Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.

Andreasen, Nancy C.; O'Leary, Daniel S.; Cizadlo, Ted; Arndt, Stephan; Rezai, Karim; Ponto, Laura L. Boles; Watkins, G. Leonard; Hichwa, Richard D.

doi:10.1073/pnas.93.18.9985

Cited by 580 publications

(363 citation statements)

References 52 publications

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“…Although the presence of a DA innervation in the cerebellum may represent a confound for this approach, the highly restricted distribution of DA axons to the cerebellar vermis, in concert with their relatively low density compared to such structures as the striatum, may render this concern more apparent than real. Andreasen et al (1996) hypothesize that disturbances in the circuitry linking the cerebellum, thalamus, and prefrontal cortex contribute to many of the abnormalities in cognition that are characteristic of schizophrenia. Although connections among these brain regions are clearly present in the primate brain ( Middleton and Strick 1994), this circuitry involves the cerebellar hemispheres and dentate nucleus, and not the vermis.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine Hydroxylase- and Dopamine Transporter-Immunoreactive Axons in the Primate Cerebellum Evidence for a Lobular- and Laminar-Specific Dopamine Innervation

Melchitzky

Lewis

2000

Neuropsychopharmacology

140

112

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The cerebellum seems to play a critical role in many motor and cognitive functions, including those that are disturbed in schizophrenia. Although dopamine is known to influence the motor or cognitive functions mediated by other brain regions and to play a role in the pathophysiologyThe primary function of the cerebellum has traditionally been considered to involve the control and integration of motor processes, including the coordination of goal-directed movements and the regulation of posture (Ito 1984). However, recent evidence suggests that the cerebellum may also be important in cognitive functions (Schmahmann 1991;Kim et al. 1994). For example, neuro-imaging studies have demonstrated activation in the cerebellum during word-association tasks (Petersen and Fiez 1993), as well as during mental imagery and mental counting (Ryding et al. 1993). These cognitive aspects of the cerebellum seem to involve the lateral hemispheres and the dentate nucleus (Schmahmann 1991;Petersen and Fiez 1993;Kim et al. 1994). In con- Received May 19, 1999; revised October 18, 1999; accepted October 22, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 5 Dopamine Axons in Primate Cerebellum 467 trast, the medial regions of the cerebellum, such as the vermis and fastigial nucleus, are primarily associated with motor control of the trunk and head, including smooth pursuit eye movements (Ito 1984).The cerebellum has also been implicated as a site of dysfunction in schizophrenia, a disorder characterized by certain types of motor and cognitive impairments. For example, many subjects with schizophrenia exhibit abnormalities in smooth pursuit eye movements (Holzman et al. 1973;Levy et al. 1994;Hutton and Kennard 1998). In addition, some of the cognitive deficits observed in individuals with schizophrenia, such as impairments in planning, verbal fluency, abstract thinking, and working memory, are present in patients with cerebellar lesions (Schmahmann and Sherman 1998). Furthermore, studies of schizophrenic subjects have revealed reductions in cerebellar volume (Jacobsen et al. 1997;Weinberger et al. 1980), metabolism (Volkow et al. 1992, and blood flow (Steinberg et al. 1995), especially in the vermal regions. Consistent with these observations, the size of Purkinje cells has been reported to be decreased in the vermis of subjects with schizophrenia (Tran et al. 1998).Abnormalities in dopamine (DA) neurotransmission have long been considered to be involved in the pathophysiology of schizophrenia (Carlsson et al. 1997;Davis et al. 1991;Grace 1991;Snyder 1972;), and DA is known to play a critical role in the regulation of motor and cognitive functions in both cortical and subcortical structures (Goldman-Rakic 1998; Lewis and Sesack 1997). However, whether DA directly influences motor or cognitive functions at the level of the cerebellum is unclear. Historically, the cerebellum was not thought to utilize DA as a neurotransmitter, and the DA present in the cerebellum was considered to serve only as a precursor for noradrenaline. Mo...

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Section: Discussionmentioning

confidence: 99%

Tyrosine Hydroxylase- and Dopamine Transporter-Immunoreactive Axons in the Primate Cerebellum Evidence for a Lobular- and Laminar-Specific Dopamine Innervation

Melchitzky

Lewis

2000

Neuropsychopharmacology

140

112

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“…Although few studies have examined the functional integrity of the cerebellum in schizophrenia, there is evidence of abnormalities from both functional MRI (Whalley et al, 2004;Takahashi et al, 2004) and positron emission tomography (Andreasen et al, 1996;Potkin et al, 2002). These functional imaging studies indicate that individuals with schizophrenia exhibit atypical cerebellar activation during sentence completion, affective processing, visual attention and verbal memory tasks.…”

Section: Introductionmentioning

confidence: 99%

Cerebellum volume and eyeblink conditioning in schizophrenia

Edwards

Newman

Bismark

et al. 2008

Psychiatry Research: Neuroimaging

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Although accumulating evidence suggests that cerebellar abnormalities may be linked to the symptoms and course of schizophrenia, few studies have related structural and functional indices of cerebellar integrity. The present study examined the relationship between the volume of specific subregions of the cerebellum and cerebellar function, as measured by eyeblink conditioning. Nine individuals with schizophrenia and six healthy comparison participants completed structural magnetic resonance imaging of the brain and a delay eyeblink conditioning procedure. Volumetric measurements were taken for the whole brain, whole cerebellum, cerebellar anterior lobules I-V and posterior lobules VI-VII. The schizophrenia group had smaller cerebellar anterior lobes and exhibited impaired eyeblink conditioning compared to the comparison group. In the comparison group, larger anterior volume correlated with earlier conditioned response onset latencies and increased amplitudes of the unconditioned blink response during paired trials (i.e., when the conditioned and unconditioned stimuli co-occurred). The findings that smaller anterior cerebellar volumes and EBC impairments were associated with schizophrenia are consistent with non-human studies showing that anterior cerebellar abnormalities are associated with associative deficits in delay eyeblink conditioning. The lack of a significant correlation between indices of eyeblink conditioning and cerebellar volume within the schizophrenic group suggests an aberrant relationship between cerebellar structure and function.

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“…22 and 23 for reviews). The concept of cognitive dysmetria, or abnormalities of cognitive function arising because of abnormal integration of fronto-cerebellar-thalamic circuits in patients with schizophrenia (10,(24)(25)(26)(27), is particularly apposite here. The circuits hypothetically implicated by cognitive dysmetria include frontal, striatal, and cerebellar regions, which we show here are abnormally associated with both early motor development and adult executive function in people with schizophrenia.…”

Section: Discontinuities Between Imd Adult Executive Function and Amentioning

confidence: 99%

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia

Ridler

Veijola

Tanskanen

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

139

122

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Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n ‫؍‬ 93) and people with schizophrenia (n ‫؍‬ 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between frontocerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.L ittle is known about how the early development of the human brain predicts its adult structure. Several twin studies have established that adult brain structure is heritable (1, 2), but these designs cannot address questions concerning the timing of genetic effects on neuroanatomical variation in adults. Hypothetically, the responsible genetic differences may be expressed during early brain development with anatomical effects being conserved over the course of childhood and adolescence, albeit conditioned by environmental factors and gene ϫ environment interactions (3).It would be useful to know more about (dis)continuities between early developmental markers and adult brain structure as a basis for better understanding of the pathogenesis of psychiatric disorders such as schizophrenia, which typically present in young adults but may be predicted, at least in part, by earlier neurodevelopmental aberration. Longitudinal epidemiological studies of schizophrenia show early developmental adversity imparting increased risk of adult psychosis, with the emergence of psychotic symptoms preceded by subtle abnormalities of motor coordination (developmental dysmetria), social function, and cognition in childhood and adolescence (4-6). Typic...

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Schizophrenia and cognitive dysmetria: a positron-emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry.

Cited by 580 publications

References 52 publications

Tyrosine Hydroxylase- and Dopamine Transporter-Immunoreactive Axons in the Primate Cerebellum Evidence for a Lobular- and Laminar-Specific Dopamine Innervation

Tyrosine Hydroxylase- and Dopamine Transporter-Immunoreactive Axons in the Primate Cerebellum Evidence for a Lobular- and Laminar-Specific Dopamine Innervation

Cerebellum volume and eyeblink conditioning in schizophrenia

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia

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