Elsevier

Biological Psychiatry

Volume 69, Issue 12, 15 June 2011, Pages 1178-1184
Biological Psychiatry

Review
Differentiating Frontostriatal and Fronto-Cerebellar Circuits in Attention-Deficit/Hyperactivity Disorder

https://doi.org/10.1016/j.biopsych.2010.07.037Get rights and content

Attention-deficit/hyperactivity disorder (ADHD) has long been conceptualized as a neurobiological disorder of the prefrontal cortex and its connections. Circuits with the prefrontal cortex relevant to ADHD include dorsal frontostriatal, orbitofronto-striatal, and fronto-cerebellar circuits. Dorsal frontostriatal circuitry has been linked to cognitive control, whereas orbitofronto-striatal loops have been related to reward processing. Fronto-cerebellar circuits have been implicated in timing. Neurobiological dysfunction in any of these circuits could lead to symptoms of ADHD, as behavioral control could be disturbed by: 1) deficits in the prefrontal cortex itself; or 2) problems in the circuits relaying information to the prefrontal cortex, leading to reduced signaling for control. This article suggests a model for differentiating between interlinked reciprocal circuits with the prefrontal cortex in ADHD. If such a differentiation can be achieved, it might permit a neurobiological subtyping of ADHD, perhaps by defining “dorsal fronto-striatal,” “orbitofronto-striatal,” or “fronto-cerebellar” subtypes of ADHD. This could be useful as a template for investigating the neurobiology of ADHD and, ultimately, clinically.

Section snippets

Neuroanatomical Substrate for Links Among Prefrontal Cortex, Striatum, and Cerebellum

In 1986, Alexander et al. (3) published a seminal article where they proposed that there were at least five parallel loops between the striatum and cortex. Each loop includes discrete areas in the striatum, globus pallidus, substantia nigra, thalamus, and cortex and is structured in a parallel manner: Cortical inputs to the striatum are passed through the basal ganglia to the thalamus and from there back to a single cortical area. Each circuit receives multiple inputs only from cortical areas

Linking Neuroanatomy to Brain Function

The prefrontal cortex is critical to cognitive control, the ability to flexibly adjust behavior to changing circumstances (5). Cognitive control has also been called “behavioral control” or simply “control.” Functions typically covered by this umbrella term include response inhibition, motor inhibition, switching, and sometimes planning. Tasks used to assess cognitive control include the go/no-go task, stop task, Stroop task, Wisconsin Card Sorting Test, and many others. To give but one

Cognitive Control and Dorsal Frontostriatal Connections

The frontostriatal circuit, which comprises reciprocal connections among the striatum, thalamus, and prefrontal areas, is critical to cognitive control. Deficits in this ability have even been suggested to be the core deficit in ADHD, underlying other cognitive differences (24). However, meta-analyses have shown that most children with ADHD do not have a measurable deficit in cognitive control, suggesting that it is not central to ADHD symptoms, at least not for all children (25).

According to

Fronto-Cerebellar Circuits in ADHD

Traditionally, much attention has been paid to the role of the prefrontal cortex and its links with the striatum in ADHD research. However, the cerebellum is another prime candidate for involvement in this disorder. It has a protracted development, is sexually dimorphic, and is susceptible to environmental influences (40). This tentatively provides support for a possible role in ADHD, because this disorder is usually diagnosed in middle childhood, when the cerebellum is still developing; is

Genetic Influences on Frontostriatal and Fronto-Cerebellar Circuits in ADHD

Attention-deficit/hyperactivity disorder is a disorder with a genetic component: 70%–80% of the phenotypic variance is estimated to be heritable (68). Differences in frontostriatal circuits in ADHD have indeed been shown to be under genetic influences: the unaffected siblings of boys with ADHD share reductions in prefrontal gray matter volume (48) and prefrontal activity during cognitive control (69). Furthermore, established risk genes for ADHD (DRD4 and DAT1) are related to both structure and

Dissociating Circuits with Prefrontal Cortex in ADHD

As discussed previously, dorsal frontostriatal, orbitofronto-striatal, and fronto-cerebellar circuits are involved in ADHD. These circuits interact through spiraling loops in the striatum and connections from the cerebellum to the prefrontal cortex and the striatum, although there are more connections within than between circuits. Dysfunction in any of these circuits might cause symptoms of ADHD: Dysfunction of the prefrontal cortex is likely to result in a reduced ability to exert control (5).

Where Next in ADHD Research?

The work described in the preceding text shows that we, as a field, are preparing to take the next step in ADHD research. To date, studies in ADHD have typically grouped children on the basis of symptoms and behavioral assessments. For example, in imaging genetics studies, the effect of candidate genes on the brain has been investigated in large samples of individuals with ADHD, categorized by their clinical diagnosis. As such, we have effectively ignored the fact that there might be multiple

Conclusions

In conclusion, there are multiple circuits with the prefrontal cortex that play a role in the pathophysiology of ADHD. Dorsal frontostriatal pathways are implicated in deficits in cognitive control, orbitofronto-striatal circuits relate to differences in reward processing, and fronto-cerebellar pathways are linked to problems with timing and building temporal predictions. Recent work suggests that it might be possible to dissociate these circuits at the cognitive level and use them for

References (89)

  • S. Durston et al.

    Differential patterns of striatal activation in young children with and without ADHD

    Biol Psychiatry

    (2003)
  • M. Ashtari et al.

    Attention-deficit/hyperactivity disorder: A preliminary diffusion tensor imaging study

    Biol Psychiatry

    (2005)
  • N.D. Davenport et al.

    Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia

    Psychiatry Res

    (2010)
  • E.J. Sonuga-Barke

    Psychological heterogeneity in AD/HD—a dual pathway model of behaviour and cognition

    Behav Brain Res

    (2002)
  • E.J. Sonuga-Barke

    Causal models of attention-deficit/hyperactivity disorder: From common simple deficits to multiple developmental pathways

    Biol Psychiatry

    (2005)
  • A. Scheres et al.

    Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder

    Biol Psychiatry

    (2007)
  • A. Ströhle et al.

    Reward anticipation and outcomes in adult males with attention-deficit/hyperactivity disorder

    Neuroimage

    (2008)
  • M.M. Plichta et al.

    Neural hyporesponsiveness and hyperresponsiveness during immediate and delayed reward processing in adult attention-deficit/hyperactivity disorder

    Biol Psychiatry

    (2009)
  • H. Tiemeier et al.

    Cerebellum development during childhood and adolescence: A longitudinal morphometric MRI study

    Neuroimage

    (2010)
  • E. Plomp et al.

    Understanding genes, environment and their interaction in attention-deficit hyperactivity disorder: Is there a role for neuroimaging?

    Neuroscience

    (2009)
  • S. Durston et al.

    Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings

    J Am Acad Child Adolesc Psychiatry

    (2004)
  • S. Carmona et al.

    Global and regional gray matter reductions in ADHD: A voxel-based morphometric study

    Neurosci Lett

    (2005)
  • G.M. McAlonan et al.

    Mapping brain structure in attention deficit-hyperactivity disorder: A voxel-based MRI study of regional grey and white matter volume

    Psychiatry Res

    (2007)
  • E.M. Valera et al.

    Functional neuroanatomy of working memory in adults with attention-deficit/hyperactivity disorder

    Biol Psychiatry

    (2005)
  • K. Rubia et al.

    Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection

    Neuroimage

    (2003)
  • C.S. Van Meel et al.

    Motivational effects on motor timing in attention-deficit/hyperactivity disorder

    J Am Acad Child Adolesc Psychiatry

    (2005)
  • L. Tian et al.

    Altered resting-state functional connectivity patterns of anterior cingulate cortex in adolescents with attention deficit hyperactivity disorder

    Neurosci Lett

    (2006)
  • J. Bledsoe et al.

    A magnetic resonance imaging study of the cerebellar vermis in chronically treated and treatment-naïve children with attention-deficit/hyperactivity disorder combined type

    Biol Psychiatry

    (2009)
  • S.V. Faraone et al.

    Molecular genetics of attention-deficit/hyperactivity disorder

    Biol Psychiatry

    (2005)
  • S. Durston et al.

    Activation in ventral prefrontal cortex is sensitive to genetic vulnerability for attention-deficit hyperactivity disorder

    Biol Psychiatry

    (2006)
  • A.C. Bédard et al.

    Dopamine transporter gene variation modulates activation of striatum in youth with ADHD

    Neuroimage

    (2010)
  • S. Durston et al.

    Dopamine transporter genotype conveys familial risk of attention-deficit/hyperactivity disorder through striatal activation

    J Am Acad Child Adolesc Psychiatry

    (2008)
  • M.J. Mulder et al.

    Familial vulnerability to ADHD affects activity in the cerebellum in addition to the prefrontal systems

    J Am Acad Child Adolesc Psychiatry

    (2008)
  • S. Durston

    Imaging genetics in ADHD

    Neuroimage

    (2010)
  • C.M. Greene et al.

    Noradrenergic genotype predicts lapses in sustained attention

    Neuropsychologia

    (2009)
  • E. Sonuga-Barke et al.

    Beyond the dual pathway model: Evidence for the dissociation of timing, inhibitory, and delay-related impairments in attention-deficit/hyperactivity disorder

    J Am Acad Child Adolesc Psychiatry

    (2010)
  • D. Slaats-Willemse et al.

    Familial clustering of executive functioning in affected sibling pair families with ADHD

    J Am Acad Child Adolesc Psychiatry

    (2005)
  • M.A. Jarrett et al.

    A conceptual review of the comorbidity of attention-deficit/hyperactivity disorder and anxiety: Implications for future research and practice

    Clin Psychol Rev

    (2008)
  • J.M. Halperin et al.

    Revisiting the role of the prefrontal cortex in the pathophysiology of attention-deficit/hyperactivity disorder

    Psychol Bull

    (2006)
  • G.E. Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annu Rev Neurosci

    (1986)
  • S. Durston et al.

    Neural and behavioral correlates of expectancy violations in attention-deficit hyperactivity disorder

    J Child Psychol Psychiatry

    (2007)
  • B.J. Casey et al.

    New potential leads in the biology and treatment of attention deficit-hyperactivity disorder

    Curr Opin Neurol

    (2007)
  • J.T. Nigg et al.

    An integrative theory of attention-deficit/ hyperactivity disorder based on the cognitive and affective neurosciences

    Dev Psychopathol

    (2005)
  • M. Steinlin

    Cerebellar disorders in childhood: Cognitive problems

    Cerebellum

    (2008)
  • Cited by (0)

    View full text