Current Drug Targets - CNS & Neurological Disorders, 2003, 2, 357-362 Exploring Genetic Influences on Cognition: Emerging Strategies for Target Validation and Treatment Optimization
John A. Fossella*, Sonia Bishop and B.J. Casey
The Sackler Institute for Developmental Psychobiology, Weill Medical College Cornell University, 1300 York Ave,New York, NY 10021, USAAbstract: Genomic research has produced an abundance of new candidate targets that remain to be validated as potential treatments for neuropsychiatric disorders. Functional neuroimaging, meanwhile, has provided detailed new insights into the neural circuits involved in emotional and cognitive control. At the growing interface between these independent lines of progress, new efforts are underway to unify our understanding of regional brain function with that of genetic and biochemical influences on behavior. Such a unified understanding of the mechanisms involved in cognitive and emotional control may open up new avenues for therapeutic intervention at the pharmacological and behavioral levels. In line with this, a new initiative sponsored by the National Institutes of Mental Health (NIMH) aims to bridge gaps between clinical diagnostics and the molecular processes that influence susceptibility to psychiatric disorders . A major goal of this initiative is to identify the neural and neurochemical substrates of basic cognitive processes that are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level. This review describes some well-known findings that are at the forefront of this interface. The progress already made indicates that the goals of the new initiative are well founded and achievable. Keywords: Genetics; Attention; Cognition; Neuroimaging; Pharmacogenetics; Psychopathology INTRODUCTION
measures of cognitive and neural function that may serve asendpoints and surrogate outcome measures in clinical trials.
The neural and neuroendocrine circuits that underlie
These measures must meet three important criteria: i) they
normal and abnormal behavior are widely distributed
must reflect a process disruption of which is central to the
throughout the brain and body. The distributed nature of
given disorder (ii) the process must be thought to have a
these circuits and their complex modulation of neural
strong genetic compenent and (iii) the measures must show
function presents obstacles to the development of drug
good test-retest reliability.The goal of this article is to
therapies aimed at remediating specific aspects of cognitive
summarize some of the notable progress associated with this
or emotional regulation. To further complicate new therapy
initiative and point out the future potential and limitations
development, the diagnostic criteria and clinically relevant
of the integration of these methods in basic and clinical
treatment goals for psychiatric disorders are often vague,
heterogeneous and not easily correlated with any specificbiochemical marker or measure of neural activity. The
To illustrate how cognitive methods can bridge the gap
integration of cognitive paradigms with neuro-imaging
between the clinical setting and molecular biology, consider
through PET and fMRI has however begun to suggest a
the case of Schizophrenia. According to DSM IV, for a
number of candidate neural circuits that may be disrupted in
diagnosis of Schizophrenia to be reached an individual needs
disorders such as Schizophrenia [2-4], depression [5,6],
to show two or more of the following symptoms:-
obsessive-compulsive disorder [7-10], anxiety disorders ,
delusions, hallucinations, disorganised speech, disorganized
attention deficit hyperactivity disorder (ADHD) [12-15] and
or catatonic behavior and ‘negative’ symptoms (a reduction
autism . At the same time, long standing evidence
or loss in normal functions such as language or goal-directed
shows that these psychiatric disorders are heavily influenced
behavior). It is immediately apparent that this leaves room
by genetic factors [17-19]. Despite the large genetic
for a huge degree of heterogeneity amongst patients meeting
contribution, it has been difficult to identify individual
these diagnostic criteria. Indeed, it hardly seems surprising
genes that contribute to the risk of illness. This may reflect
that genetic markers for ‘Schizophrenia’ per se have not been
problems with the current symptom-based measures of
forthcoming. Furthermore, it raises the question of what we
disorder. As an alternative to symptom-based diagnostic
should expect such genetic markers to predict. Do we expect
criteria, a more successful approach may be to perform
a gene for ‘hallucinations’ or a gene for ‘disorganized
genetic studies using cognitive and neurophysiological
behavior’? Surely these vague concepts relate to underlying
‘endophenotypes’ . This approach has recently gained
processes, and it is these processes which are more directly
momentum and forms the basis of a new initiative
influenced by genetic factors. One candidate process (or
sponsored by the NIMH . The initiative aims to identify
arguably class of closely-related processes) is that of‘attentional control’ or ‘executive processing’.
Attentional difficulties have been repeatedly linked to
*Address correspondence to this author at the Sackler Institute forDevelopmental Psychobiology, Weill Medical College Cornell University,
Schizophrenia (see  for a review). Attentional deficits
1300 York Ave, New York, NY 10021, USA; Tel.: +212-746-5830; E-
have been objectively quantified using sensorimotor gating
, smooth pursuit eye-tracking , set-shifting ,
1568-007X/03 $41.00+.00 2003 Bentham Science Publishers Ltd. 358 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 Fossella et al.
inhibition  and working memory tasks .
relative cost make it attractive to the research and clinical
Furthermore, performance on attentional tasks has been
communities. Many studies have found differences in brain
shown to be influenced by genetic factors. For example, the
anatomy and activity for a variety of brain disorders
d' signal detection component of performance on the
including Schizophrenia , depression , anxiety
Continuous Performance Task (CPT) has a heritability
disorders  and ADHD . MRI-based measures of brain
among normal subjects of 0.49 (suggesting about one half of
anatomy are of interest since studies in rodents, nonhuman
the overall population variability is due to genetic variation)
primates and humans have established that genes are major
. The P/N ratio of the Spontaneous Selective Attention
determinants of overall brain size [43-44]. Whole brain
Task (SSAT) has also been shown to have an heritability
volume in monozygotic and dizygotic twin populations
among normal subjects of 0.41 . Beyond this, twin
show that individual variation in cortical structure is highly
studies using normal control twins show that spatial
heritable (h2 = 0.9) [45-46]. Functional magnetic resonance
working memory, divided attention, choice reaction time
imaging (fMRI) goes beyond the structural level to quantify
and selective attention , attentional set-shifting ,
activity of brain networks during discrete time intervals.
sensorimotor gating , smooth pursuit eye tracking 
Structural (MRI) and functional (fMRI) approaches can
and executive attention  are all underlain by inherited
complement the genetic and cognitive endophenotype aims
factors. In addition, neuroimaging studies have both revealed
of the new NIMH initiative. In the context of a fMRI study,
frontal cortical abnormalities in Schizophrenia  and
Egan and colleagues  showed that a methionine/valine
indicated that the prefrontal cortex is part of the neural
polymorphism in the catechol-O-methyl transferase gene
substrate of attentional control . Taken together, these
(COMT) correlated with both performance on a working
results clearly suggest that it could be beneficial to examine
memory task and associated levels of regional neural
the influence of genetic factors in Schizophrenia in relation
activity. Specifically, those subjects with the valine allele
to their impact on measures of attention/executive processing
showed worse performance and higher levels of brain
and on associated prefrontal cortical function. An example of
activation in the prefrontal cortex. The same valine allele
this is provided by the work of Egan et al.  which is
also accounts for a portion of the genetic risk towards
Schizophrenia. Thus, by assaying a cognitive processthought to be impaired in Schizophenia, insights linkinggenetic susceptibility to both functional neural anatomy and
Target Validation: at the Interface of Genomics and
psychiatric diagnostic status were possible. Clinical
development of compounds selective for the COMT enzyme
A number of lines of research have begun to exploit the
are underway and it is hoped that ‘cognitive endpoints’ will
advantages of an integrated cognitive, genetic and
prove useful in this process . In addition, the
neuroimaging approach. Positron emission tomography
relationship between the met/val polymorphism in the
(PET) is a well-established method for measuring specific
COMT gene and PFC activity during working memory
biochemical processes in the body over time and in 3-
performance may take us a step forward to understanding any
dimensions. Individual differences in radioligand binding are
impact of a COMT-based treatment upon clinical outcome
often observed. Two genes, the dopamine transporter (DAT)
and the dopamine D2 receptor (DRD2) contain genetic
Replications of such multi-tiered genetic and imaging
polymorphisms that have been associated with psychiatric
studies are poised to expand as the focus of interest in fMRI
illness [37-39]. DRD2 and DAT levels also can be probed
studies, population genetic association studies and clinical
using specific PET radioligands suitable for quantitative
treatment studies increasingly start to overlap. For example,
measures of ligand binding. The dopamine transporter carries
genetic polymorphisms in the serotonin transporter gene that
a polymorphic 40-basepair repeat that varies in length across
have been associated with emotional dimensions of
human populations. The ability of radioligand to bind to the
psychopathology such as anxiety , have also been the
transporter seems to be influenced by the number of repeats.
focus of fMRI studies . Similarly, polymorphisms in
For example, subjects homozygous for the 10-repeat allele
the BDNF gene have been examined in clinically diagnosed
showed significantly lower dopamine transporter binding
Schizophrenia , with performance on cognitive tasks
than carriers of the 9-repeat allele . These results may
involving episodic memory and with hippocampal activation
relate to the mechanisms of alcohol addiction since DAT
assessed via fMRI during a working memory task .
polymorphisms have been associated with the severity ofwithdrawl . Similarly, PET and genetic studies show
Electroencephalographic (EEG) and event related
that genetic polymorphisms in the DRD2 gene are associated
potential (ERP) measurements have also long been used to
with differences in DRD2 receptor levels . Since these
probe psychological, cognitive and neurophysiological
polymorphisms have been found to contribute to the risk of
processes in studies of mental illness and genetics. The
Schizophrenia and alcoholism , it is possible that
extensive literature, temporal specificity, ease and low cost
receptor levels are key mediators of disease risk and perhaps
make this approach ideal for validation strategies that exploit
valid targets for clinical development and diagnosis. It
cognitive endophenotypes. Although fewer single gene
would be desirable to extend such PET studies to all genes
association studies have been reported than for MRI-based
that have been implicated in mental illness, however, it is
studies, the basis for EEG and ERP endophenotypic assays
difficult to obtain safe and selective radioligands that bind to
is well substantiated. For example, in alcoholism, a
the ever-increasing numbers of candidate targets.
reduction in the P300 amplitude in patients and in firstdegree relatives has been studied . Additional family and
Magnetic resonance imaging (MRI) is a method whose
twin studies show that individual differences in the P300 are
safety, high spatial and good temporal resolution and
at least moderately heritable [53,54]. Another ERP
Exploring Genetic Influences on Cognition Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 359
component, the P50, has been used to study early sensory
tantalisingly suggestive about how genetic factors,
processing of paired stimuli in Schizophrenia .
impairments in cognitive mechanisms and altered
Impairment in the P50 is a reliable marker for Schizophrenia
neurochemical modulation of the prefrontal cortex may tie
and has been shown to be heritable . Polymorphisms in
together to explain at least one part of the puzzle that
the alpha 7-nicotinic cholinergic receptor were shown to
Schizophenia provides. They also indicate how functional
contribute to the susceptibility of the disorder and a
neuroimaging and genomics may be used in conjunction to
advance our understanding and treatment of psychiatricdisorders. Treatment Optimization: at the Interface of
Turning briefly to the issue of adverse side effects, a
Pharmacology, Functional Neuroimaging and Genomics
good example of the potential role of functional genomicshere is provided by research into tardive dyskinesia. This is
Integrating knowledge from molecular, functional
an involuntary movement disorder of the face and body, that
anatomic and clinical levels may not only provide insight
occurs in approximately 30% of patients treated with
into the mechanisms of psychopathology, but also yield
antipsychotic medications. Pharmacogenetic analysis of the
information that can be used to optimize treatment outcome.
DRD3 gene which encodes a dopamine receptor expressed
Experience with pharmacological therapies shows that there
abundantly motor control regions including the basal ganglia
is tremendous variation in how individual patients respond
and ventral putamen, show that a serine to glycine
to medication. Schizophrenia, for example, is one of the
substitution at amino acid 9 contributes to the overall risk of
most well-studied brain disorders and there is an extensive
tardive dyskinesia [67-69]. The risk is further compounded
literature on its pharmacologic treatment. One of the
by polymorphisms in the metabolic CYP1A2 gene. Patients
difficulties in the pharmacologic treatment of Schizophrenia
who carried the high risk alleles at both DRD3 and CYP1A2
is the consistent finding that approximately 20% of patients
showed the highest levels of tardive dyskinesia while those
do not respond to initial therapy, an additional 30% do not
with the low risk alleles showed the lowest levels of tardive
sustain a response to therapy and some 20% of patients
dyskinesia. These findings on adverse effects were further
experience adverse side effects that prevent further treatment
augmented by FDG-PET studies that found that patients
. While there are many possible reasons for this finding,
with the high risk alleles of DRD3 showed elevated levels of
including diagnostic and environmental heterogeneity, one
glucose metabolism. Together, these studies have deliniated
possible reason for the individual differences in the response
a sub-group of patients for whom antipsychotic medication
to medication may be genetic differences among patients.
Pharmacogenetic studies seek to identify specific types ofgenetic variation influencing the response that individual
Just as pharmacogenetics has opened up new avenues for
patients have to a particular medication. Many processes
treatment optimization, many groups have explored the
such as drug absorption, distribution and metabolism are
possibility that neuroimaging might provide information to
known to influence drug response and genes that correspond
optimize treatment response. Differences in brain structure
to these processes such as receptors, transporters and
and function between healthy controls and patients have been
metabolic enzyme have been explored in candidate gene
documented in disorders such as Schizophrenia [2, 4, 51]
studies. Surprisingly, the predisposition to respond or not
depression , ADHD  and anxiety [11,71]. Subsequent
respond can be accounted for by variation in relatively few
studies have examined whether these structural and
genes. So-called ‘extensive metabolizers’ and ‘poor
functional differences are normalized in response to
metabolizers’ of at least 40 drugs can be distinguished by
pharmacologic treatment. For example, in Schizophrenia,
polymorphisms in the cytochrome P450 enzyme CYP2D6
there are many findings of structural abnormalities such as
[57-58]. Other P450 genes such as CYP2C19, CYP2C9,
reduced grey matter, reduced thalamus volume and increased
CYP2E1 and CYP2A6 as well as the glutathione S-
ventricle size, as well as functional abnormalities such as
low blood flow in the frontal cortex . Investigations of
acetyltransferase gene NAT2 have been shown to influence
whether any of these abnormalities can be reversed or
the metabolism of various medications. Variations in
partially reversed after treatment with antipsychotic
CYP2D6, for example, influence the toxicity of tricyclic
medication consistently find is an increase in blood flow in
antidepressants  and the breakdown of haloperidol .
the basal ganglia [72-75]. The basal ganglia shows a
The molecular genetic influences on metabolism are
structural response to treatment that is dependent on the
supported by twin and family investigations of the
class of antipsychotic medication given. Treatment with
heritability of medication response [61-63]. As an example,
typical antipsychotics such as haloperidol (DRD2
consider that only 30-60% of patients who are resistant to
antagonist) may increase the volume of the caudate nucleus
typical antipsychotics show a response to clozapine. Genetic
while atypical antipsychotics such as clozapine (mixed
polymorphisms in the serotonin system may mediate
DRD2, 5HT2A antagonist) show either no change or a
clozapine response . PET studies have shown that
reversal of the previous volume increase [4,76]. In addition,
polymorphisms in the dopamine D1 receptor (DRD1) gene
the atypical medication risperidone did not affect blood flow
influence baseline metabolic activity in the dorsolateral
in the basal ganglia, while the typical medication led to
frontal cortex in response to clozapine treatment [65, 66].
increased blood flow in the basal ganglia . These
These polymorphisms showed significant associations with
structural and functional differences may be related to
changes in attention and working memory; two cognitive
differences in improvement in positive and negative
functions that are disrupted in Schizophrenia  and which
symptoms and cognitive impairments [78,79] thus
are thought to, at least in part, be dependent upon prefrontal
providing a basis for the optimization of treatment using
cortical function. Taken together, these findings are
neuroimaging. Ideally, these studies need to be
360 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 Fossella et al.
complemented by additional work integrating
Still many regulatory and economic challenges, beyond
pschyopharmacological techniques with fMRI studies using
the scope of this review, remain. The vast economic
cognitive paradigms focusing on different aspects of
resources expended in meeting regulatory standards for safety
attentional control / executive function. Through integration
and efficacy pose a barrier to the widespread implementation
of genetic analysis, psychopharmacological studies, and both
of more advanced cognitive and genomic approaches. The
structural and functional neuroimaging techniques, together
large sample sizes needed for genetic studies and the
with careful specification of outcome endpoints in terms of
accompanying investment in genotyping and neuroimaging
symptom subsets and/or specific cognitive functions, we can
technology will be costly. The increased specificity of
hope to make greater progress in both understanding and
medicines that are custom tailored by genotype and brain
treating such heterogenous diagnostic entities as
structure/activity will fragment patient markets and conflict
with the current ‘one size fits all’ or ‘blockbuster’ drug
There is also a high degree of heterogenity within groups
development model. Even if small, genetically defined
of individuals meeting diagnostic criteria for ADHD. This
clinical trials gain FDA approval, it is not clear whether the
condition provides a second example of the attempt to
cost of development, though cheaper, will be offset by sales
improve treatment with the aid of genetics and neuro-
to a smaller, anatomically and genetically defined patient
imaging studies. Structural MRI studies on ADHD
populations. These worries however, may be overstated. The
consistently show reduced caudate nucleus volumes
Orphan Drug Act, passed by Congress in 1983 offers many
[12,13,70]. In addition, performance on cognitive tasks
financial incentives for medication development for diseases
designed to measure inhibitory control and activate the
that affect less than 200,000 people . Incentives for
frontal cortex and basal ganglia have shown that caudate
treatments that affect small, genetically fragmented
volume can be an accurate predictor of performance [25,80].
populations have been proposed . The most successful
Furthermore, this structural MRI phenotype also predicts
example of a personalized medicine is Herceptin a
response to treatment. Filipek et al.,  found that subjects
treatment designed against a specific form of breast cancer.
with smaller and more symmetrical caudate nuclei showed a
This treatment was designed based on the finding that about
more favorable response to treatment with stimulant
25% of breast cancer patients overexpress HER-2, a cell
medication. The Multimodality Treatment of ADHD (MTA)
surface marker involved in tumor growth . Genetech Inc.
project  carries out cognitive, genetic, structural and
first developed a diagnostic test to determine that HER-2
functional imaging work in various treatment groups in an
status among patients and then carried out clinical trial
effort to better understand the underlying mechanisms of
among women preselected for their HER-2 status. These
ADHD and to develop improved methods for treatment
studies, carried out from 1994 -1996 demonstrated the
optimization. Swanson et al.,  has suggested that at
clinical efficacy of the treatment in a population of patients
least two treatment groups exist in ADHD, one characterized
. Much like the current NIMH initiative hopes to ensure,
by genetic abnormalities and the other characterized by brain
FDA approval of Herceptin was based on newly approved
structure abnormalities that might respond differentially to
surrogate endpoints related to tumor shrinkage that set a
behavioral vs. medication therapy. The development of
more specific threshold of efficacy. Currently, annual sales
additional projects along these lines targeted at other
of Herceptin have vastly surpassed initial expectations and
psychiatric illnesses may well lead to similar advances in
validated the 'genetically-based' personalized medicine
our understanding of Depression, Generalised Anxiety and
strategy. The development of this compound was supported
other vitally important, common, and debilitating but yet
by personalized diagnostic tests and continues to be
remarkably poorly understood conditions.
developed through the use of functional imaging studies. FUTURE PERSPECTIVES
In summary, genomic research has produced an
abundance of new target molecules for the treatment of brain
The confluence of information relating behavior with
disorders in parallel with functional neuroimaging studies
functional anatomy, physiology and molecular biology has
providing insights into neural circuits involved in behavior.
contributed to a more comprehensive understanding the
With this progress, new efforts are underway to unify the
pathogenesis of brain disorders. Many factors bode well for
understanding of functional brain anatomy with
future progress in treatment development. Firstly,
physiological, cellular and molecular processes that influence
pharmacogenetics has already been used to optimize
behavior. In this way, cognitive neuroscience is being
treatment regimens for chemotherapy , peptic ulcer
viewed as an important intermediate step between bridging
treatment , hypertension , asthma  and anti-
cellular neurophysiology and clinical psychiatry. This review
retroviral therapy for HIV  and should be easily adapted
has described some well-known findings that bridge this gap
to psychopharmacology. Secondly, the NIMH has
based on cognitive neuroscience, functional neuroimaging
recognized that cognitive neuroscience can be used to fill
knowledge gaps between drug mechanisms and clinicaloutcome. By incorporating cognitive measures as surrogateendpoints in clinical trials, it is hoped that the so-called
‘translational bottleneck’ can be bridged. The ‘brain imaginginitiative’, a $100 million effort sponsored by the National
We wish to thank the members of the Sackler Institute
Institute for Drug Abuse (NIDA) aims to collect both brain
for helpful discussions. J.F. acknowledges support from
imaging and genetic data on thousands of human subjects
NIMH (#1 F32 MH64360-01A1) and a Young Investigator
over the next ten years and will provide more extensive
Exploring Genetic Influences on Cognition Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 361 REFERENCES
Andreasen, N.C., O'Leary, D.S., Flaum, M., Nopoulos, P., Watkins, G.L., Boles Ponto, L.L.; Hichwa, R.D. Lancet, 1997,349,
Hyman, S.E.; Fenton, W.S. Science, 2003,299, 350-1.
Meyer-Lindenberg, A.; Miletich, R.S., Kohn, P.D., Esposito, G.,
Fan, J., Flombaum, J.I., McCandliss, B.D., Thomas, K.M.; Posner,
Carson, R.E., Quarantelli, M., Weinberger, D.R.; Berman, K.F.
M.I. Neuroimage, 2003, 18, 42-57. Nat. Neurosci., 2002,5, 267-71.
Egan, M.F., Goldberg, T.E., Kolachana, B.S., Callicott, J.H.,
Berman, K.F., Illowsky, B.P.; Weinberger, D.R. Archives of
Mazzanti, C.M., Straub, R.E., Goldman, D.; Weinberger, D.R. General Psychiatry, 1988,45, 616-622. Proc. Natl. Acad. Sci. USA, 2001,98, 6917-22.
Frazier, J.A., Giedd, J.N., Kaysen, D., Albus, K., Hamburger, S.,
Cook, E.H., Jr., Stein, M.A., Krasowski, M.D., Cox, N.J., Olkon,
Alaghband-Rad, J., Lenane, M.C., McKenna, K., Breier, A.;
D.M., Kieffer, J.E.; Leventhal, B.L. Am. J. Hum. Genet., 1995,
Rapoport, J.L. Am. J. Psychiatry, 1996,153, 564-6.
Mayberg, H. Am. J. Psychiatry, 2002, 159, 1979.
Gill, M., Daly, G., Heron, S., Hawi, Z.; Fitzgerald, M. Mol.
Drevets, W.C. Biol. Psychiatry, 2000, 48, 813-29. Psychiatry, 1997,2, 311-3.
Baxter, L.R., Jr., Schwartz, J.M., Mazziotta, J.C., Phelps, M.E.,
Arinami, T., Itokawa, M., Enguchi, H., Tagaya, H., Yano, S.,
Pahl, J.J., Guze, B.H.; Fairbanks, L. American Journal of
Shimizu, H., Hamaguchi, H.; Toru, M. Lancet, 1994, 343, 703-4. Psychiatry, 1988,145, 1560-1563.
Jacobsen, L.K., Staley, J.K., Zoghbi, S.S., Seibyl, J.P., Kosten,
Swedo, S.E., Pietrini, P., Leonard, H.L., Schapiro, M.B., Rettew,
T.R., Innis, R.B.; Gelernter, J. Am. J. Psychiatry, 2000, 157, 1700-
D.C., Goldberger, E.L., Rapoport, S.I., Rapoport, J.L.; Grady, C.L. Archives of General Psychiatry, 1989, 49, 690-694.
Heinz, A., Goldman, D., Jones, D.W., Palmour, R., Hommer, D.,
Rosenberg, D.R., keshevan, M.S., O'Hearn, K.M., Dick, E.L.,
Gorey, J.G., Lee, K.S., Linnoila, M.; Weinberger, D.R.
Bagwell, W.W., Seymour, A.B., Montrose, D.M., Pierri, J.N.;
Neuropsychopharmacology, 2000,22, 133-9.
Birmaher, B. Archives of General Psychiatryj, 1997,54, 824-830.
Pohjalainen, T., Nagren, K., Syvalahti, E.K.; Hietala, J.
Rauch, S.L.; Renshaw, P.F. Harv. Rev. Psychiatry, (1995) 2, 297- Pharmacogenetics, 1999, 9, 505-9.
Cheverud, J.M., Falk, D., Vannier, M., Konigsberg, L.,
Thomas, K.M., Drevets, W.C., Dahl, R.E., Ryan, N.D., Birmaher,
Helmkamp, R.C.; Hildebolt, C. J. Hered., 1990,81, 51-7.
B., Eccard, C.H., Axelson, D., Whalen, P.J.; Casey, B.J. Arch.
Finlay, B.L.; Darlington, R.B. Science, 1995, 268, 1578-84. Gen. Psychiatry, 2001, 58, 1057-63.
Bartley, A.J., Jones, D.W.; Weinberger, D.R. Brain, 1997,120,
Castellanos, F.X., Giedd, J.N., Eckburg, P., Marsh, W.L., King,
A.C., Hamburger, S.D.; Rapoport, J.L. American Journal of
Thompson, P.M., Cannon, T.D., Narr, K.L., van Erp, T., Poutanen,
Psychiatry, 1994, 151, 1791-1796.
V.P., Huttunen, M., Lonnqvist, J., Standertskjold-Nordenstam,
Castellanos, F.X., Giedd, J.N., Marsh, W.L., Hamburger, S.D.,
C.G., Kaprio, J., Khaledy, M., Dail, R., Zoumalan, C.I.; Toga,
Vaituzis, A.C., Dickstein, D.P., Sarfatti, S.E., Vauss, Y.C., Snell,
A.W. Nat. Neurosci., 2001, 4, 1253-8.
J.W., Lange, N., Kaysen, D., Krain, A.L., Ritchie, G.F.,
Holden, C. Science, 2003. 299, 333-5.
Rajapakse, J.C.; Rapoport, J.L. Arch. Gen. Psychiatry, 1996,53,
Murphy, D.L., Li, Q., Engel, S., Wichems, C., Andrews, A.,
Lesch, K.P.; Uhl, G. Brain Res. Bull., 2001, 56, 487-94.
Vaidya, C.J., Austin, G., Kirkorian, G., Ridlehuber, H.W.Q.,
Hariri, A.R., Mattay, V.S., Tessitore, A., Kolachana, B., Fera, F.,
Desmond, J.E., Glover, G.H.; Gabrieli, D.E. Proceedings of the
Goldman, D., Egan, M.F.; Weinberger, D.R. Science, 2002, 297, National Academy of Sciences USA, 1988,95, 14494-14455.
Bush, G., Frazier, J.A., Rauch, S.L., Seidman, L.I., Whalen, P.J.,
Wassink, T.H., Nelson, J.J., Crowe, R.R.; Andreasen, N.C. Am. J.
Jenike, M.A., Rosen, B.R.; Biederman, J. Biological. Psychiatry,Med. Genet., 1999, 88, 724-8. 1999,45, 1542-1552.
Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E.,
Courchesne, E., Karns, C.M., Davis, H.R., Ziccardi, R., Carper,
Kolachana, B.S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D.,
R.A., Tigue, Z.D., Chisum, H.J., Moses, P., Pierce, K., Lord, C.,
Dean, M., Lu, B.; Weinberger, D.R. Cell, 2003, 112, 257-69.
Lincoln, A.J., Pizzo, S., Schreibman, L., Haas, R.H., Akshoomoff,
Porjesz, B., Begleiter, H., Reich, T., Van Eerdewegh, P.,
N.A.; Courchesne, R.Y. Neurology, 2001, 57, 245-54.
Edenberg, H.J., Foroud, T., Goate, A., Litke, A., Chorlian, D.B.,
Tandon, K.; McGuffin, P. Eur. J. Neurosci., 2002, 16, 403-7.
Stimus, A., Rice, J., Blangero, J., Almasy, L., Sorbell, J., Bauer,
Kendler, K.S. Arch. Gen. Psychiatry, 2001, 58, 1005-14.
L.O., Kuperman, S., O'Connor, S.J.; Rohrbaugh, J. Alcohol Clin.
Faraone, S.V.; Doyle, A.E. Child Adolesc. Psychiatr. Clin. N. Am.,Exp. Res., 1998, 22, 1317-23. 2001, 10, 299-316, viii-ix.
van Beijsterveldt, C.E., van Baal, G.C., Molenaar, P.C., Boomsma,
Polich, J.; Bloom, F.E. Alcohol, 1999, 17, 149-56.
D.I.; de Geus, E.J. Behav. Genet., 2001, 31, 533-43.
Braff, D.L. Schizophr. Bull., 1993,19, 233-59.
Anokhin, A.P., van Baal, G.C., van Beijsterveldt, C.E., de Geus,
Geyer, M.A.; Braff, D.L. Schizophr. Bull., 1987,13, 643-68.
E.J., Grant, J.; Boomsma, D.I. Behav. Genet., 2001, 31, 545-54.
Matthysse, S., Holzman, P.S.; Lange, K. J. Psychiatr. Res., 1986,
Freedman, R., Coon, H., Myles-Worsley, M., Orr-Urtreger, A.,
Olincy, A., Davis, A., Polymeropoulos, M., Holik, J., Hopkins, J.,
Pantelis, C., Barber, F.Z., Barnes, T.R., Nelson, H.E., Owen,
Hoff, M., Rosenthal, J., Waldo, M.C., Reimherr, F., Wender, P.,
A.M.; Robbins, T.W. Schizophr. Res., 1999, 37, 251-70.
Yaw, J., Young, D.A., Breese, C.R., Adams, C., Patterson, D.,
Casey, B.J., Castellanos, F.X., Giedd, J.N., Marsh, W.L.,
Adler, L.E., Kruglyak, L., Leonard, S.; Byerley, W. Proc. Natl.
Hamburger, S.D., Schubert, A.B., Vauss, Y.C., Vaituzis, A.C.,
Acad. Sci. USA, 1997,94, 587-92.
Dickstein, D.P., Sarfatti, S.E.; Rapoport, J.L. J. Am. Acad. Child
Basile, V.S., Masellis, M., Potkin, S.G.; Kennedy, J.L. Hum. Mol.Adolesc. Psychiatry., 1997, 36, 374-83. Genet., 2002,11, 2517-30.
Carter, C.S., Perlstein, W., Ganguli, R., Brar, J., Mintun, M.;
Kalow, W. Pharmacol Rev, 1997, 49, 369-79.
Cohen, J.D. Am. J. Psychiatry, 1998, 155, 1285-7.
Pfost, D.R., Boyce-Jacino, M.T.; Grant, D.M. Trends Biotechnol,
Cornblatt, B.A., Risch, N.J., Faris, G., Friedman, D.; Erlenmeyer-
2000, 18, 334-8.
Kimling, L. Psychiatry Res., 1988, 26, 223-38.
Sjoqvist, F.; Bertilsson, L. Prog. Clin. Biol. Res., 1986, 214, 169-88.
Myles-Worsley, M.; Coon, H. Psychiatry Res., 1997, 71, 163-74.
Kudo, S.; Ishizaki, T. Clin. Pharmacokinet., 1999, 37, 435-56.
Cannon, T.D., Huttunen, M.O., Lonnqvist, J., Tuulio-Henriksson,
Franchini, L., Serretti, A., Gasperini, M.; Smeraldi, E. J .
A., Pirkola, T., Glahn, D., Finkelstein, J., Hietanen, M., Kaprio, J.;
Psychiatr. Res., 1998, 32, 255-9.
Koskenvuo, M. Am. J. Hum. Genet., 2000,67, 369-82.
Pare, C.M.; Mack, J.W. J. Med. Genet., 1971, 8, 306-9.
Pardo, P.J., Knesevich, M.A., Vogler, G.P., Pardo, J.V., Towne,
Nurnberger, J.I., Jr., Gershon, E.S., Simmons, S., Ebert, M.,
B., Cloninger, C.R.; Posner, M.I. Schizophr. Bull., 2000, 26, 459-
Kessler, L.R., Dibble, E.D., Jimerson, S.S., Brown, G.M., Gold, P.,
J i m e r s o n , D . C . , G u r o f f , J . J . ; S t o r c h , F . I .
Young, D.A., Waldo, M., Rutledge, J.H., 3rd and Freedman, R. Psychoneuroendocrinology, 1982, 7, 163-76. Neuropsychobiology, 1996, 33, 113-7.
Arranz, M.J., Munro, J., Birkett, J., Bolonna, A., Mancama, D.,
Katsanis, J., Taylor, J., Iacono, W.G.; Hammer, M.A.
Sodhi, M., Lesch, K.P., Meyer, J.F., Sham, P., Collier, D.A.,
Psychophysiology, 2000,37, 724-30.
Murray, R.M.; Kerwin, R.W. Lancet, 2000, 355, 1615-6.
Fan, J., Wu, Y., Fossella, J.A.; Posner, M.I. BMC Neurosci., 2001, 2, 14. 362 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 6 Fossella et al.
Potkin, S.G., Basile, V.S., Jin, Y., Masellis, M., Badri, F., Keator,
Kern, R.S., Green, M.F., Marshall, B.D., Jr., Wirshing, W.C.,
D., Wu, J.C., Alva, G., Carreon, D.T., Bunney, W.E., Fallon, J.H.;
Wirshing, D., McGurk, S., Marder, S.R.; Mintz, J. B i o l .
Kennedy, J.L. Mol. Psychiatry, 2003, 8, 109-13. Psychiatry, 1998, 44, 726-32.
Potkin, S.G., Fleming, K., Jin, Y.; Gulasekaram, B. J. Clin.
Mataro, M., Garcia-Sanchez, C., Junque, C., Estevez-Gonzalez,
Psychopharmacol., 2001, 21, 479-83.
A.; Pujol, J. Arch. Neurol., 1997, 54, 963-8.
Basile, V.S., Masellis, M., Badri, F., Paterson, A.D., Meltzer,
Filipek, P.A., Semrud-Clikeman, M., Steingard, R.J., Renshaw,
H.Y., Lieberman, J.A., Potkin, S.G., Macciardi, F.; Kennedy, J.L.
P.F., Kennedy, D.N.; Biederman, J. Neurology, 1997, 48, 589-601. Neuropsychopharmacology, 1999, 21, 17-27.
Swanson, J.M., Kraemer, H.C., Hinshaw, S.P., Arnold, L.E.,
Liao, D.L., Yeh, Y.C., Chen, H.M., Chen, H., Hong, C.J.; Tsai, S.J.
Conners, C.K., Abikoff, H.B., Clevenger, W., Davies, M., Elliott,
Neuropsychobiology, 2001, 44, 95-8.
G.R., Greenhill, L.L., Hechtman, L., Hoza, B., Jensen, P.S.,
Lovlie, R., Daly, A.K., Blennerhassett, R., Ferrier, N.; Steen, V.M.
March, J.S., Newcorn, J.H., Owens, E.B., Pelham, W.E., Schiller,
Int. J. Neuropsychopharmacol., 2000, 3, 61-65.
E., Severe, J.B., Simpson, S., Vitiello, B., Wells, K., Wigal, T.;
Castellanos, F.X., Lee, P.P., Sharp, W., Jeffries, N.O., Greenstein,
Wu, M. J. Am. Acad. Child Adolesc. Psychiatry, 2001, 40, 168-79.
D.K., Clasen, L.S., Blumenthal, J.D., James, R.S., Ebens, C.L.,
Swanson, J., Oosterlaan, J., Murias, M., Schuck, S., Flodman, P.,
Walter, J.M., Zijdenbos, A., Evans, A.C., Giedd, J.N.; Rapoport,
Spence, M.A., Wasdell, M., Ding, Y., Chi, H.C., Smith, M., Mann,
J.L. Jama, 2002, 288, 1740-8.
M., Carlson, C., Kennedy, J.L., Sergeant, J.A., Leung, P., Zhang,
De Bellis, M.D., Casey, B.J., Dahl, R., Birmaher, B., Williamson,
Y.P., Sadeh, A., Chen, C., Whalen, C.K., Babb, K.A., Moyzis, R.;
D., Thomas, K.M., Axelson, D.A., Frustaci, K., Boring, A.M.,
Posner, M.I. Proc. Natl. Acad. Sci. USA, 2000, 97, 4754-9.
Hall, J.; Ryan, N. Biological Psychiatry, 2000, 48, 51-7.
Evans, W.E., Relling, M.V., Rodman, J.H., Crom, W.R., Boyett,
Bartlett, E.J., Brodie, J.D., Simkowitz, P., Dewey, S.L., Rusinek,
J.M.; Pui, C.H. N. Engl. J. Med., 1998338, 499-505.
H., Wolf, A.P., Fowler, J.S., Volkow, N.D., Smith, G., Wolkin, A.;
Furuta, T., Ohashi, K., Kamata, T., Takashima, M., Kosuge, K.,
et al.Am. J. Psychiatry, 1994, 151, 681-6.
Kawasaki, T., Hanai, H., Kubota, T., Ishizaki, T.; Kaneko, E.
Buchsbaum, M.S., Potkin, S.G., Marshall, J.F., Lottenberg, S.,
Ann. Intern. Med., 1998, 129, 1027-30.
Teng, C., Heh, C.W., Tafalla, R., Reynolds, C., Abel, L., Plon, L.;
Exner, D.V. New Eng. J. Med. 2001, 1351, 1355-1357. et al.Neuropsychopharmacology, 1992, 6, 155-63.
Drysdale, C.M., McGraw, D.W., Stack, C.B., Stephens, J.C.,
Dolan, R.J., Fletcher, P., Frith, C.D., Friston, K.J., Frackowiak,
Judson, R.S., Nandabalan, K., Arnold, K., Ruano, G.; Liggett, S.B.
R.S.; Grasby, P.M. Nature, 1995,378, 180-2. Proc. Natl. Acad. Sci. USA, 2000, 97, 10483-8.
Holcomb, H.H., Cascella, N.G., Thaker, G.K., Medoff, D.R.,
Chaix-Couturier, C. Pharmacoeconomics, 2000, 18, 325-432.
Dannals, R.F.; Tamminga, C.A. Am. J. Psychiatry, 1996, 153, 41-
Lawler, A. Science, 2002, 297, 748-9.
Aoki, N. Boston Globe, 2001, July 25th.
Chakos, M.H., Lieberman, J.A., Bilder, R.M., Borenstein, M.,
Kuhlik, B.N. Food Drug Law J., 2000, 55, 21-5.
Lerner, G., Bogerts, B., Wu, H., Kinon, B.; Ashtari, M. Am. J.
Bazell, R. in Her-2: The Making of Herceptin, a Revolutionary
Psychiatry, 1994, 151, 1430-6.
Treatment for Breast Cancer, 2001 Random House Publishers,
Miller, D.D., Andreasen, N.C., O'Leary, D.S., Watkins, G.L.,
Boles Ponto, L.L.; Hichwa, R.D. Biol. Psychiatry, 2001, 49, 704-
Kobayashi, H., Shirakawa, K., Kawamoto, S., Saga, T., Sato, N.,
Hiraga, A., Watanabe, I., Heike, Y., Togashi, K., Konishi, J.,
Kee, K.S., Kern, R.S., Marshall, B.D., Jr.; Green, M.F. Schizophr.
Brechbiel, M.W.; Wakasugi, H. Cancer Res., 2002, 62, 860-6. Res., 1998, 31, 159-65.
ORGANISATION INTERGOUVERNEMENTALE POUR LES TRANSPORTS INTERNATIONAUX FERROVIAIRES ZWISCHENSTAATLICHE ORGANISATION FÜR DEN INTERNATIONALEN EISENBAHNVERKEHR INTERGOVERNMENTAL ORGANISATION FOR INTER- NATIONAL CARRIAGE BY RAIL OCTI/RID/CE/ 40/4b) RID: 40th Session of the Committee of Experts on the Transport of Dangerous Goods (Sinaia (Romania), 17 - 21 November 2003)
Center for Advanced Studies in Science & Technology Policy Information • Technology • National Security Brief No. 06-14 Preparedness? Essay by K. A. Taipale As telecommunications reform legislation winds its way through the Congress, “net neutrality” has emerged as the latest beltway buzzword and the subject of a contentious lobbying war between large internet content