Anatomical Evidence for Cerebellar and Basal Ganglia Involvement in Higher Cognitive Function

Middleton, Frank A.; Strick, Peter L.

doi:10.1126/science.7939688

Cited by 1,214 publications

(594 citation statements)

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“…They suggested that the correlation between the two structures may reflect a developmental link between the two abnormalities, despite reported differences in the type of neural abnormalities in frontal and cerebellar cortex reported in post-mortem studies (e.g., Bailey et al, 1998). Specifically, abnormal cerebellar activity induced by Purkinje neuron reduction may cause the maldevelopment of frontal cortex via known cerebello-thalamo-cortical projections (Middleton and Strick, 1994). Given current evidence of early brain growth dysregulation and ongoing neuroinflammatory processes in autism (see below), it is possible that the relationship between neural abnormalities in the cerebellum and the frontal lobes changes with age as both structures continue to suffer the effects of neuroinflammation and concomitant cell damage.…”

Section: Discussionmentioning

confidence: 99%

N-acetyl aspartate in autism spectrum disorders: Regional effects and relationship to fMRI activation

et al. 2007

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Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 agematched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD.

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Section: Discussionmentioning

confidence: 99%

N-acetyl aspartate in autism spectrum disorders: Regional effects and relationship to fMRI activation

et al. 2007

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“…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. Thus, although DA is known to play a critical role in cognitive functions mediated by other brain regions, such as the prefrontal cortex (Brozoski et al 1979;Sawaguchi et al 1988;Sawaguchi and GoldmanRakic 1991), the results of the present study suggest that DA is unlikely to have an influence on cognitive processing at the level of the cerebellum.…”

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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“…Worsening of dyskinesia or dystonia can appear during initial DBS programming sessions, but these symptoms decline after several hours of continuous stimulation. 160 Deep brain stimulation can generate cognitive side effects as well, including mood changes, 161 depression, 162 decreased working memory performance, 163,164 impulsivity, 165 and hallucinations. 166 One explanation for the emergence of such cognitive side effects is that suprathreshold currents spread into nonmotor regions within the basal ganglia and thalamocortical networks.…”

Section: What To Avoid: Targets That Lead To Undesirable Side Effectsmentioning

confidence: 99%

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

et al. 2008

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Summary:Chronic electrical stimulation of the brain, known as deep brain stimulation (DBS), has become a preferred surgical treatment for medication-refractory movement disorders. Despite its remarkable clinical success, the therapeutic mechanisms of DBS are still not completely understood, limiting opportunities to improve treatment efficacy and simplify selection of stimulation parameters. This review addresses three questions essential to understanding the mechanisms of DBS. 1) How does DBS affect neuronal tissue in the vicinity of the active electrode or electrodes? 2) How do these changes translate into therapeutic benefit on motor symptoms? 3) How do these effects depend on the particular site of stimulation? Early hypotheses proposed that stimulation inhibited neuronal activity at the site of stimulation, mimicking the outcome of ablative surgeries. Recent studies have challenged that view, suggesting that although somatic activity near the DBS electrode may exhibit substantial inhibition or complex modulation patterns, the output from the stimulated nucleus follows the DBS pulse train by direct axonal excitation. The intrinsic activity is thus replaced by high-frequency activity that is time-locked to the stimulus and more regular in pattern. These changes in firing pattern are thought to prevent transmission of pathologic bursting and oscillatory activity, resulting in the reduction of disease symptoms through compensatory processing of sensorimotor information. Although promising, this theory does not entirely explain why DBS improves motor symptoms at different latencies. Understanding these processes on a physiological level will be critically important if we are to reach the full potential of this powerful tool.

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Anatomical Evidence for Cerebellar and Basal Ganglia Involvement in Higher Cognitive Function

Cited by 1,214 publications

References 47 publications

N-acetyl aspartate in autism spectrum disorders: Regional effects and relationship to fMRI activation

N-acetyl aspartate in autism spectrum disorders: Regional effects and relationship to fMRI activation

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

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

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