Cognition, 50 (1994) 133-149

OOlO-0277/94/$07.00 0 1994 - Elsevier Science B.V. All rights reserved.

Developmental dyslexia and animal studies:

at the interface between cognition and
neurology

Albert M. Galaburda
Departmerltof Neurology. Beth Israel Hospital and Harvard Medical School, Boston, MA 02215. USA

Abstract

Recent findings in autopsy studies, neuroimaging, and neurophysiology indicate

that dyslexia is accompanied by fundamental changes in brain anatomy and
physiology, involving several anatomical and physiological stages in the processing
stream, which can be attributed to anomalous prenatal and immediately postnatal
brain development. Epidemiological evidence in dyslexic families led to the
discovery of animal models with immune disease, comparable anatomical changes
and learning disorders, which have added needed detail about mechanisms of
injury and plasticity to indicate that substantial changes in neural networks
concerned with perception and cognition are present. It is suggested that the
disorder of language, which is the cardinal finding in dyslexic subjects, results from
early perceptual anomalies that interfere with the establishment of normal cognitive-
linguistic structures, coupled with primarily disordered cognitive processing associ-
ated with developmental anomalies of cortical structure and brain asymmetry. This
notion is supported by electrophysiological data and by findings of anatomical
involvement in subcortical structures close to the input as well as cortical structures
involved in language and other cognitive functions. It is not possible at present to
determine where the initial insult lies, whether near the input or in high-order
cortex, or at both sites simultaneously.

The author thanks Dr. Lisa Schrott, presently at the Department of Psychiatry, University of
Colorado Health Sciences Center, for help in the preparation of the report on behavioral studies in
immunedefective mice. The author thanks his colleagues Drs. Gordon F. Sherman and Glenn D.
Rosen for their collaboration. The preparation of this review was supported by grant 2POl HD20806
from NIHINICHD.

SSDI OOlO-0277(93)00607-9
I. Introduction

An important aim of behavioral neurology in the clinics and its sister specialty
concerned with normal biology, cognitive neuroscience, is the mapping of
behavior onto neurophysiology and brain structure. Where it concerns complex
behaviors such as the elements of language, high-level vision, biographical
memory. consciousness and attention, and the clinical syndromes in which these
functions fail, progress has been slow. This is in part the result of the fact that to a
large extent animal models have not been possible for capturing behaviors
thought to be either purely human, or considered to have achieved qualitative or
quantitative uniqueness (or both) only in human beings. Developmental disorders
offer a partial advantage in this regard in that they concern the early acquisition
of cognitive capacities, whereby relatively simpler biological and environmental
factors may prove to be more important. Thus, for instance, sensory and
perceptual deficits are more likely to play a role in language acquisition than they
do after language has been implemented in the brain, and it is relatively easier to
model sensory and perceptual abnormalities in animal models than it is to model
cognitive processes like language. Our recent work is being driven by the
hypothesis that the condition known as developmental dyslexia, also known as
specific reading disability, originates as a disorder of perception affecting the
brain at a vulnerable time (before the age of 1 year) when phonological structures
relating to the native language are being organized in the developing brain. In this
review, I will outline some of the findings in the brains of dyslexics and in suitable
animal models. which have led to this hypothesis.
Dyslexia remains a diagnosis that is made on educational grounds, that is,
based on detection in the schools and on results of psychoeducational test
batteries. Some specific cognitive anomalies are thought to be present in nearly all
dyslexics, for example phonological deficits (Fischer, Liberman, & Shankweiler,
1978; Morais, Luytens, & Alegria, 1984), but it is likely that many with similar
deficits are not dyslexic and some dyslexics do not exhibit phonological deficits
(see recent discussions in Cognition, Volume 48, Number 3, September 1993).
Thus, there is no absolute cognitive marker, as yet, for the diagnosis of dyslexia.
This should not be surprising in a skill for which many areas of mental capacity on
the one hand and cultural influences on the other play such an important role.
In terms of brain loci and etiology, the diagnosis of dyslexia probably
encompasses several biological subtypes, as yet unidentified. Although it is
theoretically possible to learn to be dyslexic, in which case the brain would be
found to be normal, brains of individuals with this diagnosis, which have come to
post-mortem examination, have exhibited fairly uniform neuropathological find-
ings (see below). Autopsy studies have not disclosed differences between dyslexics
of the visual and auditory types, either reflecting the fact that available methods
are not capable of showing such differences or the fact that phonological cases,
 A.M. Galaburda I Cognition 50 (1994) 133-149 135

being more common, have constituted the bulk of the anatomical studies.
Findings so far, however, indicate that the brain is affected widely, including
much of the perisylvian cortex containing both auditory and visual areas
(Humphreys , Kaufmann , & Galaburda, 1990), as well as subcortical regions
closer to the input (Galaburda & Livingstone, 1993; Livingstone, Rosen,
Drislane, & Galaburda, 1991).
The areas of anatomical abnormality are likely to interact with each other
during development so that it is not possible to state with confidence at present
whether the cortical changes are primary, causing developmental changes both
upstream and downstream in the interconnected neural networks, or are in
themselves secondary to changes occurring upstream or downstream first.
Another possibility, more difficult to justify on the basis of available information,
is that of injury to multiple stages of processing at the same developmental time.
Our present research is directed in part toward answering the question of whether
subcortical damage, or damage at early stages of processing, is the first step,
which would support the hypothesis that cognitive deficits are secondary to early
perceptual deficits.

2. Neuroanatomical characteristics

My colleagues and I have reported alterations in the pattern of brain

asymmetry of language areas as minor cortical malformations in four male and
three female dyslexic brains (Galaburda, Sherman, Rosen, Aboitiz, & Gesch-
wind, 198.5; Humphreys et al., 1990). Specifically there is absence of the ordinary
pattern of leftward asymmetry of the planum temporale, and the perisylvian
cortex displays minor cortical malformations, including foci of ectopic neurons in
the molecular layer and focal microgyria. The planum temporale is a part of the
temporal lobe thought to make up a portion of Wernicke’s speech area. The
perisylvian cortices affected by the minor malformations include inferior frontal
cortex, both in the region of and anterior to the classical Broca’s area, cortex of
the parietal operculum often involved by lesions producing conduction aphasia,
cortex of the inferior parietal lobule often involved in anemic aphasia with writing
disturbances, cortex of the superior temporal gyrus (part of Wernicke’s area
again), and cortex belonging to the “what” portion of the visual pathway in the
middle and inferior temporal gyrus.
A second set of observations is made on the human dyslexic thalamus. We have
found that both neurons in the magnocellular layers of the lateral geniculate
nucleus and in the left medial geniculate nucleus are smaller than expected
(Galaburda & Livingstone, 1993; Livingstone et al., 1991). The former is
associated with slowness in the early segments of the magnocellular pathway as
assessed by evoked response techniques addressing magnocellular function
separately from parvocellular (Livingstone et al.. 1991). The latter may relate to
the temporal processing abnormalities described in the auditory system of
language impaired children (Tallal & Piercy. 1973); similar temporal processing
abnormalities have long been suspected to underlie deficits of aphasic patients
(Efron, 1963). The relationship between the two elements of the first set of
findings, that is, the anomaly in asymmetry and the cortical malformations, and
the relationship between the first and second set, that is, the anomaly in rapid
temporal processing associated with thalamic changes, is another focus of research
with possibilities for resolution in animal models.
Animal research has also aimed at explaining the question of how minor
malformations could lead to noticeable and even clinically persistent disorders of
cognitive function. Some answers have come from the study of strains of mice that
spontaneously develop autoimmune disease, which also may display foci of
neocortical ectopic neurons (Sherman, Galaburda, Behan, & Rosen, 1987;
Sherman, Galaburda, & Geschwind. lY85). Thus, associated with these “ec-
topias”, there may be significant changes in some cortical neuronal subtypes
(Sherman. Stone, Rosen, & Galaburda, 1YYO). prominent alterations in cortico-
cortical connectivity (Sherman. Rosen, Stone, Press, & Galaburda. 1992). and
moditication of behavior (see below). Furthermore, ectopic animals show altera-
tions in the usual pattern of brain asymmetry. thus suggesting an interaction
between very early developmental events and the expression of cortical
asymmetry (Rosen. Sherman, Mehler, Emsbo, 8r Galaburda, 1989). In the
normal state, both in the mouse and human brains, increasing size asymmetry
between homologous areas of the two hemispheres is associated with decreasing
number of neurons and decreasing amount of cortex on the small side
(Galaburda. Aboitiz, Rosen, & Sherman, 1086; Galaburda, Corsiglia. Rosen, &
Sherman, 1987) (rather than increasing amount on the large side). This relation-
ship breaks down in animals with ectopias. in which asymmetry and size and
number of neurons interrelate randomly. Such a discovery was not possible in the
dyslexic brain sample alone. since all of them displayed symmetry of the planum
temporale. One could suggest. therefore, that variable degrees of asymmetry
work well only when a specific relationship between degree of asymmetry and
neuronal numbers is allowed to take place, and that the development of ectopias
may interfere with this relationship. There is an additional formal relationship
between asymmetry and callosal connectivity (Rosen, Sherman. 6i Gaiaburda.
lYSY), which we anticipate will also break down in the presence of ectopias
(research in progress). This would add further support to the notion that
symmetry in the presence of ectopias, as is the case in dyslexic brains, is likely to
be associated with fundamental changes in the functional properties of networks
participating in perceptual and cognitive activities.
Early on there were reports of neuroimaging aberrations in the pattern of brain
 A.M. Galaburda I Cognition 50 (1994) 133-149 137

asymmetry in dyslexic subjects (Hier, LeMay, Rosenberger, & Perlo, 1978).

More recently, in a magnetic resonance imaging (MRI) study, Hynd and
colleagues (Hynd, Semrud-Clikeman, Lorys, Novey, & Eliopulos, 1990) ex-
amined for the specificity of the asymmetry changes reported in dyslexic brains.
Their study found that symmetry of the planum was significantly more common in
dyslexics as compared with normals and individuals with attention deficit dis-
order/hyperactivity syndrome (ADD/H). The study also found that both ADD/
H and dyslexics had a narrower right anterior temporal area, and dyslexics alone
had bilaterally smaller insular regions and significantly reduced left plana
temporale. A recent study by Leonard and colleagues, which parceled the region
of the planum and adjacent parietal operculum on MRI, described a shift toward
increased right parietal opercular tissue in the dyslexic sample, away from
temporal tissue, as well as anomalies in folding of the cortex in that region
(Leonard et al., 1993). This reduction in the size of the left planum is in contrast
to research, again in normal experimental animals, showing that symmetry, as
compared to asymmetry, reflects bilaterally large symmetrical regions rather than
bilaterally small symmetrical regions (Galaburda et al., 1987) and relatively
excessive numbers of neurons (Galaburda et al., 1986) and interhemispheric
connections (Rosen et al., 1989; Witelson, 1985). However, as seen in the mice
with ectopias, the normal interaction between asymmetry and size no longer exists
in the latter (see above), and this may explain why different imaging studies find
different effects on the planum temporale. Another explanation, and this is this
author’s experience, is that different investigators use somewhat different criteria
and methods for outlining the planum temporale (Galaburda, 1993).
Larsen and colleagues (Larsen, Hoien, Lundberg, & Odegaard, 1990) recon-
structed and measured the planum temporale in 19 eighth-grade dyslexics and
appropriate controls using MRI. In the dyslexics 70% of the brains showed
symmetry of the planum, as compared to only 30% of the control sample. Among
the dyslexic subgroup exhibiting phonological deficits, 100% of the brains showed
absence of asymmetry of the planum, leading the authors to suggest that
asymmetry of the planum is necessary for normal phonological awareness.
Another MRI study examined neuroanatomical differences between dyslexics
and normals (Duara et al., 1991). This study found that a brain segment lying
anterior to the occipital pole was larger on the right in dyslexics but not in
controls. Relative area measurements of the midsagittal corpus callosum (CC)
showed that female dyslexics had the largest CC, followed by male dyslexics,
followed in turn by normal readers. The splenium of the callosum was also largest
in female dyslexics, followed by male dyslexics, followed by normal males,
followed by normal females. None of the brain segments corresponded to the
planum temporale of other studies, so comparisons were not possible. The
splenium contains fibers from the posterior temporal and parietal cortices, which
participate in language functions. Moreover, this report, too, supports the notion
that alterations in the CC may be characteristic of dyslexic brains and may
underlie, in part, their reading difficulties.
There have been several functional tomographic studies using positron emis-
sion tomography (PET) (Hagman et al., 1992; Rumsey et al., 1992). Rumsey and
colleagues (1992) demonstrated anomalies in cerebral blood flow in the left
temporoparietal region in dyslexic men - an area important for language.
Some studies have found increased left-handedness in dyslexics and increased
dyslexia in left-handers (Geschwind & Behan, 1982; Schachter, Ransil, &
Geschwind, 1987). and left-handcrs, like dyslexics, often show aberrant patterns
of brain asymmetry (LeMay, 1977). A recent study (Steinmetz, Volkmann.
Jancke. & Freund, lYY1) confirmed this finding in MRI scans. The authors
reconstructed and measured the planum temporale in 52 normal subjects - 26
right-handers and 26 left-handers - and found that left-handers had a lesser
degree of leftward planum asymmetry than right-handers. This study produced
particularly accurate reconstructions of the planum temporale from MRI scans.
which corresponded most closely to studies done directly on post-mortem
material.

3. Neurophysiological studies

Altered brain potentials have been described in dyslexics. One recent study
(Landwchrmeyer. Gerling, & Wallesch. 1990) looked at auditory potentials
evoked by a variety of linguistic and non-linguistic stimuli in dyslexics and
non-dyslexics. Both groups showed increased right hemisphere surface negativity
in a non-linguistic stimulus. Unlike normal readers, however. dyslexics failed to
show increased left hemisphere negativity to linguistic stimuli, but instead showed
increased right hemisphere negativity. thus suggesting that linguistic stimuli are
treated in part as non-linguistic stimuli by this group. Another study (Chayo-
Dichy, Ostrosky-Solis. Meneses. Harmony, & Guevara, 1990) looked at contin-
gent negative variation (CNV), or expectancy wave. The resolution of this wave
is called the postimperative negative variation (PINV). Both amplitude and
latency differences at a left parietal site were documented in the PINV and
amplitude differences in the CNV in a sample of nine right-handed preadolescent
boys, as compared to matched controls. This suggested to the authors that
significant differences existed in expectancy, attention and brain activity signal
processing. A third study (Stelmack & Miles. lY90) found that disabled readers
seemed to have a failure to engage long-term semantic memory, as demonstrated
by their N400 responses to visually presented primed and unprimed words. These
are the waves occurring at 400 ms from the stimulus onset and presumably reflect
activity in cognitively related cortex. These results, combined, indicate that
physiological differences exist between dyslexic and normal readers in cognitive
processing, particularly affecting linguistic categories. What is less well recognized
 A.M. Galaburda I Cognition M (1584) 1.13-149 139

is their difficulties at the more peripheral levels of sensory processing and

perception.
The flicker fusion rate, which is the fastest rate at which a contrast reversal of a
stimulus can be seen, is abnormally slow in dyslexic children at low spatial
frequencies and low contrasts (Lovegrove, Garzia, & Nicholson, 1990). Another
evoked potentials study (Livingstone et al., 1991) reported visual findings in
dyslexics that can be attributed to perceptual anomalies and do not therefore
primarily implicate language dysfunction. Flickering checkerboard patterns were
presented to dyslexics and non-dyslexics at different contrasts and rates, and the
transient and sustained visual evoked potentials were recorded. The parvocellular
pathway, which is slow, relatively contrast insensitive, and color selective,
appeared to function normally in the dyslexic group. On the other hand, the
dyslexics showed abnormalities when fast, low-contrast stimuli were presented.
These stimuli are handled by the magnocellular pathway of the visual system,
which is segregated already in the retina and continues to be separate through the
lateral geniculate nucleus (LGN), the primary visual cortex (Vl) and higher-
order visual cortices (Livingstone & Hubel, 1988). On the other hand, there is an
ongoing debate as to the extent to which the two subsystems remain segregated,
beginning even in Vl, and whether the separation changes in character altogether
(Ferrera, Nealey, & Maunsell, 1992; Lachica, Beck, & Casagrande, 1993).
The timing of the physiological abnormality in the dyslexics suggested a
magnocellular deficit early in the pathway, implicating the retina, the LGN
and/or Vl, none of which is currently thought to mediate cognitive functions.
Moreover, in the same study, the neurons present in the magno- and parvocellu-
lar layers of the LGN were measured in five dyslexic and five control brains, and
it was found that the magno cells only were smaller in the dyslexic group, thus
complementing the physiological findings of a slowed magnocellular system. The
parvo cells were not changed in size, but in some specimens both magno and
parvo layers displayed disorganization of their architecture. Earlier evidence
suggested a similar defect in fast auditory processing (Tallal & Piercy, 1973) and
proposed that fast processing may be abnormal in several modalities, including
the visual and auditory, and that such abnormalities may interfere with auditory
and visual language acquisition and efficient language processing at loci where fast
processing is required for extraction of meaning. Williams and Lecluyse (1990)
have taken advantage of this possibility and have showed that image blurring,
which reduces the contrast of high spatial frequencies, is capable of re-establishing
normal temporal processing of words in disabled readers.
We have also found preliminary evidence that the types of anatomical
abnormalities described in the visual thalamus may extend to the auditory
thalamus as well. We have measured the cell bodies of representative regions of
the medial geniculate nuclei of dyslexic and control brains and have found that
there is a shift in the former toward smaller neurons, especially affecting the left
140 A.M. Galaburda I Cognition 50 (1994) I.%-I49

hemisphere (Galaburda & Livingstone. 1993). Such a shift may reflect a

corruption of a hitherto not well-understood large-celled system, and lesser
differences between this large-celled system and a slower small-celled system,
which could again produce difficulties in the processing of rapidly changing
auditory information (Tallal & Piercy, 1973).
It is not possible to state at this stage in the research program whether the
functional deficits demonstrated early on in the pathway, associated with ana-
tomical changes also relatively close to the sensory organs, represent a primary
failure or the result of changes that have begun downstream and have propagated
toward the periphery (as well as further downstream). Although all possibilities
are predicted from current notions of developmental plasticity, animal models are
being developed in our laboratory to study this question specifically vis-&vis the
relationship between cortical anomalies and changes in the thalamus - which
came first‘?

4. Behavioral studies in animals with anomalous cortex

As indicated above, NZB and BXSB mice are being used as an animal model
of cortical malformations associated with the human dyslexic condition (Denen-
berg, Mobraaten et al., 1991; Denenberg, et al., 1992; Denenberg, Sherman,
Schrott, Rosen, & Galaburda, 1991; Sherman et al., 1987). Because dyslexia is a
specific learning disorder and may be accompanied by enhancement of certain
abilities (Geschwind & Galaburda, 1985a, 1985b, 1985c), the use of a behavioral
battery is crucial. The battery of behavioral tasks that we have administered
includes four measures of learning (discrimination, spatial, complex maze and
avoidance learning), as well as tests of lateralization and activity. A priori any
behavioral abnormalities demonstrated in the immune-defective mice could be
attributed either to the presence of cortical malformations, the existence of
abnormalities in immune function making the animal sick, or to a combination of
both. We have been able to separate the behavioral deficits into two types:
ectopia-associated behaviors; and autoimmune-related behavior.

4.1. Ectopia-associated behaviors

In working with inbred strains, one of the most difficult problems encountered
is the choice of an appropriate control group. Comparing across inbred strains is
risky, since behaviors are known to be influenced by the vastly different genetics
of each strain. Therefore, within-strain comparisons were used to examine the
behavior of NZB and BXSB mice. In the investigation of ectopia-associated
behaviors, this was easily accomplished since 40-50% of NZB and BXSB mice
 A.M. Galaburda I Cognition 50 (1994) 133-149 141

develop ectopias. Three measures in the behavioral battery were found to be

sensitive to the presence of ectopias: a non-spatial discrimination learning task,
and two spatial measures, -water escape and the Morris maze.
Ectopias depressed performance on discrimination learning. This test utilized a
two-arm swimming T-maze, with a grey stem, and a black and a white alley. An
escape ladder hung at the end of the alley designated to be positive (Wimer 8.~
Weller, 1965). Reinforcement consisted of escape from the water plus being
placed in a dry box beneath a heat-lamp. The left-right location of the positive
stimulus was altered in a semi-random sequence, so the animals had to use an
associative, rather than spatial or positional strategy, to solve the task. Measures
included number of correct choices and time to reach the escape ladder. Mice
received 10 trials for 5 days (Denenberg, Talgo, Schrott, & Kenner, 1990). In this
task, NZB mice with ectopias made fewer correct choices and took longer to find
the escape ladder over the first 4 days of testing, but caught up by day 5. In
ectopic NZB mice, a significant improvement in both performance measures was
seen if they were reared in an enriched environment as compared to standard
cages. No such effects were seen in non-ectopic mice (Schrott, Denenberg,
Sherman, Waters, Rosen, & Galaburda, 1992).
A similar pattern of behavior is seen in the Morris maze. This is a complex
spatial task requiring the animal to find a hidden escape platform using extra-
maze cues. The starting point varies from one of four locations in a semi-random
sequence. Time and distance to reach the escape platform were measured. In
addition, the maze is divided into four quadrants and three annuli and the
percentage of time spent in each portion was also measured. Mice received 4 trials
a day for 5 days (Denenberg et al., 1990). Ectopic NZB mice were slower to find
the escape platform and spent more time in the outermost annulus of the maze,
reflecting a different pattern of learning than NZB mice without ectopias. Rearing
in an enriched environment, however, was able to compensate for the deficit in
ectopic mice. Enriched ectopic NZB mice had similar performance to their
enriched non-ectopic littermates (Schrott, Denenberg, Sherman, Waters, et al.
1992). This is in itself interesting, since it supports the notion that focal brain
injury early on can be, at least in part, compensated for in the presence of
alternative strategies available in enriched early environments.
The presence of ectopias also interacts with an animal’s paw preference. On
the discrimination learning task, right-pawed BXSB male mice had better
performance than their left-pawed ectopic littermates. The opposite relationship
was seen for the spatial water escape task. In this task an animal was placed in
one end of an oval tub and had to swim to find a hidden escape platform at the
other end using extra-maze spatial cues. The mice received 5 trials on a single day
of testing and time to reach the platform was recorded. For water escape learning,
left-pawed NZB males and females and BXSB males had faster times than their
right-pawed counterparts. No paw preference effects were seen in non-ectopic
 142 A.M. Gulahurdu I Cognition A) (1994) 133-149

mice of either strain (Denenberg, Talgo, Carroll, Freter, & Deni, 1991). Again
this is interesting in the light of claims that dyslexics are more likely than
non-dyslexics to be left-handed (Geschwind & Behan, 1982), thus suggesting that
ectopias could have more or less severe functional consequences according to
laterality.
The behavioral consequences of ectopia presence are task-specific. No main
ectopia effects are seen for measures of lateralization, activity, the Lashley maze
or avoidance conditioning. Ectopic mice are capable of learning, but often at a
slower rate or with poorer scores. In addition, ectopias interact with other
variables, such as paw preference and environmental enrichment. Across numer-
ous studies it has been found that the presence of an ectopia, rather than its
architectonic location, hemisphere or size, is the crucial characteristic for these
associations. Most likely this is because the damage from an ectopia is more
widespread than the focal lesion itself. The disruption of underlying fiber
architecture, alterations in neuronal circuitry and neurotransmitter abnormalities
that accompany an ectopia reflect a brain that has developed abnormally
(Sherman, Morrison, Rosen, Behan, & Galaburda, 1990; Sherman, Rosen,
Stone, Press, & Galaburda, 1992; Sherman, Stone, Press, Rosen, & Galaburda,
1990; Sherman, Stone, Rosen, & Galaburda, 1990). Whether the learning deficits
are a direct consequence of the ectopia or whether an ectopia is a marker for
aberrant development in general, with concomitant learning deficits, is not known
at present.

4.2. Autoimmune-related behavior

It should be remembered that ectopias arise from influences on brain develop-

ment taking place as early as the 13th embryonic day, and that subsequently with
increasing age many mice with or without ectopias acquire autoimmune disease
consisting of humoral and cell-mediated injury to many organs other than the
brain. In fact, after formation of the blood-brain barrier soon after birth, the
brain is relatively protected from autoimmunity. On the other hand, metabolic
changes arising from failure of organs such as the kidneys and liver, which are
often involved in autoimmunity, could cross the blood-brain barrier and in-
directly affect brain function.
Poor performance in active and passive avoidance conditioning has been
consistently associated with autoimmune mice (Denenberg, Mobraaten et al.,
1991; Denenberg et al., 1992; Forster, Retz, & Lal, 1988; Nandy, Lal, Bennet, &
Bennett, 1983; Schrott, Denenberg, Sherman, Waters et al., 1992; Spencer.
Humphries, Mathis, & Lal, 1986). In the present set of studies avoidance
conditioning was conducted in a two-way shuttlebox. The box was separated into
two compartments by a divider. Five seconds of a pulsed light served as the
 A.M. Galaburda I Cognition 50 (1994) 133-149 143

conditioned stimulus, while up to 20 s of 0.4 mA footshock acted as the

unconditioned stimulus. The number of avoidances, escapes (and the time to
make them), as well as null responses were recorded. The most striking
characteristic of NZB and BXSB mice is their very poor performance. Escape
from the shock is their preferential response, with few avoidances made. It is
interesting to note that failure to avoid or escape the shock (a null response) is not
extinguished rapidly, as would typically be found in an animal learning this task.
Instead, null responses and the latency to escape often increased across days.
This response pattern is associated with a high degree of autoimmunity (the
more autoimmune a mouse, the poorer the avoidance performance). The negative
relationship between these two variables was more difficult to establish than the
relationships between ectopias and behavior because of the lack of a proper
control. Comparing avoidance performance across strains (an autoimmune strain
vs. a strain with normal immune functioning) is problematic because an avoidance
difference could result from any number of genetic differences unrelated to
immune functioning. Comparing avoidance performance within a strain was not
possible, because all mice within a strain develop an autoimmune condition and
there is insufficient variability in avoidance performance (all mice have poor
performance). This difficulty was solved in a rather complicated way. A set of
embryo transfer studies permitted comparison of genetically identical mice who
differed with regard to their immune status, as a function of the uterine
environment in which they were raised. Transfer of a non-autoimmune DBA
embryo to an autoimmune BXSB maternal host induced autoimmune disease in
the adult animal, as well as impaired avoidance performance. Conversely, when
the severity of the disease was reduced by transferring an NZB embryo to a
non-autoimmune hybrid mother, avoidance performance was improved
(Denenberg, Mobraaten et al., 1991).
Further support for this association was provided by a study with BXSB-DBA
reciprocal hybrids. The hybrid offspring were autosomally identical but differed in
degrees of immune reactivity. The DBA x BXSB cross yielded offspring with
greater immune reactivity and poorer avoidance performance than the BXSB X
DBA cross (Denenberg et al., 1992). Finally, in a group of genetically related
mice - NXRF recombinant inbred lines-the line with the greatest degree of
autoimmunity had the poorest avoidance performance (Schrott, personal com-
munication). Thus, in four groups of mice with vastly different rearing histories,
the degree of autoimmunity was negatively related to performance on an active
avoidance conditioning task.
The degree of autoimmunity was not associated with any of the other tasks in
the behavioral battery. Environmental enrichment had no effect on avoidance
learning, nor were any ectopia interactions present (Denenberg, Mobraaten et
al., 1991; Denenberg et al., 1992; Schrott, Denenberg, Sherman, Waters et al.,
1992). In addition, pharmacological manipulations including cholinomimetics,
144 A.M. Galahurda I Cognition SO (1994) 13.1-149

nootropics and antidepressants failed to improve performance (Schrott, Denen-

berg, Sherman, Waters et al., 1992). Although the negative neuroanatomical and
neurochemical findings cannot conclusively prove that immune dysregulation
mediates active avoidance deficits in autoimmune mice, they are consistent with
this hypothesis. Possible immune mechanisms include (1) immune complex
deposition on brain membranes and subsequent alterations in the permeability of
the blood-brain barrier, (2) effects of circulating autoantibodies or other
autoimmune factors, (3) cytokine effects, (4) altered stress responses and/or
hormonal interactions, and (5) developmental aspects. These possible mecha-
nisms are by no means mutually exclusive.

4.3. Other behaviors

One behavior that does not fit into either of these categories is the Lashley
maze - a complex maze which can be solved using spatial and/or associative
learning strategies. BXSB mice have excellent performance on this task, while
NZB have great difficulty learning it, even when given additional trials and cues
(Schrott, Denenberg, Sherman, Rosen, 81 Galaburda, 1992). NZB mice are
known to have abnormalities of the hippocampus, including the formation of
ectopias and a small infrapyramidal mossy fiber tract system (Anstatt, 1988; Fink,
Zilles, & Schleicher, 1991; Nowakowski, 1988). These abnormalities are not seen
in BXSB mice (Sherman et al., unpublished data) and may account for the poor
performance of NZBs in the Lashley maze. In addition, NZB mice have a low
incidence of callosal agenesis (approximately 7%). Certain recombinant inbred
lines with NZB as one of the progenitors develop a higher incidence of callosal
agenesis, and this abnormality affects spatial learning (Schrott, personal com-
munication).

4.4. Temporal processing in rats

Language-impaired individuals exhibit severe deficits in the discrimination of

rapidly presented auditory stimuli, including phonological and non-verbal stimuli
(i.e., sequential tones; (Tallal, 1984; Tallal & Piercy, 1973); Fig. 1). In an effort
to relate these results, male rats with neonatally induced focal malformation of
the cortex (the resultant malformation is similar to one of the forms found in
dyslexic brains (Humphreys, Rosen, Press, Sherman, & Galaburda, 1991)) were
tested in an operant paradigm for auditory discrimination of stimuli consisting of
two sequential tones. Subjects were shaped to perform a go-no-go target
identification, using water reinforcement. Stimuli were reduced in duration from
750 to 375 ms across 24 days of testing. Results showed that all rats were able to
 A.M. Galaburda I Cognition 50 (1994) 133-149 145

pasuq
xapq uogeupupx~a
 146 A.M. Galaburda I Cognition .50 (19944) 133-149

discriminate at longer stimulus durations. However, bilaterally lesioned rats

showed specific impairment at stimulus durations of 400 ms or less. and were
significantly depressed in comparison to shams. Right- and left-lesioned subjects
were significantly depressed in comparison to shams at the shortest duration
(250 ms; Fig. 1). Interestingly, the neonatal lesion did not substantially involve
the auditory pathways, thus suggesting that any nearby lesion may propagate
along connectionally related areas to result in changes in those areas incompatible
with normal temporal processing capacity. The experiments could not address the
question of whether the cortical lesion propagates upstream and results in
temporal processing anomalies early in the process, or whether all the results
could be explained by late slowing. These questions arc, however, undergoing
further experimental investigation.

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