- Email: [email protected]
Abstract Thinking: Thinking Inside the Box
In This Issue
HERE Volume 48, Number 1: January 2009 Instead of Thinking Outside the Box, Looking Across the Diagnostic Box
In many areas of medicine, there is pressure to better define the biology behind disorders. With DSM-V in the pipeline, there is a focus on reevaluating comorbidity and symptom overlap and developing models to define each psychiatric illness in relation to its behavioral, cognitive, social, and neurological aspects. The expression of psychiatric disorder is not separate from other neurological functions. As we better define the pathways, neurotransmitters, and long-term consequences of mental illness, it is becoming clear that emotional well-being is integrally related to other domains, including basic health parameters, cognitive function, social competence, and even overall mortality. The Journal begins 2009 with a series of articles that look across domains and Boutside the box[ of standard diagnosis. Rapoport et al. (p. 10) present a novel view of the long-debated overlap between autism and schizophrenia. Fliers et al. (p. 25) and Shreeram et al. (p. 35) look at associations of other domains with attention-deficit/ hyperactivity disorder (ADHD), whereas the article by Joekela et al. (p. 19) examines the relations between childhood behavioral problems and death by midlife. Finally, in the second installment of Lombroso and Ogren (p. 5) on learning and memory, we appreciate how a careful exploration of the molecular genetic pathology of fragile X syndrome is helping advance our understanding of the molecular underpinnings of normal learning and memory. The accompanying There section expands on such cross-domain thinking by exploring cognitive function across different psychiatric disorders. Cross-Domain Relations in ADHD
Two articles in this issue of the Journal examine ADHD and impairments in domains outside hyperactivity and impulsivity. Shreeram et al. (p. 35) explore the prevalence of enuresis in U.S. children and its co-occurrence with ADHD. Both disorders have been shown to be associated with poor self-image and poor school performance. The findings that children with enuresis have a threefold increased risk for ADHD and that treatment for ADHD may decrease incidence of enuresis support a common etiology for the disorders. One possible common link is that both enuresis and ADHD may be related to delayed central nervous system development. In addition, the authors demonstrate specificity for the ADHD-enuresis associationVno similar relations between enuresis and other disorders were detected in this fairly large epidemiological study. An alternative cross-dimensional comorbidity with ADHD is found in the study by Fliers et al. (p. 25), who found a shared genetic etiology between motor problems and ADHD. Using a concordant and discordant twin design, they provide support for a common etiological basis and note that the association was particularly high between ADHD and problems with fine motor skills. Whereas the authors posit either an attentional component or mediation through the dopamine pathway as causative of this association, an alternative hypothesis may be that fine motor skills are indicative of more mature cortical development. Thus, delayed central nervous system development could again relate these cross-domain findings. Looking Across Domains in Autism
The review article by Rapoport et al. (p. 10) again takes a broader view, looking across disorders at the relations between autism/ pervasive developmental disorder and childhood-onset schizophrenia. Although the link between ADHD and other domains may involve delayed brain development, Rapoport et al. postulate the opposite for childhood-onset schizophrenia and pervasive developmental disorder, two disorders with high co-occurrence. They note growing evidence for accelerated patterns of brain development, in particular at age of onset, for both these disorders. Again, the genetic overlap between the two disorders highlights the possibility of a common neurobiological process. Turning away from diagnostic criteria and focusing instead on specific social and communication deficits may demonstrate overlap between these two disorders, which were separated initially based primarily on age of onset. This month’s There explores Binside the box[ of the brainVlooking for convergent neural circuits in childhood psychiatric disorders and specifically by considering the relation between cognition and illness.
J. AM . ACAD. CHILD ADOLESC. PSYCH IATRY, 48:1, JANUARY 2009
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1
Abstract Thinking
THERE Thinking Inside the Box Cognitive Function Abnormalities in ADHD and Anorexia
Individuals with ADHD have deficits in cognitive function, including in school performance, attention, and executive function. Stimulant treatment improves both core ADHD symptoms and measures of sustained attention. When Biederman et al.1 examined attention and executive function separately, however, they found that stimulant treatment corrected deficits in visualYspatial organization, sustained attention, and verbal learning but did not improve executive function. Medications may correct neural circuits that are already developed, such as those involved in attention, but may be unable to influence the immature neuronal pathways involved in executive function. If medication improves only some of the deficits in ADHD, then clinicians should be reminded to also direct their efforts toward psychoeducational interventions to improve executive function. Abnormalities of cognitive function and brain structure have also been studied in anorexia nervosa (AN). AN is hypothesized to interfere with normal brain development, but the mechanism is unclear, and the reversibility of these deficits is uncertain. A recent study of cognitive function and brain structure in young adult women with a history of AN examines this.2 Although many of the women no longer met diagnostic criteria for AN, they demonstrated volumetric differences in the lateral ventricles and showed deficits in verbal ability and cognitive efficiency when compared with controls. These findings illustrate that resolution of a diagnosis may not mean that the impact of the illness is gone. Moreover, this highlights the importance of evaluating cognitive function when designing treatments. Finding the Missing Link
Genes are a likely candidate linking cognitive function to psychopathology. Two recent studies have elegantly examined functional genetic variation using cross-domain analysis and found a clear association among genes, neurophysiology, cognition, behavior, and psychopathology.3,4 Gatt et al.4 hypothesized that a common genetic variation could contribute to both cognitive and psychological function. Using parallel path modeling, they demonstrated that genetic variation in brain-derived neurotrophic factor (BDNF) is linked to both the event-related potentials response to facial emotions and to working memory. They further demonstrated a link from both of these endophenotypes directly to depressive symptoms, with BDNF as the common factor between the emotional and cognitive components of depression. Smoller et al.3 used animal models and variations within the regulator of G-protein signalingY2 (RGS2) gene to link temperament, personality, brain activation, and anxiety. After noting that mice with a Bknockout[ of the RGS2 gene exhibited high levels of fear behavior, they looked for an association in humans between polymorphisms in RGS2 and intermediate phenotypes for anxiety, including behavioral inhibition and introversion. In a task linked to anxiety, they found specific associations between activation in the insula and amygdala and the same polymorphism in RGS2. The brain is not static, and few pathways function in isolation. Aberrant neural circuit formation and changes in the rate of neurodevelopment certainly contribute to psychiatric illness. It may be prudent to spend more time exploring across emotional, cognitive, social, and behavioral domains for both research and clinical purposes. Perhaps this kind of cross-domain thinking can help differentiate the neurobiological pathways associated with disorders. In turn, this may foster development of strategies for the treatment and prevention of a variety of psychiatric conditions. Stacy Drury, M.D., Ph.D. [email protected] DOI: 10.1097/CHI.0b013e3181908c2c _______________
Disclosure: The author reports no conflicts of interest.
REFERENCES 1. Biederman J, Seidman L, Petty C et al. Effects of stimulant medication on neuropsychological functioning in young adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69:1150Y1156. 2. Chui H, Christensen B, Zipursky R et al. Cognitive function and brain structure in females with a history of adolescent-onset anorexia nervosa. Pediatrics. 2008;122:e427Ye437. 3. Smoller J, Paulus M, Fagerness J et al. Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry. 2008;65:298Y308. 4. Gatt J, Clark C, Kemp A, Liddell B, Dobson-Stone C, Kuan S. A genotype-endophenotype path model of depressed mood: integrating cognitive and emotional markers. J Integr Neurosci. 2008;6:75Y104.
2
WWW.JAACAP.COM
J. A M. ACAD . CHILD ADOLESC. PSYC HIAT RY, 48:1, JANUA RY 2009
HERE Volume 48, Number 1: January 2009 Instead of Thinking Outside the Box, Looking Across the Diagnostic Box
In many areas of medicine, there is pressure to better define the biology behind disorders. With DSM-V in the pipeline, there is a focus on reevaluating comorbidity and symptom overlap and developing models to define each psychiatric illness in relation to its behavioral, cognitive, social, and neurological aspects. The expression of psychiatric disorder is not separate from other neurological functions. As we better define the pathways, neurotransmitters, and long-term consequences of mental illness, it is becoming clear that emotional well-being is integrally related to other domains, including basic health parameters, cognitive function, social competence, and even overall mortality. The Journal begins 2009 with a series of articles that look across domains and Boutside the box[ of standard diagnosis. Rapoport et al. (p. 10) present a novel view of the long-debated overlap between autism and schizophrenia. Fliers et al. (p. 25) and Shreeram et al. (p. 35) look at associations of other domains with attention-deficit/ hyperactivity disorder (ADHD), whereas the article by Joekela et al. (p. 19) examines the relations between childhood behavioral problems and death by midlife. Finally, in the second installment of Lombroso and Ogren (p. 5) on learning and memory, we appreciate how a careful exploration of the molecular genetic pathology of fragile X syndrome is helping advance our understanding of the molecular underpinnings of normal learning and memory. The accompanying There section expands on such cross-domain thinking by exploring cognitive function across different psychiatric disorders. Cross-Domain Relations in ADHD
Two articles in this issue of the Journal examine ADHD and impairments in domains outside hyperactivity and impulsivity. Shreeram et al. (p. 35) explore the prevalence of enuresis in U.S. children and its co-occurrence with ADHD. Both disorders have been shown to be associated with poor self-image and poor school performance. The findings that children with enuresis have a threefold increased risk for ADHD and that treatment for ADHD may decrease incidence of enuresis support a common etiology for the disorders. One possible common link is that both enuresis and ADHD may be related to delayed central nervous system development. In addition, the authors demonstrate specificity for the ADHD-enuresis associationVno similar relations between enuresis and other disorders were detected in this fairly large epidemiological study. An alternative cross-dimensional comorbidity with ADHD is found in the study by Fliers et al. (p. 25), who found a shared genetic etiology between motor problems and ADHD. Using a concordant and discordant twin design, they provide support for a common etiological basis and note that the association was particularly high between ADHD and problems with fine motor skills. Whereas the authors posit either an attentional component or mediation through the dopamine pathway as causative of this association, an alternative hypothesis may be that fine motor skills are indicative of more mature cortical development. Thus, delayed central nervous system development could again relate these cross-domain findings. Looking Across Domains in Autism
The review article by Rapoport et al. (p. 10) again takes a broader view, looking across disorders at the relations between autism/ pervasive developmental disorder and childhood-onset schizophrenia. Although the link between ADHD and other domains may involve delayed brain development, Rapoport et al. postulate the opposite for childhood-onset schizophrenia and pervasive developmental disorder, two disorders with high co-occurrence. They note growing evidence for accelerated patterns of brain development, in particular at age of onset, for both these disorders. Again, the genetic overlap between the two disorders highlights the possibility of a common neurobiological process. Turning away from diagnostic criteria and focusing instead on specific social and communication deficits may demonstrate overlap between these two disorders, which were separated initially based primarily on age of onset. This month’s There explores Binside the box[ of the brainVlooking for convergent neural circuits in childhood psychiatric disorders and specifically by considering the relation between cognition and illness.
J. AM . ACAD. CHILD ADOLESC. PSYCH IATRY, 48:1, JANUARY 2009
WWW.JAACAP.COM
1
Abstract Thinking
THERE Thinking Inside the Box Cognitive Function Abnormalities in ADHD and Anorexia
Individuals with ADHD have deficits in cognitive function, including in school performance, attention, and executive function. Stimulant treatment improves both core ADHD symptoms and measures of sustained attention. When Biederman et al.1 examined attention and executive function separately, however, they found that stimulant treatment corrected deficits in visualYspatial organization, sustained attention, and verbal learning but did not improve executive function. Medications may correct neural circuits that are already developed, such as those involved in attention, but may be unable to influence the immature neuronal pathways involved in executive function. If medication improves only some of the deficits in ADHD, then clinicians should be reminded to also direct their efforts toward psychoeducational interventions to improve executive function. Abnormalities of cognitive function and brain structure have also been studied in anorexia nervosa (AN). AN is hypothesized to interfere with normal brain development, but the mechanism is unclear, and the reversibility of these deficits is uncertain. A recent study of cognitive function and brain structure in young adult women with a history of AN examines this.2 Although many of the women no longer met diagnostic criteria for AN, they demonstrated volumetric differences in the lateral ventricles and showed deficits in verbal ability and cognitive efficiency when compared with controls. These findings illustrate that resolution of a diagnosis may not mean that the impact of the illness is gone. Moreover, this highlights the importance of evaluating cognitive function when designing treatments. Finding the Missing Link
Genes are a likely candidate linking cognitive function to psychopathology. Two recent studies have elegantly examined functional genetic variation using cross-domain analysis and found a clear association among genes, neurophysiology, cognition, behavior, and psychopathology.3,4 Gatt et al.4 hypothesized that a common genetic variation could contribute to both cognitive and psychological function. Using parallel path modeling, they demonstrated that genetic variation in brain-derived neurotrophic factor (BDNF) is linked to both the event-related potentials response to facial emotions and to working memory. They further demonstrated a link from both of these endophenotypes directly to depressive symptoms, with BDNF as the common factor between the emotional and cognitive components of depression. Smoller et al.3 used animal models and variations within the regulator of G-protein signalingY2 (RGS2) gene to link temperament, personality, brain activation, and anxiety. After noting that mice with a Bknockout[ of the RGS2 gene exhibited high levels of fear behavior, they looked for an association in humans between polymorphisms in RGS2 and intermediate phenotypes for anxiety, including behavioral inhibition and introversion. In a task linked to anxiety, they found specific associations between activation in the insula and amygdala and the same polymorphism in RGS2. The brain is not static, and few pathways function in isolation. Aberrant neural circuit formation and changes in the rate of neurodevelopment certainly contribute to psychiatric illness. It may be prudent to spend more time exploring across emotional, cognitive, social, and behavioral domains for both research and clinical purposes. Perhaps this kind of cross-domain thinking can help differentiate the neurobiological pathways associated with disorders. In turn, this may foster development of strategies for the treatment and prevention of a variety of psychiatric conditions. Stacy Drury, M.D., Ph.D. [email protected] DOI: 10.1097/CHI.0b013e3181908c2c _______________
Disclosure: The author reports no conflicts of interest.
REFERENCES 1. Biederman J, Seidman L, Petty C et al. Effects of stimulant medication on neuropsychological functioning in young adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69:1150Y1156. 2. Chui H, Christensen B, Zipursky R et al. Cognitive function and brain structure in females with a history of adolescent-onset anorexia nervosa. Pediatrics. 2008;122:e427Ye437. 3. Smoller J, Paulus M, Fagerness J et al. Influence of RGS2 on anxiety-related temperament, personality, and brain function. Arch Gen Psychiatry. 2008;65:298Y308. 4. Gatt J, Clark C, Kemp A, Liddell B, Dobson-Stone C, Kuan S. A genotype-endophenotype path model of depressed mood: integrating cognitive and emotional markers. J Integr Neurosci. 2008;6:75Y104.
2
WWW.JAACAP.COM
J. A M. ACAD . CHILD ADOLESC. PSYC HIAT RY, 48:1, JANUA RY 2009