Exploring the connectivity between the cerebellum and motor cortex in humans

Daskalakis, Zafiris J.; Paradiso, Guillermo; Christensen, Bruce K.; Fitzgerald, Paul B.; Gunraj, Carolyn; Chen, Robert

doi:10.1113/jphysiol.2003.059808

Cited by 300 publications

(280 citation statements)

References 47 publications

(76 reference statements)

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“…afferent synaptic activity. That FA values measured in cerebellar outflow pathways were found to correlate negatively with sensorimotor metabolic activity is consistent with the hypothesized role of the ascending CbTC system in facilitating intracortical inhibition via thalamocortical projections to inhibitory interneurons in the sensorimotor cortex (18,19). In this regard, more severe involvement of the proximal (i.e., cerebellothalamic) pathway segment in mutant animals was associated with relatively greater loss of local cortical inhibition and corresponding increases in regional neural activity (15).…”

Section: Discussionsupporting

confidence: 59%

“…This correlation was positive, however, and of smaller magnitude than that with the proximal pathway lesion. One interpretation of these findings is that the thalamocortical tract abnormality serves to modulate the increases in sensorimotor cortical activity that, in dystonia gene carriers, have been attributed to reduced cerebellothalamic facilitation of inhibitory cortical interneurons (6,15,18,19).…”

Section: Resultsmentioning

confidence: 99%

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Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

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

113

112

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The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent micro-PET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.connectivity | regional metabolism | brain networks I n recent years, advanced imaging technologies such as PET and magnetic resonance diffusion tensor imaging (DTI) have provided unique information regarding the impact of specific genetic mutations on brain structure and function. However, to control for variability in genetic background and additional confounders such as age and sex, many more mutation carriers (and control subjects) are required than can conveniently be scanned, even in a multicenter design. Human imaging studies may also suffer from relatively low spatial resolution and sensitivity. These considerations motivated the current study in which high field magnetic resonance DTI was performed ex vivo in an experimental genetic model of a brain disorder.Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2). DYT1 dystonia, the most common inherited form of the disease, is caused by a dominantly inherited 3-bp in-frame deletion in the TOR1A gene that removes a single glutamic acid (ΔE) from the torsinA protein (3). This lowprevalence mutation (approximately 1 in 30,000...

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Section: Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

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

113

112

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“…The physiology of the CTC pathway activated by magnetic stimulation has recently been clarified (Koch, 2010). It has been proposed that cerebellar TMS activates the Purkinje cells of the superior cerebellum, resulting in inhibition of the dentate nucleus, which is known to exert a background tonic facilitatory drive onto the contralateral M1 through a synaptic relay in the ventral lateral thalamus (Daskalakis et al, 2004;Middleton and Strick, 2000). This in turn leads to inhibition of the contralateral M1, due to a reduction of the dentato-thalamo-cortical facilitatory drive (Ugawa et al, 1994(Ugawa et al, , 1995.…”

Section: Discussionmentioning

confidence: 99%

“…Curr Opin Neurobiol 21:596-601. Daskalakis ZJ, Paradiso GO, Christensen BK, et al (2004).Exploring the connectivity between the cerebellum and motor cortex in humans. J Physiol 557:689-700.…”

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confidence: 99%

Cerebellar theta burst stimulation in stroke patients with ataxia

Bonnı̀

Ponzo

Caltagirone

et al. 2014

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SummaryEvidence for effective improvement of the symptoms of cerebellar stroke is still limited. Here, we investigated the effects of repetitive transcranial magnetic stimulation (rTMS) applied over the injured cerebellar hemisphere in six patients with posterior circulation stroke. We applied a two-week course of cerebellar intermittent theta burst stimulation (iTBS). Before and after the iTBS treatment, paired-pulse TMS methods were used to explore: i) the functional connectivity between the cerebellar hemisphere and the contralateral primary motor cortex (M1), by means of the cerebellar brain inhibition (CBI) protocol; and ii) the intracortical circuits in the contralateral M1, by means of the short intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) protocols. Patients were also evaluated using the Modified International Cooperative Ataxia Rating Scale (MICARS). Cerebellar iTBS induced a decrease in CBI and an increase in ICF at an interstimulus interval of 15 msec. These neurophysiological changes were paralleled by a clinical improvement, shown by the MICARS posture and gait subscale scores. Cerebellar iTBS could be a promising tool to promote recovery of cerebellar stroke patients. KEY WORDS: cerebellar stroke; theta burst stimulation; intracortical facilitation IntroductionPatients affected by ischemic or hemorrhagic stroke present motor disturbances such as ataxia, intention tremor, axial latero-pulsion and dysarthria. Ataxia is a common impairment after posterior circulation stroke Cerebellar theta burst stimulation in stroke patients with ataxia (PCS) involving the cerebellum or brainstem, and it restricts patients in their mobility and activities of daily living (Teasell et al., 2002). Various strategies have been suggested to improve the symptoms of cerebellar stroke, but the evidence of their effectiveness is still limited (Kruger et al., 2007). Repetitive transcranial magnetic stimulation (rTMS) has recently been proposed as a potentially useful method for modulating the excitability of cerebellothalamo-cortical (CTC) pathways, which could have a favorable effect on the cerebellar deficit (Koch, 2010). The current study was conducted to investigate the effects of a two-week course of cerebellar intermittent theta burst stimulation (iTBS) in a sample of six chronic stroke patients affected by PCS. This protocol is known to induce an increase in the excitability of the CTC pathways (Koch et al., 2008). Before and after the iTBS treatment we used paired-pulse TMS methods to explore: i) the functional connectivity between the affected cerebellar hemisphere and the contralateral motor cortex (M1), assessing cerebellar brain inhibition (CBI), and ii) the excitability of the contralateral M1, assessing short intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF). In addition, all the patients were submitted to clinical evaluation: the Modified International Cooperative Ataxia Rating Scale (MICARS) was administered to investigate whether the iTBS protocol could improve ...

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“…The cerebellum imposes a level of tonic inhibition over M1 via the cerebello-thalamo-cortical pathway, which can be investigated using paired-pulse TMS [36][37][38]. A weak conditioning magnetic pulse over the cerebellum suppresses the magnitude of a second pulse applied to M1, known as cerebellar-brain inhibition (CBI).…”

Section: The Cerebellum and Dystoniamentioning

confidence: 99%

Non-invasive cerebellar stimulation in dystonia

Graetz

Bradnam

2013

Translational Neuroscience

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Primary isolated dystonia is a hyperkinetic movement disorder whereby involuntary muscle contractions cause twisted and abnormal postures. Dystonia of the cervical spine and upper limb may present as sustained muscle contractions or task-specific activity when using the hand or upper limb. There is little understanding of the pathophysiology underlying dystonia and this presents a challenge for clinicians and researchers alike. Emerging evidence that the cerebellum is involved in the pathophysiology of dystonia using network models presents the intriguing concept that the cerebellum could provide a novel target for non-invasive brain stimulation. Non-invasive stimulation to increase cerebellar excitability improved aspects of handwriting and circle drawing in a small cohort of people with focal hand and cervical dystonia. Mechanisms underlying the improvement in function are unknown, but putative pathways may involve the red nucleus and/or the cervical propriospinal system. Furthermore, recent understanding that the cerebellum has both motor and cognitive functions suggests that non-invasive cerebellar stimulation may improve both motor and non-motor aspects of dystonia. We propose a combination of motor and non-motor tasks that challenge cerebellar function may be combined with cerebellar non-invasive brain stimulation in the treatment of focal dystonia. Better understanding of how the cerebellum contributes to dystonia may be gained by using network models such as our putative circuits involving red nucleus and/or the cervical propriospinal system. Finally, novel treatment interventions encompassing both motor and non-motor functions of the cerebellum may prove effective for neurological disorders that exhibit cerebellar dysfunction.

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Exploring the connectivity between the cerebellum and motor cortex in humans

Cited by 300 publications

References 47 publications

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Cerebellar theta burst stimulation in stroke patients with ataxia

Non-invasive cerebellar stimulation in dystonia

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