NEUROBIOLOGIA 68 (1): Jan-Mar; 2005
NEUROBIOLOGIA 2005 - Memories and perspectives section:
The legacy of Norman Geschwind’s ideas about handedness,
brain symmetry, language and neuropsychiatric disorders
O legado de Norman Geschwind sobre dominância manual,
simetria cerebral, linguagem, e nas doenças neuropsiquiátricas
Recently, Dr. Catani from the Psychiatry Institute
of the King’s College – London , reported a third region
of the brain associated with language, and composed
by an anterior segment connecting the Broca’s area
with the inferior parietal lobe and a posterior segment
connecting the inferior parietal lobe to Wernicke’s area.
This region was named as “Geschwind’s territory”.
Dr. Norman Geschwind (1926-1984), often
remembered as a brilliant and extraordinary American
neurologist, changed the notion of the dichotomy
between right and left-handers, suggesting that
handedness was a continuum. He was the first to
conclusively confirm the anatomical basis of language
laterality in a seminal paper published in Science in
1968. Later his ideas evolved to the point that he,
together with other colleagues, including Dr. António
Damásio and Dr. Albert Galaburda, could infer that those
hand skills were also related to language and various
other cognitive aspects of the human brain. More recently,
the use of various molecular, neuroimaging, and cognitive-
behavioral approaches have allowed us to explore his
legacy of ideas using several modern models and
paradigms (Geschwind, 1999).
The Geschwind-Galaburda theories have been
also widely used to understand the neurological
background of skills performance in human subjects,
such as Gifted children (Winner, 1996). They noticed
that individuals with right-hemisphere abilities (this would
include the spatial domains of math, music and art)
tended to be non-right handed. He theorized that the
association between right-hemisphere (spatial) gifts, left-
hemisphere (linguistic) deficits, and non-right
handedness and immune disorders, such as asthma
and allergies, was due to the effect of the hormone
testosterone, which altered the organization of the
developing fetal brain. Some of these individuals had a
higher frequency of linguistic deficits including dyslexia,
stuttering, delayed language acquisition and autism,
which is associated with impaired language and immune
system disorders, due to a precocious exposure of the
thymus gland to testosterone. Elevated testosterone in
utero inhibits growth in certain posterior areas of the left
hemisphere. Thus, a delay in the posterior left
hemisphere (relevant to language) could lead to growth
in areas nearby (related to calculation ability) and to
parallel right-hemisphere area (related to spatial and
musical abilities).
The current analysis of heritability of lobar brain
volumes in twins supports genetic models of cerebral
laterality and handedness (Geschwind, 2001, 2002).
Genetic factors contributed twice the influence to left
and right hemispheric volumes in right-handed twin pairs,
suggesting a large decrement in genetic control of
cerebral volumes in the nonright-handed twin pairs. This
loss of genetic determination of the left and right cerebral
hemispheres in the nonright-handed twin pairs is
consistent with models postulating a right hand/left-
hemisphere-biasing genetic influence, a “right-shift”
genotype that is a lost in nonright handers, resulting in
decreased cerebral asymmetry. This was a model
supported by Geschwind and Galaburda in the seminal
two part manuscript on the biological basis of laterality
published in 1985 in Archives of Neurology.
Klinefelter’s syndrome, for example, caused by
the presence of one (47, XXX) or more extra X-
chromosomes, is a model of anomalous cerebral
laterality, associated with decreased testosterone
production, impaired spermatogenesis, small testis and
gynecomasthia (Geschwind D 1998a,b; Boone, 2001; Itti
E, 2003; Simpson, 2003; Fales, 2003 ). Analysis of
cerebral asymmetry through the use of microarray
expression studies have allowed us to identify the most
relevant panel of genes expressed at the different regions/
sides of the brain (Geschwind, 1998,Luo,2001).
Understanding the factors that govern human
forebrain regionalization along the dorsal-ventral and left-
right axes is likely to be relevant to a wide variety of
neurodevelopmental and neuropsychiatric conditions.
Among these are the Wingless-Int (WNT) proteins,
involved in the formation of dorsal central nervous system
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(CNS) structures, as well as in visceral left-right asymmetry (Abu-Khalil A, 2003).

Temporolimbic epilepsy (TLE) and behavior were also an area of Dr. Geschwind’s interest. Historically, the
term “Geschwind’s syndrome” was used for a group of broad neuropsychiatric features associated with TLE,
including exhilarated mood, bipolar disorder, irritability, tendency to self recrimination, obsessive-compulsive features,
mystical states, rage attacks, desire to punish offenders, stickiness, keeping extensive diaries, etc. (Mesulam,
2000). Today we know that many of those personality traits can also be seen in patients who suffer from other
neurological or psychiatric disorders, however, a new group of evidences suggest that neuronal migration disorder
at the limbic system might be behind the manifestation of mood symptoms (Oliveira, 2000).
Although his studies used to have an integrative approach, he also built some of his hypotheses based on
clinical reports of some classic cases, such as the patient “Earl” studied during the sixties. This patient had an
important resection at the left hemisphere, generated during a brain surgery, and later manifested as aphasia
associated with full conscience state, often using mimic and short exclamations to communicate and to express
his thoughts (Damasio, 1999).
Dr. Geschwind’s ideas have been in constant debate and the significant number of scientists that had the
privilege to work with him is the most important responsible for continuously pursuing, testing and perpetuating his
theories and work. His papers and books are continuously reprinted and since 1999 the American Society of
Neurology awards the Norman Geschwind Prize in Behavioral Neurology for outstanding research in the field of
Cognitive Neurology. Dr. Galaburda is currently the Landau Professor of Neurology at the Harvard Medical School.

Acknowledgments: This essay is written In memoriam of our dearest friend and collaborator,
Zheng Lou, MS (1969-2004). His work at the laboratory of Dr. Daniel Hal Geschwind (UCLA) was fundamental to
optimize and apply various techniques to study several aspects of brain asymmetry through the use of microarray
expression studies, In situ hybridization and “whole mount” hybridization. We thank Dr Daniel Geschwind, Dr and
Aaron Rowe for the helpful suggestions during the writing of this manuscript.

References:

Abu-Khalil A, Fu L, Grove EA, Zecevic N, Geschwind DH.Wnt genes define distinct boundaries in the developing
human brain: implications for human forebrain patterning.
Annett M. Hand preference observed in large healthy samples: classification, norms and interpretations of increased
non-right-handedness by the right shift theory.
Br J Psychol. 2004 Aug;95(Pt 3):339-53.

Boone KB, Swerdloff RS, Miller BL, Geschwind DH, Razani J, Lee A, Gonzalo IG, Haddal A, Rankin K, Lu P, Paul
L. Neuropsychological profiles of adults with Klinefelter syndrome. J Int Neuropsychol Soc. (2001) 7(4):446-56.

Damasio A. The feeling of what happens-Body and emotion in the making of consciousness (1999).

Fales CL, Knowlton BJ, Holyoak KJ, Geschwind DH, Swerdloff RS, Gonzalo IG. Working memory and relational
reasoning in Klinefelter syndrome.

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J Int Neuropsychol Soc. 2003 ;9(6):839-46.

Geschwind DH, Boone KB, Miller BL, Swerdloff RS. Neurobehavioral phenotype of Klinefelter syndrome.
Ment Retard Dev Disabil Res Rev. 2000;6(2):107-16.

Geschwind DH, Gregg J, Boone K, et al (1998). Klinefelter’s syndrome as a model of anomalous cerebral laterality:
Testing gene dosage in the X chromosome pseudoautosomal region using a DNA microarray . Developmental
Genetics 23:215-229.

Geschwind DH, Gregg J, Boone K, Karrim J, Pawlikowska-Haddal A, Rao E, Ellison J, Ciccodicola A, D’Urso M,
Woods R, Rappold GA, Swerdloff R, Nelson SF. Klinefelter’s syndrome as a model of anomalous cerebral laterality:
testing gene dosage in the X chromosome pseudoautosomal region using a DNA microarray.
Dev Genet. 1998;23(3):215-29.

Geschwind DH, Iacoboni M. Structural and functional asymmetries of the frontal lobes. In Miller BL, Cummings JL
(eds), The Frontal Lobes. New York: Guilford Publications, 1999, pp 45-70.

Geschwind DH, Miller BL (2001). Molecular approaches to cerebral laterality: Development and neurodegeneration.
American Journal of Medical Genetics 101:370-381.
Geschwind DH, Miller BL, DeCarli C, Carmelli D (2002). Heritability of lobar brain volumes in twins supports
genetic models of cerebral laterality and handedness. Proceedings of the National Academy of Sciences USA
99:3176-3181.

Geschwind N, Galaburda AM. Cerebral lateralization. Biological mechanisms, associations, and pathology: III. A
hypothesis and a program for research.
Arch Neurol. 1985 Jul;42(7):634-54

Geschwind N, Galaburda AM. Cerebral lateralization. Biological mechanisms, associations, and pathology: II. A
hypothesis and a program for research.
Arch Neurol. 1985 Jun;42(6):521-52.

Geschwind N, Galaburda AM.Cerebral lateralization. Biological mechanisms, associations, and pathology: I. A

hypothesis and a program for research.
Arch Neurol. 1985 May;42(5):428-59.

Geschwind N, Levitsky W. Human brain: left-right asymmetries in temporal speech region.

Science. 1968 ;161(837):186-7.
J Comp Neurol 2004; 474(2): 276-88.

Luo Z, Geschwind DH (2001). Microarray applications in neuroscience. Neurobiol Dis 8(2):183-93.

Mesulam MM. Principles of behavioral and cognitive neurology. 2nd (2000), Oxford University Press.

Oliveira JRM. (2000) News about disturbances of neuronal migration bring views to bipolar disorder. Molecular
Psychiatry 5: 462-464.

Simpson JL, de la Cruz F, Swerdloff RS, Samango-Sprouse C, Skakkebaek NE, Graham JM Jr, Hassold T,
Aylstock M, Meyer-Bahlburg HF, Willard HF, Hall JG, Salameh W, Boone K, Staessen C, Geschwind D, Giedd J,
Dobs AS, Rogol A, Brinton B, Paulsen CA. Klinefelter syndrome: expanding the phenotype and identifying new
research directions. Genet Med. 2003 Nov-Dec;5(6):460-8.

Winner E. Gifted children: Myths and realities. Basic books. 1996