just underneath the interventricular foramen.
neath the splenium. The inferior surface of the splenium covers the The lamina terminalis is attached superiorly to the midline segment of
pineal region. the anterior commissure and inferiorly to the upper surface of the optic
The layers of the septum pellucidum are attached superiorly to the chiasma; the optic recess of the third ventricle is the cleft between the
callosal trunk, anteriorly to the genu, and inferiorly to the rostrum lamina terminalis and the midportion of the superior surface of the
(anteriorly) and the bodies of the fornices (posteriorly); the two layers chiasma.
correspond to the medial walls of the frontal horns and bodies of the Each side of the anterior commissure is composed of a well-defined
lateral ventricles. Both layers of the septum pellucidum end at the level posterolateral bundle (the hemispheric part) and a smaller, anterior
where the bodies of the fornices become crura and attach to the inferior component (the olfactory part) (Déjérine 1895). The anterior compo-
surface of the splenium, thereby establishing the anatomical limit nent curves forwards and vertically through the anterior perforated


between the lateral ventricular body and the atrium within each hemi- substance towards each olfactory tubercle. The hemispheric component
sphere (Rhoton 2003). curves posterolaterally, passing through a deep groove on the anteroin-
The splenium of the corpus callosum overhangs the posterior ends ferior aspect of the globus pallidus (see Fig. 25.31), and fanning out
of the thalami, the pineal gland and tectum, but is separated from them mostly to the anterior part of the temporal lobe, including the parahip-
by several structures. On each side the crus of the fornix and gyrus pocampal gyrus, but also reaching the occipital lobe posteriorly.


Cerebral hemispheres
393.e1
52
reTpahC
Genu of Forceps minor
corpus callosum
Medial
longitudinal
stria
Trunk of
corpus
callosum
Lateral
longitudinal
Splenium
stria
Forceps
major
Fig. 25.40 The superior aspect of the corpus callosum revealed by partial
removal of the cerebral hemispheres.


Cerebral hemispheres
394
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NOiTCes
When passing under the inferior limiting sulcus of the insula, supe- mainly to the interpeduncular nucleus of the mesencephalon and to
rior to the temporal horn of the lateral ventricle, the fibres of the ante- the rostral salivatory nucleus in the floor of the fourth ventricle to acti-
rior commissure join the temporal stem, merging with the fibres of the vate reflex salivation (Peltier et al 2011). The pineal gland is attached
uncinate and inferior fronto-occipital fasciculi. They pass posteriorly as superiorly to the habenular commissure and inferiorly to the posterior
the sagittal stratum, together with the inferior fronto-occipital fasciculus commissure, and so the pineal recess of the third ventricle lies between
and the fibres of the optic radiation, over the lateral aspect of the tem- these two commissures.
poral horn and ventricular atrium. Within the temporal stem, the fibres
of the anterior commissure are mostly medial to the uncinate fasciculus;
both are inferior to the inferior fronto-occipital fasciculus. Within the PROJECTION FIBRES
sagittal stratum, they intermingle but run predominantly below the
inferior fronto-occipital fasciculus, superior to the fibres of the optic Projection fibres connect the cerebral cortex with lower levels in the
radiation. The line between the anterior and posterior commissures, the brain and spinal cord. They include large numbers of both corticofugal
AC–PC line, is a very important landmark in stereotactic atlases, used and corticopetal projections. Corticofugal projection fibres converge
when localizing neuroanatomical targets for stereotactic neurosurgical from all directions to form the dense subcortical white matter mass of
procedures. the corona radiata (Figs 25.41–25.42). Large numbers of fibres pass to
the corpus striatum and the thalamus, intersecting commissural fibres
Hippocampal commissure of the corpus callosum en route. The corona radiata is continuous with
the internal capsule, which contains the majority of the cortical projec-
tion fibres.
The hippocampal commissure (commissure of the fornix) is a thin


triangular sheet of fibres that lies between the crura of the fornices,
Internal capsule
connecting the hippocampi. It is situated underneath and attached to
the splenium, overhanging the pineal region.
The internal capsule has the shape of a V in horizontal section (axial
Posterior commissure images), with its vertex (genu) located medially between the head of
the caudate nucleus and the thalamus. For descriptive purposes, the
internal capsule is arbitrarily divided into five parts: anterior limb,
The posterior commissure lies below the pineal recess of the third ven-
located between the putamen and the head of the caudate nucleus;
tricle, crossing the midline along the caudal lamina of the pineal stalk,
genu, approximating to its vertex; posterior limb, located between the
at the level of the upper aspect of the cerebral aqueduct. It contains
putamen and the thalamus; retrolenticular or retrolentiform portion,
both decussating and commissural fibres that connect diencephalic and
located posterior to the putamen; and sublenticular (or sublentiform)
mesencephalic nuclei: the interstitial and dorsal nuclei of the posterior
portion, located inferior to the putamen (see Fig. 25.19; Figs
commissure located within the periventricular grey matter; nucleus of
25.43–25.44).
Darkschewitsch of the periaqueductal grey matter; interstitial nucleus
Cortical efferent fibres of the internal capsule converge as they
of Cajal located at the rostral end of the oculomotor nucleus and closely
descend. Fibres derived from the frontal lobe tend to pass posteromedi-
linked with the medial longitudinal fasciculus; and posterior thalamic,
ally, while temporal and occipital fibres pass anterolaterally. Many, but
pretectal, tectal and habenular nuclei.
not all, corticofugal fibres pass into the crus cerebri of the ventral mid-
brain. Here, corticospinal and corticonuclear fibres are located in the
Habenular commissure
middle half of the crus. Frontopontine fibres are located medially,
whereas corticopontine fibres from temporal, parietal and occipital


The habenular commissure lies between the habenulae, small protuber- cortices are found laterally.
ances of the thalami located at the distal ends of the striae medullaris. The anterior limb of the internal capsule contains frontopontine
It contains both decussating fibres (e.g. tectohabenular) and commis- fibres, which arise from the cortex in the frontal lobe. They synapse
sural fibres (connecting the habenular nuclei). The habenular nuclei with cells in the pontine nuclei. Axons of these cells enter the oppo-
receive olfactory inputs from the septal nuclei, and transmit them site cerebellar hemisphere through the middle cerebellar peduncle.
CorRad Fig. 25.41 A diffusion tensor imaging
reconstruction of the corona radiata (CorRad),
superior longitudinal fasciculus (SupLF) and
inferior fronto-occipital fasciculus (IFOF). (Courtesy
of Prof. Edson Amaro Jr MD, Department of
Radiology, University of São Paulo Medical
School.)
IFOF SupLF


Cerebral hemispheres
394.e1
52
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A B
Insula
C D
Putamen
E F
Corona radiata
Internal capsule
Crus cerebri
Pons Crus cerebri
Fig. 25.42 A series of dissections of the left cerebral hemisphere at progressively deeper levels to demonstrate the relationships of the internal capsule.
A, Intact brain. B, Cortical gyri of the insula exposed by removal of the frontal, temporal and parietal opercula. C, Removal of the insular cortex, extreme
capsule, claustrum and external capsule to expose the lateral aspect of the putamen. D, Removal of the lentiform complex to display fibres of the
internal capsule. E, Removal of part of the temporal lobe to show the internal capsule fibres converging on the crus cerebri of the midbrain. F, Removal
of the optic tract and superficial dissection of the pons and upper medulla, emphasizing the continuity of the corona radiata, internal capsule, crus
cerebri, longitudinal pontine fibres and the medullary pyramid. (Dissection by E.L. Rees; photograph by Kevin Fitzpatrick on behalf of GKT School of
Medicine, London; figure enhanced by B Crossman.)


White matter of the cerebral hemispheres
395
52
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Head of caudate
Anterior limb of nucleus
internal capsule
Putamen
Genu of
internal capsule Thalamus
Globus
pallidus
Retrolenticular part
of internal capsule
Posterior limb
of internal capsule
Fig. 25.43 A horizontal section of the brain through the frontal and
occipital poles of the cerebral hemispheres. (Figure enhanced by B
Crossman.)
Head of caudate Thalamocortical Fig. 25.45 A diffusion tensor imaging reconstruction of the corticospinal
nucleus fibres tracts of the right (red) and left (green) cerebral hemispheres. (Courtesy of
Prof. Edson Amaro Jr MD, Department of Radiology, University of São
Anterior limb of Corticofugal Paulo Medical School.)
internal capsule fibres
Genu of internal
capsule converging, the corticospinal tract fibres undergo an internal rotation
Lentiform
of approximately 90 degrees, since the main axes of the precentral gyrus
complex
Thalamocortical and of the internal capsule genu and posterior limb are almost perpen-
fibres
dicular. Throughout their convergence and rotation the fibres keep
their somatotopical motor arrangement, originated according to the
Posterior limb of
homuncular cortical representation, and end up having an anterior-
internal capsule
cranial to a posterior-caudal disposal along the genu and the anterior
Auditory
radiation portion of the internal capsule posterior limb. Radiologically and surgi-
Thalamus
cally, this important portion of the internal capsule can have its topog-
Retrolenticular raphy estimated from the position of the interventricular foramen (of
Medial geniculate body part of internal Monro) that lies medially and adjacent to the internal capsule genu,
capsule which contains the corticonuclear bundle.
Lateral geniculate body Other descending axons include frontopontine fibres, particularly
Optic radiation
from areas 4 and 6, and corticorubral fibres, which connect the frontal
lobe to the red nucleus. Most of the posterior limb also contains fibres
Ascending thalamocortical fibres of the superior thalamic radiation (the somaesthetic radiation) ascend-
ing to the postcentral gyrus.


Descending cortical efferent fibres to thalamus, brainstem and spinal cord
The retrolenticular part of the internal capsule contains parietopon-
Fig. 25.44 A horizontal section through the internal capsule illustrating its tine, occipitopontine and occipitotectal fibres. It also includes the pos-
main fibre components. terior thalamic radiation and the optic radiation, and interconnections
between the occipital and parietal lobes and caudal parts of the thala-
mus, especially the pulvinar.
The fibres of the optic radiation arise from the lateral geniculate
Anterior thalamic radiations interconnect the medial and anterior tha- body and the pulvinar, join the retrolenticular and the sublenticular
lamic nuclei and various hypothalamic nuclei and limbic structures parts of the internal capsule, run within the sagittal stratum over the
with the frontal cortex. The genu of the internal capsule is usually inferior horn and ventricular atrium, and project posteriorly, passing
regarded as containing corticobulbar fibres, which are mainly derived superiorly and inferiorly to the posterior horn as part of the posterior
from area 4 and terminate mostly in the contralateral motor nuclei of thalamic peduncle to reach both the superior and inferior lips of the
cranial nerves. Anterior fibres of the superior thalamic radiation, calcarine sulcus. Within the temporal lobe, the fibres of the optic radia-
between the thalamus and cortex, also extend into the genu. The pos- tion are located along the depths of the superior and middle temporal
terior limb of the internal capsule includes the corticospinal or pyram- gyri about 2 cm from the brain surface, inferior to the vertical segment
idal tract. The fibres concerned with the upper limb are anterior, and of the superior longitudinal fasciculus, and always superior to the infe-
the more posterior regions contain fibres representing the trunk and rior temporal sulcus. In coronal sections, the optic radiation appears
lower limbs. predominantly flat anteriorly and comma-shaped posteriorly. Its fibres
The corticospinal tract fibres that arise within the precentral gyrus are divided into anterior, central and posterior bundles.
are disposed as a fan throughout the corona radiata and converge The sublenticular part of the internal capsule contains temporopon-


towards the internal capsule genu and posterior limb (see Figs 25.31, tine and some parietopontine fibres, the auditory radiation from the
25.41; Fig. 25.45). The corticospinal fibres’ transition between the medial geniculate body to the superior temporal and transverse tempo-
corona radiata and the internal capsule is defined medially by the ral gyri (areas 41 and 42), and a few fibres that connect the thalamus
superior aspect of the body of the caudate nucleus and the fibres of the with the temporal lobe and insula. Fibres of the auditory radiation
splenium, collectively forming the lateral upper edge of the body of sweep anterolaterally below and behind the lentiform complex to reach
the lateral ventricle, and laterally by the superior aspect of the putamen the cortex, and are superior to the inferior horn, the atrium and the
and the superior insular sulcus. To join the internal capsule, as well as optic radiation.


Cerebral hemispheres
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NOiTCes
particularly in the interpretation of neuroimages and in temporal lobe
OVERVIEW OF CORTICAL CONNECTIVITY
microneurosurgery. Although there is debate as to their exact composi-
tion, in broad outline, the temporal stem lies anterior to the inferior
All neocortical areas have axonal connections with other cortical areas horn and connects anteromedial temporal structures to the basolateral
on the same side (association fibres) and the opposite side (commis- frontal portion of the hemisphere. The sagittal stratum corresponds to
sural fibres), and with subcortical structures (projection fibres). The fibres running along the inferior limiting sulcus of the insula forming
primary somatosensory, visual and auditory areas give rise to ipsilateral the roof and lateral walls of the inferior horn and ventricular atrium.
corticocortical connections to the association areas of the parietal,
occipital and temporal lobes, respectively, which then progressively
project towards the medial temporal limbic areas: notably, the parahip- CEREBRAL CENTRAL CORE
pocampal gyrus, entorhinal cortex and hippocampus. Thus, the first
(primary) somatic sensory area (SI) projects to the superior parietal The cerebral central core, lying between the insula and the midline,
cortex (Brodmann’s area 5), which in turn projects to the inferior pari- contains all the white matter fibres and grey matter nuclei that connect
etal cortex (area 7). From here, connections pass to cortex in the walls the cerebral cortex with subcortical nuclei in the brainstem and spinal
of the superior temporal sulcus, and so on to the posterior parahip- cord. It therefore includes the extreme, external and internal capsules;
pocampal gyrus, and on into limbic cortex. Similarly, for the visual claustrum; putamen; globus pallidus; caudate nucleus; amygdala; dien-
system, the primary visual cortex (area 17) projects to the parastriate cephalon; substantia innominata; fornix; anterior commissure; mam-
cortex (area 18), which in turn projects to the peristriate region (area millothalamic tract; fasciculus retroflexus; thalamic peduncles, including


19). Information then flows to inferotemporal cortex (area 20), to optic and auditory radiations; ansa peduncularis; thalamic fasciculus;
cortex in the walls of the superior temporal sulcus, then to medial and lenticular fasciculus. On either side, the central core is attached to
temporal cortex in the posterior parahippocampal gyrus, and so to the rest of the cerebral hemisphere by the cerebral isthmus, a bundle
limbic areas. The auditory system shows a similar progression from of white matter fibres located between the dorsolateral margin of the
primary auditory cortex to temporal association cortex, and so to the caudate nucleus and the full circumference of the circular sulcus of
medial temporal lobe. the insula. The rostral fibres of the corpus callosum are included in
In addition to this stepwise outward progression from sensory areas the frontal portion of the cerebral isthmus.
through posterior association cortex, connections also occur at each The extreme capsule lies beneath the superior and inferior limiting
stage with parts of the frontal cortex. Thus, taking the somatic sensory sulci of the insula (see Fig. 25.48A). It runs between the inferior frontal
system as an example, primary somatic sensory cortex (SI) in the post- gyrus (Broca’s area) and the superior temporal gyrus, extending into the
central gyrus is reciprocally connected with the primary motor cortex inferior parietal lobule (Wernicke’s area); its outer layer contains
(area 4) in the precentral gyrus. The next step in the outward progres- U-shaped fibres connecting individual insular gyri and the frontopari-
sion, the superior parietal lobule (area 5), is interconnected with the etal and temporal operculi. The extreme capsule has been described as
premotor cortex (area 6), and this in turn is connected with area 7 in distinguishable from adjacent fasciculi (uncinate fasciculus; external
the inferior parietal lobule. This has reciprocal connections with pre- capsule; middle longitudinal fasciculus; arcuate bundle; components of
frontal association cortex on the lateral surface of the hemisphere (areas the superior longitudinal fasciculus and inferior longitudinal fascicu-


9 and 46), and temporal association areas, which connect with more lus) (Makris and Pandya 2009); alternatively, it has been described as
anterior prefrontal association areas and, ultimately in the sequence, having a deeper portion that consists of fibres of the occipitofrontal and
with orbitofrontal cortex. Similar stepwise links exist between areas on uncinate fasciculi (Wang et al 2011).
the visual and auditory association pathways in the occipitotemporal The claustrum (meaning enclosed or hidden space) is a fine lamina
lobe and areas of the frontal association cortex. The connections of grey matter beneath the extreme capsule, along the entire rostrocau-
between sensory and association areas are reciprocal. dal extent of the striatum (Fernández-Miranda et al 2008b) (see Fig.
All neocortical areas are connected with subcortical regions, although 25.19). Its ventral portion is thinner and populated by small islands of
their density varies between areas. First among these are connections grey matter within the white matter; its dorsal portion is thicker and
with the thalamus. All areas of the neocortex receive afferents from better defined. Little is known about the connections and functional
more than one thalamic nucleus, and all such connections are recipro- significance of the claustrum in the human brain; several hypotheses
cal. The vast majority of, if not all, cortical areas project to the striatum, have been put forward (Mathur 2014, Smythies et al 2014). The external
tectum, pons and brainstem reticular formation. Additionally, all corti- capsule lies beneath the claustrum and consists mainly of fibres origi-
cal areas are reciprocally connected with the claustrum; the frontal nating within the claustrum; anteriorly, its fibres intermingle with those
cortex connects with the anterior part and the occipital lobe with the of the uncinate and inferior occipitofrontal fasciculi (Fernández-
posterior part. Miranda et al 2008b).
All cortical areas receive topographically organized cholinergic pro-
jections from the basal forebrain, noradrenergic fibres from the locus
coeruleus, serotoninergic fibres from the midbrain raphe nuclei, CEREBRAL ASYMMETRY


dopaminergic fibres from the ventral midbrain, and histaminergic fibres
from the posterior hypothalamus. The two human cerebral hemispheres are not simply mirror images of
Different cortical areas have widely different afferent and efferent each other. Much information on the lateralization of cerebral function
connections. Some have connections that are unique, e.g. the corticos- has come from studying patients in whom the corpus callosum had
pinal tract arises from pyramidal cells in a restricted area around the been divided (commissurotomy) as a treatment for intractable epilepsy
central sulcus. (Sperry 1974), and from those rare individuals who lack part, or all, of
Widely separated, but functionally interconnected, areas of cortex their corpus callosum. Commissurotomy produces the ‘split-brain’ syn-
share common patterns of connections with subcortical nuclei, and drome, which has provided evidence supporting the notion that abili-
within the neocortex. For example, contiguous zones of the striatum, ties or functions are predominantly associated with one or other
thalamus, claustrum, cholinergic basal forebrain, superior colliculus hemisphere. Knowledge of the lateralization of function has been
and pontine nuclei connect with anatomically widely separated areas advanced significantly by functional brain imaging techniques, such as
in the prefrontal and parietal cortex, which are themselves intercon- positron emission tomography (PET) and fMRI.
nected. In contrast, other functionally distinct cortical regions, e.g. areas The left hemisphere usually prevails for verbal and linguistic func-
in the temporal and parietal cortex, do not share such contiguity in their tions, for mathematical skills and for analytical thinking. The right
subcortical connections. hemisphere is mostly non-verbal. It is more involved in spatial and
holistic or ‘Gestalt’ thinking, in many aspects of musical appreciation
and in some emotions. Memory also shows lateralization. Thus, verbal
THE TEMPORAL STEM AND THE
memory is primarily a left hemisphere function, while non-verbal
SAGITTAL STRATUM memory is represented in the right hemisphere. These asymmetries are
relative, not absolute, and vary in degree according to the function and
The term temporal stem is derived from the appearance of temporal individual concerned. Moreover, they apply primarily to right-handed


lobe fibres on coronal sections of the brain (Horel 1978, Choi et al men. Those men with left-hand preference, or mixed handedness, make
2010). As these fibres converge towards the medial part of the temporal up a heterogeneous group, which (as an approximation) shows reduced
lobe along the inferior aspect of the inferior limiting sulcus of the or anomalous lateralization, rather than a simple reversal of the situa-
insula, they resemble the stem of an inclined tree. The terms temporal tion in right-handers. For example, speech representation can occur in
stem and sagittal stratum are a means of conceptualizing the arrange- either or both hemispheres. Women show less functional asymmetry,
ment of fibre tracts within the temporal lobe. They are of significance on average, than men.


Cerebral hemispheres
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The most anterior fibres in the tree correspond to the upper exten- The ansa peduncularis sweeps around the cerebral peduncle and
sion of the posterior aspect of the anterior half of the uncus, and appear contains amygdaloseptal, amygdalohypothalamic and amygdalotha-
as a true neural peduncle located between the limen insulae and the lamic fibres (Gloor 1997, Peuskens et al 2004). The extracapsular tha-
inferior horn of the lateral ventricle (Figs 25.46–25.47). The external lamic peduncle lies immediately posterior and superior to the ansa
surface of this peduncle is the transverse insular gyrus along the limen peduncularis, carrying fibres from the amygdala and the cortex of the
insulae, connecting the insula to the posteromedial orbital lobule. This anterior temporal region to the medial thalamic nucleus and the
gyrus harbours, from anterior to posterior, the anterobasal aspect of the hypothalamus. As its name implies, the extracapsular thalamic pedun-
extreme capsule (subcortical insular white matter); the uncinate fascicu- cle runs within the ventral striatopallidal region and not through the
lus (connecting mesial temporal structures with the fronto-orbital internal capsule. The ansa lenticularis runs posterior to the extracapsu-
region); the inferior fronto-occipital fasciculus (runs immediately pos- lar thalamic peduncle. The amygdala extends posteriorly, partially cov-
terior to the uncinate fasciculus); the ventral amygdalofugal fibres of ering the head of the hippocampus. The stria terminalis runs along the
the ansa peduncularis; the anterior commissure; and, more medially, roof of the inferior horn medially to the tail of the caudate nucleus,
the superior extension of the amygdala towards the globus pallidus. towards the bed nucleus of the stria terminalis (Párraga et al 2012).
PostcentGyr CentSul PrecentGyr ParsOper ParsTri ChPlex ALG CentSul PSG MSG ASG
ALG
PLG


Apex
LimenIns
A InfLimSul CentInsSul PSG Apex LimenIns MSG ASG AntLimSul AccGyr B HippoBody PLG TempStem HippoHead Amygdala
Fig. 25.46 A, The lower and upper portions of the frontal and temporal opercula respectively have been removed to reveal the relationships between
opercular and insular structures. The central insular sulcus courses superficial to, and almost parallel with, the central sulcus. B, Sagittal section,
dissected to show the relationship between the insula and the temporal horn. The temporal stem is between the lower circular sulcus of the insula and
the roof of the temporal horn. Abbreviations: AccGyr, accessory gyrus; ALG, anterior long gyrus; AntLimSul, anterior limiting sulcus; ASG, anterior short
gyrus; CentInsSul, central insular sulcus; CentSul, central sulcus; ChPlex, choroid plexus; HippoBody, body of hippocampus; HippoHead, head of
hippocampus; InfLimSul, inferior limiting sulcus; LimenIns, limen insula; MSG, middle short gyrus; ParsOper, pars opercularis; ParsTri, pars triangularis;
PLG, posterior long gyrus; PostcentGyr, postcentral gyrus; PrecentGyr, precentral gyrus; PSG, posterior short gyrus; TempStem, Temporal stem. (With
permission from Wang F, Sun T, Li X, et al, Microsurgical and tractographic anatomical study of insular and transsylvian transinsular approach, Neurol
Sci 2011 Oct;32(5):865–74.)
MFG PreCG CS PostCG SPLob Fig. 25.47 Removal of the inferior frontal gyrus,
the basal aspects of the pre- and postcentral gyri,
and of the supramarginal, angular, superior and
middle temporal gyri to expose the insular surface
and the subcortical white matter of the temporal
lobe. Abbreviations: CS, central sulcus;
InfTempSulcus, inferior temporal sulcus; InfLimS,
inferior limiting sulcus; ITG, inferior temporal gyrus;
MFG, middle frontal gyrus; PostCG, postcentral
gyrus; PreCG, precentral gyrus; SPLob, superior


parietal lobule; TePo, temporal pole; TeWM,
subcortical temporal white matter over sagittal
stratum. (Courtesy of Richard Gonczalo Párraga).
Insula
Limen TePo InfLimS InfTempSulcus ITG TeWM


Cerebral hemispheres
396.e2
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Anteriorly, the tail of the caudate nucleus merges with the amygdala, ascend and vanish within the external capsule; the fibres of the anterior
still within the roof of the inferior horn. A ventral extension of the commissure, which group more anteriorly and medially; the posterior
centromedial amygdala, running along the basal forebrain and also and inferior thalamic peduncles, which include the auditory and optic
towards the bed nucleus of the stria terminalis, has also been described. radiations; and the tapetum (Ludwig and Klingler 1956, Türe et al
The amygdala is situated inside the anterior half of the uncus, which 2000). The tapetum lies under the optic radiation and is separated from
means that all these extensions of the amygdala and the fibres and the ventricular cavity only by the ependymal; it connects both posterior
cortex that lie over them have to be surgically severed in order to dis- temporal areas (Catani et al 2012) (Fig. 25.48). The fibres in the ante-
connect the anterior part of the temporal lobe; on that basis, these rior commissure leave the sagittal stratum and join the anterior and
structures are therefore included within the anteromedial temporal mesial temporal peduncle. The most anterior fibres in Meyer’s loop
peduncle. reach the anterior temporal peduncle but stay lateral to it and do not
The sagittal stratum lies beneath the subcortical white matter of the group with its fibres. Any dorsal temporal surgical approach to the
temporal lobe and the temporal extension of the superior longitudinal inferior horn or to the ventricular atrium will divide the sagittal stratum,
fasciculus; its fibres are organized in layers. From superior to inferior, including the fibres of the optic radiation, to some degree.
the layers are the fibres of the inferior fronto-occipital fasciculus, which
CoRa SupLongFasc Fig. 25.48 A, A lateral view of the left hemisphere:
the vertical segment of the superior longitudinal
fasciculus (SupLongFasc) has been removed. The
tapetum is exposed via a window in the sagittal


stratum (SagStr). B, A medial view of the left
hemisphere: the ependyma of the lateral ventricle
has been removed. The tapetum lies underneath
the optic radiation along the lateral wall of the
atrium. Other abbreviations: AntCom, anterior
commissure; CorpCall, corpus callosum; CoRa,
corona radiata; ExtCap, external capsule; ExtrCap,
extreme capsule; Hab, habenula; LoG, long gyri of
insula; MaBo, mammillary body; OcN, oculomotor
nerve; PiGl, pineal gland; PostComm, posterior
commissure; StrMedTh, stria medullaris thalami;
SubNucl, subthalamic nucleus; ThRad, thalamic
radiation. (Courtesy of Richard Gonczalo Párraga.
Adapted from: Párraga RG, Ribas GC, Welling LC,
Alves RV, de Oliveira E. Microsurgical anatomy of
the optic radiation and related fibres in
3-dimensional images. Neurosurgery 2012,
71[ONS Suppl 1]:ons160–ons172.)
A ExtCap ExtrCap LoG SagStr Tapetum
Thalamus PiGl Fornix StrMedTh ThRad
Tapetum Hab Thalamus CorpCall AntCom
B PostComm Aqueduct Red Nucleus OcN MaBo SubNucl


Cognitive functions
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Certain cerebral anatomical asymmetries are apparent at both the of recognition of visual percepts (associative visual agnosia) and faces
macroscopic and histological levels. One of the most notable is in the (prosopagnosia), and objects can be copied or matched but not identi-
planum temporale, which is usually larger on the left than the right fied for meaning or name.
side. Subtle asymmetries in the superior temporal lobe have been dem- The premotor areas (frontal association cortex, parietal and tempo-
onstrated in terms of overall size and shape, sulcal pattern and cytoar- ral association cortex) combine to form the ‘language area’ in the cortex
chitecture, and at the neuronal level. It seems reasonable to assume that that surrounds the lateral fissure in the left dominant hemisphere
these differences underlie some of the functional asymmetry for lan- (Ojemann et al 1989). Focal lesions of the language area lead to break-
guage representation. down in verbal communication (aphasia) and loss of the ability to read
Asymmetries in areal size, cytoarchitecture or neurocytology occur (alexia), write (agraphia) and calculate (acalculia). The aphasic syn-
elsewhere in the cerebral cortex as well as subcortically. For example, dromes of Broca, conduction and Wernicke correspond to lesions
many brains have a wider right frontal pole and a wider left occipital within the frontal, parietal and temporal cortical areas, respectively.
pole. Brodmann’s area 45 in the inferior frontal lobe, corresponding to Lesions of the parietal cortex immediately posterior to the language area
Broca’s area, contains a population of large pyramidal neurones that (angular gyrus) can lead to alexia, agraphia and acalculia, in the absence
are found only on the left side. The cortical surface surrounding the of aphasia.
central sulcus is larger in the left hemisphere, especially in the areas The prefrontal association cortex and its connections with the
containing the primary somatosensory and motor maps of the arm, limbic system, and in particular, with the amygdala, are essential for


suggesting that one cerebral manifestation of hand preference is a larger problem-solving behaviour (executive functions) and the affective
amount of neural circuitry in the relevant parts of the cortex. Histologi- motivational aspects of behaviour. Bilateral lesions of these areas (e.g.
cal asymmetries are also found in areas that are not usually considered in frontotemporal dementia) lead to the ‘frontal lobe syndrome’, in
to be closely related either to language or to handedness. The left which there is a radical change in personality, with loss of reason,
entorhinal cortex has significantly more neurones than the right. judgement and insight, together with loss of personal and social feel-
ings (sympathy and empathy). The restricted involvement of the orbital
frontal areas and limbic connections leads to overactivity and disinhi-
COGNITIVE FUNCTIONS
bition (pseudo-psychopathic behaviour). Spread of lesions into the
dorsolateral surface of the prefrontal area leads to an inert, apathetic
The cognitive or high cortical functions of perception, spatial analysis, state (pseudo-depression). Unilateral focal lesions of the prefrontal
learned skilled movement, language, memory, problem-solving (all areas are not usually associated with obvious cognitive or behavioural
executive functions) and emotion are organized within the cerebral change.
hemispheres (Fig. 25.49). According to Mesulam, five well-defined net- The limbic allocortex and its connections comprising the Papez
works are most relevant to clinical practice: a left-dominant perisylvian circuit (hippocampus, mammillary body, anterior nucleus of the thala-
network for language; a right-dominant parietofrontal network for mus and cingulate gyrus) are thought to be responsible for the laying
spatial cognition; an occipitotemporal network for face and object down of autobiographical (episodic) memory. Medial diencephalic
recognition; a limbic network for retentive memory; and a prefrontal structures such as the nucleus reuniens and retrosplenial cortex may
network for attention and comportment (Mesulam 2011, Catani et al also have mnemonic functions independent of the hippocampus, sug-
2005). gesting that there may be parallel, disynaptic routes enabling prefrontal


The organization of cognitive functions is highly localized and control of hippocampal activity (Aggleton 2014). Bilateral lesions (e.g.
involves the association areas of the neocortex and the limbic system. in Alzheimer’s disease) or following alcoholic encephalopathy (Korsa-
The parietal association areas are concerned with the perceptual recog- koff psychosis) lead to the loss of the ability to learn new information
nition of objects by kinaesthetic and visual stimuli, and the visuospatial (anterograde amnesia) or remember experiences in the relatively recent
orientation of the body and its parts in space. Large focal lesions (par- past (retrograde amnesia), although perceptual information about the
ticularly of the right cerebral hemisphere) and bilateral lesions (e.g. in world and language (semantic memory) is preserved because the tem-
Alzheimer’s disease) lead to visual disorientation in space, with an poral neocortical association areas are spared.
inability to navigate the environment, locate objects, and dress in rela- Patients with chronic epilepsy who have undergone surgical section
tionship to body parts. Acute focal lesions (especially of the right cere- of the corpus callosum in order to relieve their seizures portray few
bral hemisphere) lead to neglect of the body and space in the opposite difficulties under normal circumstances. However, when these ‘split-
side of corporeal and visual space (neglect). Failure of recognition of brain’ patients undergo psychological testing, the two halves of the
objects by touch or vision represents tactile or visual agnosia. The brain appear to behave relatively autonomously, e.g. visual informa-
parietal–temporal cortical connections are particularly important for tion directed to the right cerebral hemisphere alone does not evoke a
visual object recognition and lesions lead to an inability to identify, verbal response, and consequently individuals cannot name objects or
copy or match objects (apperceptive visual agnosia). read words solely presented to the left visual field. A single lesion in
The anterior superior parts of the parietal lobes and the related con- the splenium of the corpus callosum interrupting white matter tracts
nections with the premotor areas, including the supplementary motor running from the visual cortices of both hemispheres to the left
areas, are concerned in the execution of skilled movements through angular gyrus, or lesions to the splenium and the left primary visual


development and experience (praxis). Lesions of these areas lead to cortex, or lesions involving the splenium and the lateral geniculate
contralateral loss of skilled movements of the face, mouth and limbs nucleus, either by posterior cerebral artery territory infarct, tumours or
(ideomotor apraxia). demyelinating disease such as multiple sclerosis, lead to the posterior
The anterior temporal neocortex (middle and inferior temporal gyri) disconnection syndrome of ‘alexia without agraphia’. Disconnection of
is concerned in ascribing meaning to perceptual stimuli. Bilateral visual processes in the right hemisphere from the verbal processes of
lesions of these areas (e.g. in semantic dementia) lead to loss of recogni- the dominant left cerebral hemisphere means that the language zone
tion of words and percepts. Unilateral lesions in the left hemisphere is robbed of its visual inputs but remains intact, and so these individu-
particularly affect word meaning and naming (semantic or transcortical als speak and write without difficulty but cannot understand written
aphasia), whereas lesions of the right hemisphere lead primarily to loss material (alexia).
Bonus e-book images
Fig. 25.2 The basic organization of the main Fig. 25.11 The hand motor activation site Fig. 25.12 A reconstruction of the short
cerebral gyri. corresponds to a knob-like cortical area of U-shaped (red) and long projection (green)
the contralateral precentral gyrus, which in tracts of the hand-knob motor region in the
Fig. 25.9 The main sulci and gyri of the MRI axial planes usually resembles an left hemisphere.
superolateral surface of the brain. inverted omega shape and may be identified
by its relationship to the posterior end of the Fig. 25.13 Functional magnetic resonance
Fig. 25.10 The main sulci and gyri of the superior frontal sulcus. images (fMRI) of the language cortical areas
medial and basal temporo-occipital surfaces (left cerebral hemisphere), activated by
of the right side of the brain.
Continued


Cerebral hemispheres
397.e1
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Executive function Central sulcus Praxis Spatial function
(frontal lobe syndrome) (apraxia) (spatial disorientation,
neglect)
Perception
Lateral fissure (apperceptive
agnosia)
Semantic conceptual system
(semantic aphasia, Memory Language
associative agnosia) (amnesia) (aphasia, alexia, agraphia, acalculia)
Fig. 25.49 Regional localization of cognitive function (dysfunction) in the
cerebral hemisphere.


Cerebral hemispheres
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NOiTCes
Bonus e-book images—cont’d
rhyme tasks, semantic tasks and fluency Fig. 25.36 A progressive fibre dissection of insular structures. B, Sagittal section,
tasks. the lateral aspect of the left cerebral dissected to show the relationship between
hemisphere. the insula and the temporal horn.
Fig. 25.14 Components of the frontoparietal
operculum. Fig. 25.37 A diffusion tensor imaging Fig. 25.47 Removal of the inferior frontal
reconstruction of the superior longitudinal gyrus, the basal aspects of the pre- and
Fig. 25.17 A superior view of the cerebral fasciculus. postcentral gyri, and of the supramarginal,
hemispheres. angular, superior and middle temporal gyri
Fig. 25.40 The superior aspect of the in order to expose the insular surface and
Fig. 25.18 The basal temporo-occipital corpus callosum revealed by partial removal the subcortical white matter of the temporal
surface. of the cerebral hemispheres. lobe.
Fig. 25.20 A, An anterior view of cerebral Fig. 25.42 A series of dissections of the left Fig. 25.48 A, Lateral view of the left
hemispheres. B, A view of the basal cerebral hemisphere at progressively deeper hemisphere. B, Medial view of the left
frontotemporal surface. levels to demonstrate the relationships of hemisphere.
the internal capsule.
Fig. 25.22 The temporal opercular surface, Fig. 25.49 Regional localization of cognitive
the insula and the temporal stem, right side. Fig. 25.46 A, The lower and upper portions function (dysfunction) in the cerebral
of the frontal and temporal opercula hemisphere.
Fig. 25.27 The fornix and related structures, respectively have been removed to reveal
right side of the brain. the relationships between opercular and
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The resting human brain and the
COMMENTARY
predictive potential of the default
3.1
mode network
Stefano Sandrone
Wilton Street, London, August 1858. Having completed the main text (Biswal et al 1995, Biswal 2012). It is true that a similar brain fluctua-
of Anatomy: Descriptive and Surgical, Henry Gray opened the preface to tion had already been recorded in 1929 by means of the electroen-
his book with the following sentence: ‘This Work is intended to furnish cephalogram (Berger 1929, Raichle and Snyder 2007), but at that time
the Student and Practitioner with an accurate view of the Anatomy of this activity was considered to be uninformative noise and not worthy
the Human Body, and more especially the application of this science to of investigation.
Practical Surgery.’ At that time, the idea of generating a non-invasive At the beginning of the new millennium, the boundaries of this
view of the human brain and of using that view to predict imminent resting activity started to be defined. It was demonstrated that during
events within the brain was inconceivable. Today, view-based predic- resting state a spontaneously organized neural activity occurs in a
tions are tangibly close to realization. unique constellation of brain regions. Defined as the default mode
The development of neuroimaging techniques, such as computed network (DMN), this constellation mainly involves the posterior cin-
axial tomography (CAT scanning), functional magnetic resonance gulate cortex, the precuneus and regions of the ventromedial prefrontal
imaging (fMRI) and positron emission tomography (PET), has been cortex (Fig. 3.1.1) (Raichle et al 2001, Buckner 2012, Snyder and
one of the major biomedical achievements of the past hundred years. Raichle 2012). In the face of a certain degree of scepticism (Morcom
These techniques gave new impetus to medicine, neurology, psychiatry, and Fletcher 2007), research on this topic continued, producing
psychology, philosophy and related fields by providing two unprece- inter-species, longitudinal, inter-individual and physiopathological
dented types of insight. On the one hand, by yielding structural images studies.


of brain anatomy, these techniques enabled the detection of pathologi- DMN activity has subsequently also been detected in chimpanzees
cal abnormalities, and hence constituted a major breakthrough in (Rilling et al 2007), monkeys (Kojima et al 2009, Mantini et al 2011)
medical diagnosis. On the other hand, as well as providing functional and rats (Lu et al 2012), findings that suggest that such activity could
insights, neuroimaging has shed ample light on philosophical ques- be a fundamental aspect of the mammalian brain. The same activity
tions that are intimately linked to ‘who we are’ and are as old as also manifests at several stages in the human life cycle, from its emer-
mankind. gence in 2-day-old newborns (Gao et al 2009) to its disappearance in
While medicine was focused on diagnostic imaging and neuro- brain-dead patients (Boly et al 2009). DMN-related differences between
science in the designing of experimental paradigms that might isolate individuals (Power et al 2010) and between healthy and pathological
human emotion, thoughts, language, and consciousness, etc. (i.e. task- conditions have started to emerge (Sandrone 2012).
based modes of investigation), ancillary fMRI recordings of the brain Remarkably, these differences and abnormalities not only constitute
during resting state, namely a behavioural state characterized by quiet neuropathophysiological correlates of in fieri neurological and psychi-
repose with the eyes either closed or open, with or without visual fixa- atric diseases (Fox and Raichle 2007), but also offer informative and
tion (Raichle 2009), showed regular and low-frequency cerebral fluctua- predictive markers about the pathology that is going to impact on the
tions indicating that the brain was active even when in a resting state brain (Sandrone 2012). In fact, they often appear before the overt
PFC
IPL
Ins
LTC
dMPFC
pCC / Rsp
vMPFC
A B
HF+
Fig. 3.1.1 Modern descriptions of the default mode network. A, A surface projection of the default mode network is displayed from the Shulman et al.
(1997) data. The regions in blue represent those regions more active during passive task states than a variety of active tasks. B, A near-complete


topography of the default network can be accounted for by exploring regions functionally coupled to the posterior cingulate, dorsal medial prefrontal
cortex (dMPFC) and hippocampal formation (HF+). However, detailed analysis of the coupling properties reveals that the default network is not a single,
coherent system but rather is made up of multiple, functionally interacting subsystems. Other abbreviations: Ins, insula; IPL, inferior parietal lobule; LTC,
lateral temporal cortex; pCC, posterior cingulate cortex; PFC, prefrontal cortex; Rsp, retrosplenial cortex; vMPFC, ventral medial prefrontal cortex. (With
permission from Buckner RL 2012 The serendipitous discovery of the brain’s default network. NeuroImage 62: 1137–1145; Elsevier.) e39


The resTing human brain and The predicTive poTenTial of The defaulT mode neTwork
e40
3
noiTces
onset of pathological phenotypes: abnormal patterns of DMN activity ments on larger samples is crucial to test and improve the accuracy rate
and connectivity seem to anticipate future behavioural phenotypes of every prediction. Additionally, resting state acquisition is currently
and clinical impairment (Sandrone 2013). They can represent reliable performed differently by different research groups, and greater experi-
non-invasive biomarkers for differential diagnosis and disease moni- mental design homogeneity is needed. Methodological guidelines
toring, providing us with novel views on the functional architecture of should accordingly be standardized to ensure comparability between
the human brain and opening up an intriguing medical field. all resting-state studies (Northoff et al 2010, Northoff et al 2011).
This predictive potential of DMN has been seen in a plethora of Resting-state fMRI data coherencies still need to be further characterized
diseased conditions (Table 3.1.1). For example, clinicopathological and quantified across subjects and sessions (Damoiseaux et al 2006);
phenotypes of dementia with Lewy bodies and Alzheimer’s disease technical optimization, experimental refinement and a balanced com-
often overlap, making discrimination difficult; notably, DMN func- parison between the differing methods are required (Cole et al 2010,
tional connectivity abnormalities can support early discrimination Birn 2012, Lee et al 2013).
between them (Galvin et al 2011) and tracks clinical deterioration in Further work is needed to clarify the anatomical and functional
Alzheimer patients (Damoiseaux et al 2012). Functional disruption of boundaries of the cerebellar contribution to intrinsic connectivity net-
DMN in cognitively unimpaired patients with Parkinson’s disease has works (Habas et al 2009, Krienen and Buckner 2009), given that most
been reported even in the absence of significant structural differences of the human cerebellum is linked to association networks including
between patients and controls (Tessitore et al 2012, Sandrone and the executive control network and the DMN (Buckner 2013). An inte-
Catani 2013). Changes of resting-state functional connectivity predict grative exploration of the ‘functional connectome’ and the related aber-


the persistence of cognitive rehabilitation effects in patients with mul- rant intrinsic networks across diseases (Menon 2011, but see also
tiple sclerosis (Parisi et al 2014). The extent of DMN reduction depends Barkhof et al 2014 and Fox et al 2014), as well as detailed guidelines
on the clinical severity of the manifestations in disorders of conscious- for research on clinical populations (Fox and Greicius 2010, Sandrone
ness (vegetative state versus minimally conscious state versus emerging 2013), are needed to bridge the gap between basic research studies and
from a minimally conscious state) (Fernández-Espejo et al 2012), and their translational application. Basic research studies rely on homogen-
DMN connectivity may serve as an indicator of the extent of cortical eous criteria, whereas clinical practice deals with heterogeneous condi-
disruption and predict reversible impairments in consciousness (Norton tions and comorbidity of diseases. Moreover, the ontological meaning
et al 2012). Specific differences in resting-state functional network con- of this resting activity still needs to be fully elucidated: so far, activations
nectivity might be candidate psychosis endophenotypes discriminating and deactivations of DMN brain regions have often been related to
between schizophrenia and psychotic bipolar probands and unaffected self-specific processes in both healthy (Gusnard et al 2001) and dis-
relatives (Meda et al 2012). Moreover, whole-brain resting-state func- eased subjects (Sheline et al 2009, Irish et al 2012).
tional connectivity analyses can identify subjects with major depressive DMN-based research will certainly enrich our understanding of
disorder from healthy controls, with the most discriminating connec- brain function and will undoubtedly gravitate to the centre-stage of
tions located across or within the DMN (Zeng et al 2012). Failure to medical investigation. From an epistemological point of view, the pre-
deactivate the DMN has been highlighted as a possible endophenotype dictive potential of DMN and resting state does not belong a priori to
of autism (Spencer et al 2012), and other reports also point towards the any academic domain, and its impact will necessarily be cross-
feasibility of a functional connectivity MRI diagnostic assay for autism disciplinary. As such, it will challenge the boundaries of medical sci-


with DMN regions playing a key role (Anderson et al 2011, but see also ences and neutralize the traditional demarcations between neurology
Lynch et al 2013). These promising resting biomarkers are of particular and psychiatry.
interest because they avoid performance-related confounding variables We will witness an intriguing paradigm shift (Kuhn 1962). Although
that are commonly present in patients with cognitive or sensorimotor time-to-completion estimates would be foolhardy, research will gener-
defects (Zhang and Raichle 2010). ate a DMN-based ‘functional taxonomy’ of the human brain, in which
Observation of the resting brain as a predictor of clinical outcome clinical subpopulations and subtypes are identified on the basis of their
and the use of DMN abnormalities as pathological markers and diag- resting cerebral activity (Sandrone 2013). In the challenging and never-
nostic and prognostic tools are great challenges for the coming years. resting search for a better understanding of the human brain and a cure
Future research will undoubtedly shed light on the ability of DMN to for cerebral diseases, it will be a resting person inside a neuroimaging
discriminate single patients from single healthy controls with increasing scanner who will push forward the medical field and revolutionize the
sensitivity and high specificity. Systematic replication of DMN experi- way we deal with medical diagnosis and prognosis.
Table 3.1.1 The predictive potential of the DMN in disease
Condition Evidence Reference
Ageing, amnestic mild cognitive Functional alteration patterns of DMN derived from simultaneous comparison of the three Cha et al 2013 Eur J Neurosci 37:1916–24
impairment and Alzheimer’s disease different groups
Amnestic mild cognitive impairment Disrupted functional brain connectome in amnestic mild cognitive impairment individuals Wang et al 2013 Biol Psychiatry 73:472–81
at risk for Alzheimer’s disease
Early onset of the functional/topological reorganization of the DMN Wang et al 2013 Radiology 268:501–14
Alzheimer’s disease and frontotemporal Behavioural variant frontotemporal dementia and Alzheimer’s disease lead to divergent Zhou et al 2010 Brain 133:1352–67; but see also Zhou and
dementia network connectivity patterns Seeley 2014 Biol Psychiatry 75:565–73


Alzheimer’s disease and dementia with Resting blood oxygen level-dependent (BOLD) fMRI differentiates Alzheimer disease from Galvin et al 2011 Neurology 76:1797–803
Lewy bodies dementia with Lewy bodies
Alzheimer’s disease DMN activity distinguishes Alzheimer’s disease from healthy ageing Greicius et al 2004 Proc Natl Acad Sci U S A 101:4637–42
Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease Sorg et al 2007 Proc Natl Acad Sci U S A 104:18760–5;
Wang et al 2013 Biol Psychiatry 73:472–81; but see also
Fjell et al 2013 J Neurosci 33:8237–42 and Jacobs et al
2013 Neurosci Biobehav Rev 37:753–65
Resting-state functional connectivity in preclinical Alzheimer’s disease Sheline and Raichle 2013 Biol Psychiatry 74:340–7
Functional connectivity tracks clinical deterioration in Alzheimer’s disease Damoiseaux et al 2012 Neurobiol Aging 33:828.e19–30
Functional disruption of the DMN occurs early in the course of autosomal dominant Chhatwal et al 2013 Neurology 81:736–44
Alzheimer’s disease, beginning before clinically evident symptoms and worsening with
increased impairment
Amyotrophic lateral sclerosis Changes of resting-state brain networks in amyotrophic lateral sclerosis Mohammadi et al 2009 Exp Neurol 217:147–53
Divergent brain network connectivity and alteration of large-scale functional networks Agosta et al 2013 Neurobiol Aging 34:419–27
associated with cognition, even in the absence of overt dementia
Independent component analysis and machine learning can support identification of the Welsh et al 2013 Front Hum Neurosci 7:251
amyotrophic lateral sclerosis diseased brain
Autism spectrum disorder Functional connectivity MRI classification/diagnostic assay for autism Anderson et al 2011 Brain 134:3742–54
Failure to deactivate the DMN as possible endophenotype of autism Spencer et al 2012 Mol Autism 3:15
Differential deactivation during mentalizing and classification of autism based on DMN Murdaugh et al 2012 PLoS One 7:e50064
connectivity


Large-scale evaluation of the intrinsic brain architecture in autism Di Martino et al 2014 Mol Psychiatry 19:659–67
Bipolar disorder Correlation of DMN activation with bipolarity index in young people with mood disorders Ford et al 2013 J Affect Disord 150:1174–8; but see also Vargas
et al 2013 J Affect Disord 150:727–35


The resting human brain and the predictive potential of the default mode network
e41
1.3
YraTnemmoc
Table 3.1.1 The predictive potential of the DMN in disease—cont’d
Condition Evidence Reference
Disorder of consciousness DMN connectivity is decreased in severely brain-damaged patients in proportion to their Vanhaudenhuyse et al 2010 Brain 133:161–71; see also Norton
degree of consciousness impairment et al 2012 Neurology 78:175–81
DMN integrity correlates with the level of remaining consciousness in coma, vegetative Fernández-Espejo et al 2012 Ann Neurol 72:335–43;
state and minimally conscious state Guldenmund et al 2012 Arch Ital Biol 150:107–21
Connectivity biomarkers can differentiate patients with different levels of consciousness Höller et al 2014 Clin Neurophysiol 125:1545–55
Generalized anxiety disorder Functional network dysfunction in anxiety and anxiety disorders Andreescu et al 2014 Int J Geriatr Psychiatry 29:704–12;
Sylvester et al 2012 Trends Neurosci 35:527–35
Epilepsy The decoupling of functional and structural connectivity may reflect the progress of Zhang et al 2011 Brain 134:2912–28
long-term impairment in idiopathic generalized epilepsy
Resting-state network disruption in temporal lobe epilepsy Voets et al 2012 Brain 135:2350–7; Cataldi et al 2013 Epilepsia
54:2048–59
DMN connectivity indicates episodic memory capacity in mesial temporal lobe epilepsy McCormick et al 2013 Epilepsia 54:809–18
Huntington’s disease DMN changes identified at preclinical level Wolf et al 2012 Exp Neurol 237:191–8
Reduced brain connectivity before and after disease onset Dumas et al 2013 Neuroimage: Clin 2:377–84; Werner et al
2014 Hum Brain Mapp 35:2582–93
Major depression Whole-brain functional connectivity analyses can identify major depressive individuals Zeng et al 2012 Brain 135:1498–1507
from healthy controls, with the most discriminating connections located across and
within the DMN


Evidence of a dissociation pattern in resting-state DMN connectivity in first-episode, Zhu et al 2012 Biol Psychiatry 71:611–17
treatment-naïve major depression patients
Persistent abnormal functional connectivity within the anterior subnetwork in recovered Li et al 2013 Biol Psychiatry 74:48–54
depressed subjects may constitute a biomarker of asymptomatic depression and
potential for relapse
Machine learning approaches to major depression Lord et al 2012 PLoS One 7:e41282; Zeng et al 2014 Hum Brain
Mapp 35:1630–41
Obsessive–compulsive disorder Disrupted cortical network as a vulnerability marker for obsessive–compulsive disorder Peng et al 2014 Brain Struct Funct 219:1801–12; but see also
Stern et al 2012 PLoS One 7:e36356 and Beucke et al 2014
Br J Psychiatry 205:376–82
Multiple sclerosis Functional abnormalities concerning DMN occur in patients with relapsing–remitting Rocca et al 2012 Neurology 79:1449–57; but see also Kingwell
multiple sclerosis 2012 Nat Rev Neurol 8:593
Maintenance of DMN activity during sustained attention is a sensitive and specific Sumowski et al 2013 Mult Scler 19:199–208
neurophysiological biomarker of episodic memory functioning
Changes of brain resting-state functional connectivity predict the persistence of cognitive Parisi et al 2014 Mult Scler 20:686–94
rehabilitation effects
Parkinson’s disease Dysfunctions of cerebral networks precede recognition memory deficits in early Ibarretxe-Bilbao et al 2011 Neuroimage 57:589–97
Parkinson’s disease
Functional disruption of the DMN in cognitively unimpaired patients with Parkinson’s Tessitore et al 2012 Neurology 79:2226–32; Sandrone and
disease in the absence of significant structural differences between patients and Catani 2013 Neurology 81:e172–5
controls
DMN integrity is levodopa equivalent dose-dependent Krajcovicova et al 2012 J Neural Transm 119:443–54
Schizophrenia Brain network connectivity in individuals with schizophrenia and their siblings Repovs et al 2011 Biol Psychiatry 69:967–73


Subjects at increased genetic risk of developing schizophrenia exhibit abnormal intrinsic van Buuren et al 2012 Schizophr Res 142:237–43; Whitfield-
connectivity within the midline DMN Gabrieli and Ford 2012 Annu Rev Clin Psychol 8:49–76
Links among resting-state DMN, salience network, and symptomatology in schizophrenia Orliac et al 2013 Schizophr Res 148:74–80; but see also
Wotruba et al 2014 Schizophr Bull 40:1095–104
Schizophrenia and psychotic bipolar Specific differences in resting-state functional network connectivity might be candidate Meda et al 2012 Biol Psychiatry 71:881–9; Khadka et al 2013
probands psychosis endophenotypes discriminating between schizophrenia and psychotic bipolar Biol Psychiatry 74:458–66
probands and unaffected relatives
Traumatic brain injury DMN connectivity predicts sustained attention deficits after traumatic brain injury Bonnelle et al 2011 J Neurosci 31:13442–51; Sandrone and
Bacigaluppi 2012 J Neurosci 32:1915–17
Resting-state fMRI activity and connectivity and cognitive outcome Palacios et al 2013 JAMA Neurol 70:845–51; but see also Zhou
and Lui 2013 Neurology 80:1822–3
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