doi:10.1093/brain/awh622Brain (2005) Page 1 of 16
The rises and falls of disconnection syndromes
Marco Catani and Dominic H. ffytche
Centre for Neuroimaging Sciences, Institute of Psychiatry, De Crespigny Park, London, UK
Correspondence to: Marco Catani, Centre for Neuroimaging Sciences, PO 89, Institute of Psychiatry,
De Crespigny Park, London, UK
In a brain composed of localized but connected specialized areas, disconnection leads to dysfunction. This
simple formulation underlay a range of 19th century neurological disorders, referred to collectively as dis-
connection syndromes. Although disconnectionism fell out of favour with the move against localized brain
theories in the early 20th century, in 1965, an American neurologist brought disconnection to the fore once
more in a paper entitled, ‘Disconnexion syndromes in animals and man’. In what was to become the manifesto
of behavioural neurology, Norman Geschwind outlined a pure disconnectionist framework which revolution-
ized both clinical neurology and the neurosciences in general. For him, disconnection syndromes were higher
function deficits that resulted from white matter lesions or lesions of the association cortices, the latter acting
as relay stations between primary motor, sensory and limbic areas. From a clinical perspective, the work
reawakened interest in single case studies by providing a useful framework for correlating lesion locations
with clinical deficits. In the neurosciences, it helped develop contemporary distributed network and connec-
tionist theories of brain function. Geschwind’s general disconnectionist paradigm ruled clinical neurology for
20 years but in the late 1980s, with the re-emergence of specialized functional roles for association cortex, the
orbit ofits remit began todiminishandit becameincorporated into moregeneralmodelsofhigher dysfunction.
By the 1990s, textbooks of neurology were devoting only a few pages to classical disconnection theory. Today,
new techniques to study connections in the living human brain allow us, for the first time, to test the classical
formulation directly and broaden it beyond disconnections to include disorders of hyperconnectivity. In this
review, on the 40th anniversary of Geschwind’s publication, we describe the changing fortunes of disconnection
theory and adapt the general framework that evolved from it to encompass the entire spectrum of higher
function disorders in neurology and psychiatry.
Keywords: white matter fibre pathways; visual agnosia; diffusion tensor tractography; apraxia; aphasia
Received May 13, 2005. Revised July 10, 2005. Accepted July 26, 2005
As originally outlined by Wernicke in his associationist the-
ory, higher brain functions were the product of associative
connections between cortical areas storing motor and sensory
images. It followed that disorders of higher function resulted
from a disconnecting breakdown of associative connections
through white matter lesions (Wernicke, 1874). Today,
this disconnection paradigm is still to be found within the
2001) and dyslexia (Demonet et al., 2004), where disconnect-
ing ‘lesions’ remain inferred rather than demonstrable.
However, it was not always so. For the first half of the
20th century, function in general was thought to relate to
the brain as an equipotential whole, cortical connections,
disconnections and the location of lesions becoming an irrele-
vance. One man is credited with the re-emergence of the
disconnection paradigm, and 2005 is the 40th anniversary
of the publication that founded the neo-associationist school.
Norman Geschwind’s ‘Disconnexion syndromes in animals
and man’, published in Brain in two parts for editorial con-
venience although, in effect, a single monograph, outlined a
general theory of higher brain function founded on what
today might be called distributed brain networks. The impor-
tanceof thepaperisdemonstrated bytheexponential increase
in citations from 1965 to 1985, at one time the paper being
cited once every 5 days (Absher and Benson, 1993).
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Behavioural neurology, cognitive neurology, neuropsychiatry
and neuropsychology share at least one thing in common—
they each owe much to Geschwind.
Geschwind’s disconnection framework was both general
and specific, giving it immediate clinical appeal. On the
one hand, it helped classify higher dysfunction into a limited
set of syndromes and on the other hand, it allowed a cus-
tomized neuroanatomical account of a given patient’s deficit
pattern. For some higher dysfunctions our contemporary
accounts remain largely as Geschwind left them, and for
others, explanations have moved on with the recognition
of specialized functional roles in association cortex. Yet, it
is not the neurological details of Geschwind’s model that have
been his legacy—it has been the ambition of an overarching
clinical theory, the return of clinicopathological correlations
to neurology and the facilitation of a discourse between clinic
and neuroscience laboratory.
Geschwind’s theory, and that of Wernicke’s school before
him, was founded on the anatomy of connections, the knowl-
edge of which was derived from human post mortem dis-
sections and, for Geschwind, studies of the monkey brain.
More recently, the advent of novel techniques for tracing
connections non-invasively, such as diffusion tensor imaging
(Le Bihan and Breton, 1985; Moseley et al., 1990; Basser et al.,
1994) and tractography (Conturo et al., 1999; Jones et al.,
1999; Morietal.,1999;Basser etal.,2000; Pouponet al.,2000)
allow us to study connections in the living human brain, both
in normal subjects and patients with neurological and psy-
chiatric disorders. Other developments in electrophysiology
and neuroimaging are focusing attention on connections by
studying the implied connectivity of brain regions revealed by
statistical correlation. For the first time we are in a position,
not only to correlate disconnecting lesions with their clinical
symptoms in vivo, thus testing the classical disconnectionist
paradigm directly, but also to correlate clinical symptoms
with increased connectivity between brain regions. In what
follows we celebrate Geschwind’s contribution with a review
of disconnection theory and its syndromes before, during
and after him, outlining the ebb and flow of their fortunes
over the last two centuries. In the final section we update the
connectivity evidence in the spirit of the neurological revo-
lution of 1965.
Disconnection syndromes before
In the late 19th century a new paradigm emerged with which
to understand normal brain function and its disorders. The
paradigm was based on two central tenets: that of the locali-
zation of function in discrete cortical areas and that of
connections between such cortical areas through white matter
association pathways. Although the idea of localized
functions in specific parts of the brain predates Franz Joseph
the specific functional importance of the cortex (Zola-
Morgan, 1995). Often forgotten as a widely acclaimed
neuroanatomist, Gall established the basic division between
grey and white matter, recognizing that white matter was
nating from or projecting to the cortex. Gall developed a
system of organology in which functional variations were
correlated with the size of specific cortical regions (cortical
organs) both across and within species. Of course, his use of
external cranial features as an indirect measure of cortical
organ size was flawed and the system fell into disrepute. In
England Gall’s ideas evolved into phrenology; in France, they
had an important influence on the later clinicopathological
correlation studies of Jean-Baptiste Bouillaud (1796–1881),
Paul Broca (1824–80) and Jean Martin Charcot (1825–93).
The credit for the detailed anatomy of white matter path-
ways falls to Theodore Meynert (1833–92), the Professor of
Psychiatry in Vienna, who, like Gall, was a neuroanatomist
of international repute. He was the first to recognize the
important functional role played by fibres connecting differ-
ent parts of a single hemisphere, which he termed association
fibres. He was also the first to classify white matter fibres into
three groups. The first group consisted of projection fibres,
in the cortex, the second of commissural fibres which con-
fibres which connected cortical regions within a hemisphere.
Figure 1 shows tractography reconstructions of the major
white matter tracts of the human brain as classified by
Meynert (Catani et al., 2002).
Although Meynert used his neuroanatomical findings
to develop a theory of psychological function which had
profound influence on the early development of psychiatry,
including Freud’s early work, it is Karl Wernicke (1848–1904)
who is considered the father of disconnection theory.
Wernicke conceived the brain as a mosaic-like arrangement
of areas containing ‘fundamental psychic elements’ or
‘memory images’ related to motor acts and sensory experi-
ences. These memory images areas were localized in primary
sensory and motor areas according to the following principle:
the acoustic images find their abode within the cortical
terminals of the acoustic nerve; the visual images,
within the cortical endings of the optic nerve; and
the olfactory images in that of the olfactory nerve;
and so on. Likewise the motor images or movement-
representation could be located in the cortical sites of
the motor nerve origins. (Wernicke, 1885)
Perhaps in an attempt to distance himself from phrenological
theory, Wernicke was adamant that the higher functions
were not localized in specific regions but were the result of
associative connections between motor and sensory memory
image areas. Thus, for Wernicke
Any higher psychic process, exceeding these mere
primary assumptions, could not, I reasoned, be
Page 2 of 16Brain (2005)M. Catani and D. H. ffytche
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localised, but rested on the mutual interaction of these
fundamental psychic elements mediated by means of
their manifold connections via the association fibres
This is the doctrine of Wernicke’s associationist school. Here
higher functions arise through associative connections and
disorders of higher function from their breakdown. Critically,
there was no place for cortical specializations beyond those
of primary sensory and motor functions in the classical asso-
ciationist account. This theoretical framework helped explain
today, are referred to collectively as classical disconnection
Written at the age of 26 years, Wernicke’s MD thesis
‘The aphasic symptom-complex’ contained a description of
the disconnection syndrome that was to become the proto-
type for all others—conduction aphasia (Leitungsaphasie)
Wernicke held that the motor component of language (the
imagesofspeech movements) waslocalizedin afrontalregion
(Broca’s area) and that the sensory component of language
(auditory images of words) was localized in the posterior part
ofthesuperior temporal gyrus(latertermed Wernicke’sarea).
Lesions of the Broca and Wernicke centres led, respectively,
to pure motor aphasia (impaired fluency but normal com-
prehension) and pure sensory aphasia (impaired comprehen-
sion but normal fluency). Wernicke hypothesized that lesions
of the association tracts connecting them led to a conduction
aphasia, a pure disconnection syndrome which, in its modern
view, consists of a repetition deficit and paraphasic speech
(the use of incorrect words or phonemes while speaking) with
intact comprehension and fluency. Although not a part of
Wernicke’s original description, in his later work he argued
that repetition deficits related to the failure of transfer of
heard words from Wernicke’s to Broca’s area. Paraphasia
was thought to relate to the loss of a higher internal moni-
toring function which relied on intact connections between
Wernicke’s and Broca’s areas, the ‘unconscious, repeated
activation and simultaneous mental reverberation of the
acoustic image which exercises a continuous monitoring of
the motor images’ (Wernicke, 1874). Figure 2 (top left) shows
a schematic representation of Wernicke’s proposed neuro-
anatomical explanation for conduction aphasia. Although
in his early work he proposed that frontal and temporal
language centres were connected through the insula, he
later argued that the important pathway was the arcuate
fasciculus and that lesions to this pathway would result in
did not end with conduction aphasia, many key figures of
the associationist school being linked to his psychiatric clinic
in Breslau. Heinrich Lissauer (1861–91), an assistant in
Wernicke’s clinic, was one such figure. The year before he
80-year-old salesman who, following a loss of consciousness
Fig. 1 Meynert’s classification of white matter tracts visualized
with diffusion tensor tractography and superimposed on medial
and lateral views of the brain surface. Projection tracts
connect cortical to subcortical structures. The corona radiata
contains descending fibres projecting from the motor cortex to
basal ganglia, midbrain motor nuclei (corticobulbar tract) and the
spinal cord (pyramidal tract) and ascending fibres from the
thalamus to the cortical mantle (thalamic projections). The
fornix connects the medial temporal lobe to hypothalamic nuclei.
Commissural tracts connect the two hemispheres. The corpus
callosum is the largest white matter bundle and connects cortical
regions within frontal, parietal, occipital and temporal lobes. The
anterior commissure connects the left and right amygdalae and
ventromedial temporo-occipital cortex. Association tracts run
within each hemisphere connecting distal cortical areas. The
cingulum connects medial frontal, parietal, occipital, temporal and
cingulate cortices. The arcuate/superior longitudinal fasciculus
connects perisylvian frontal, parietal and temporal cortices. The
uncinate fasciculus connects orbitofrontal to anterior and medial
temporal lobes. The inferior longitudinal fasciculus connects the
occipital and temporal lobes. The inferior fronto-occipital
fasciculus connects the orbital and lateral frontal cortices to
occipital cortex (Catani et al., 2002).
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