Cortical inhibitory deficits in premanifest and early Huntington’s disease

Philpott, April L.; Cummins, Tarrant; Bailey, Neil W.; Churchyard, Andrew; Fitzgerald, Paul B.; Georgiou‐Karistianis, Nellie

doi:10.1016/j.bbr.2015.09.030

Cited by 33 publications

(26 citation statements)

References 45 publications

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“…However, investigations using TMS in HD patients reveal inconsistent results. AMT and RMT were found higher in preclinical and early HD when compared with healthy participants in one study, but normal in other studies, whereas the I/O curve was flatter in preclinical and HD when compared with controls when assessed at rest, but normal under activation . This suggests that, in the resting state, excitability is lower than normal but that it can be normalized by voluntary contraction …”

Section: Methodsmentioning

confidence: 79%

The interindividual variability of transcranial magnetic stimulation effects: Implications for diagnostic use in movement disorders

et al. 2019

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Background A large number of methods have been described that use transcranial magnetic stimulation to probe the physiology of the human motor cortex. Since the 1990s, hundreds of papers have used them to investigate neurophysiological signatures of different types of movement disorders. However, in recent years there has been increasing recognition of the interindividual variability of these measures and a focus on estimating their reliability and reproducibility. Although this work has been carried out in healthy individuals, it is highly relevant to movement disorders because it may impact the validity of some accepted (“canonical”) neurophysiological biomarkers. The aim of this review is to reexamine the diagnostic usefulness of transcranial magnetic stimulation methods in movement disorders in the context of present knowledge of methodological variability. Methods We conducted a search of the PubMed database for research and review articles on transcranial magnetic stimulation and its diagnostic utility in movement disorders (specifically Parkinson's disease and atypical parkinsonism, dystonia, Tourette syndrome and other chronic tic disorders, Huntington's disease, and essential tremor). We highlighted contradictions in the literature and common misconceptions with the aim of providing a clearer picture of the reliability of these measures in differential diagnosis of movement disorders. Conclusion Although there is no doubt that these studies have provided useful insight into the pathophysiology of movement disorders, there is a clear disagreement among many studies that questions the validity of some of the so called “canonical” findings as diagnostic markers. However, useful findings remain and even those with higher variability can be used to support clinical diagnosis in selected cases. © 2019 International Parkinson and Movement Disorder Society

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Section: Methodsmentioning

confidence: 79%

The interindividual variability of transcranial magnetic stimulation effects: Implications for diagnostic use in movement disorders

et al. 2019

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“…60,61 Transcranial magnetic stimulation investigations have revealed significant GABA-mediated cortical inhibitory deficits in premanifest and early symptomatic HD patients. 62 The most thorough and recent investigations on GABAergic neurotransmission, including molecular and functional analyses, have been conducted on transgenic rodent models. Interestingly, quantitative autoradiography has been used to assess neurotransmitter receptor densities in several brain regions in a rat model for the HD mutation.…”

Section: Alter Ati On Of the G Aba Sys Tem In The Hd B R Ainmentioning

confidence: 99%

Alteration of GABAergic neurotransmission in Huntington's disease

Garret

Chazalon

et al. 2018

CNS Neurosci Ther

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Hereditary Huntington's disease (HD) is characterized by cell dysfunction and death in the brain, leading to progressive cognitive, psychiatric, and motor impairments. Despite molecular and cellular descriptions of the effects of the HD mutation, no effective pharmacological treatment is yet available. In addition to well-established alterations of glutamatergic and dopaminergic neurotransmitter systems, it is becoming clear that the GABAergic systems are also impaired in HD. GABA is the major inhibitory neurotransmitter in the brain, and GABAergic neurotransmission has been postulated to be modified in many neurological and psychiatric diseases. In addition, GABAergic neurotransmission is the target of many drugs that are in wide clinical use. Here, we summarize data demonstrating the occurrence of alterations of GABAergic markers in the brain of HD carriers as well as in rodent models of the disease. In particular, we pinpoint HD-related changes in the expression of GABA receptors (GABA Rs). On the basis that a novel GABA pharmacology of GABA Rs established with more selective drugs is emerging, we argue that clinical treatments acting specifically on GABAergic neurotransmission may be an appropriate strategy for improving symptoms linked to the HD mutation.

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“…These brain abnormalities may therefore represent the consequences of a developmental diathesis induced by aberrant polyglutamine expansion (polyQ) in huntingtin (Htt). These putative developmental sequelae include impairments in the inhibitory GABAergic system (Philpott et al, 2015), oligodendrocyte abnormalities (Gomez-Tortosa et al, 2001; Myers et al, 1991) and white matter micro-architectural changes (Di Paola et al, 2014; Gregory et al, 2015; Phillips et al, 2014), as well as region-specific brain volumetric alterations (Aylward et al, 2013; Nopoulos et al, 2011; Paulsen et al, 2006). In line with these findings, we and other groups have reported significant developmental abnormalities in striatal and cortical neurogenesis in HD mice (Molero et al, 2009; Molina-Calavita et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

Arteaga-Bracho

Gulinello

Winchester

et al. 2016

Neurobiology of Disease

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The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington’s disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdhd•hyp). We demonstrated that Hdhd•hyp mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdhd•hyp embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.

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Cortical inhibitory deficits in premanifest and early Huntington’s disease

Cited by 33 publications

References 45 publications

The interindividual variability of transcranial magnetic stimulation effects: Implications for diagnostic use in movement disorders

The interindividual variability of transcranial magnetic stimulation effects: Implications for diagnostic use in movement disorders

Alteration of GABAergic neurotransmission in Huntington's disease

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

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