Altered motor cortical plasticity in patients with hepatic encephalopathy: A paired associative stimulation study
Introduction
Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction due to liver failure (Häussinger et al., 2021, Haussinger and Schliess, 2008, Häussinger and Sies, 2013), which occurs in about 30–45 % of patients with liver cirrhosis (Vilstrup et al., 2014). HE comprises a broad spectrum of neuropsychiatric impairments, including motor impairments, deficits in visual and tactile perception, cognitive dysfunction, and impaired consciousness (Felipo, 2013, Henderson, 2008, Kircheis et al., 2002, Lazar et al., 2018). While historically, HE has been viewed as a single syndrome, the diversity of symptoms is currently thought to be mediated by different underlying mechanisms (Felipo, 2013). Yet, it is generally agreed that both systemic inflammation and hyperammonemia are crucial for symptom development (Coltart et al., 2013, Desjardins et al., 2012, Rose, 2012). Although potentially reversible, manifest HE often results in frequent and recurring hospitalization and thus constitutes a substantial burden for both patients and healthcare systems (Stepanova et al., 2012).
Previous work demonstrated decreased cortical synaptic plasticity in HE (Wen et al., 2013). Presumably, such alterations result from oxidative stress in neurons and glial cells due to accumulation of neurotoxins, especially ammonia (Haussinger and Schliess, 2008). Specifically, hyperammonemia has been connected to reductions in extrasynaptic reserve pools of AMPA-type glutamate receptors, which in turn severely limits synaptic plasticity (Schroeter et al., 2015). Importantly, alterations in synaptic plasticity are interpreted as precursor for the global cortical slowing of neuronal oscillatory activity (Butz et al., 2013, May et al., 2014, Timmermann et al., 2005), which is suggested to lead to the perceptual (Baumgarten et al., 2018, Götz et al., 2013) and motor deficits (Cantarero et al., 2013, Timmermann et al., 2008) present in HE. Thus, cortical synaptic plasticity changes are thought to represent a key mechanism connecting disease-related effects on the molecular level with impaired behavioral parameters. Although different forms of cortical synaptic plasticity have been described, the present work focusses on long-term potentiation (LTP; Malenka and Bear, 2004), since this process can be experimentally assessed in vivo in HE patients directly by means of non-invasive brain stimulation methods.
Transcranial magnetic stimulation (TMS) offers a non-invasive and painless method to investigate cortical physiology (Hallett, 2000, Rothwell, 1997). Paired associative stimulation (PAS; Stefan et al., 2002, Stefan et al., 2000), an experimental TMS paradigm combining afferent electrical and cortical magnetic stimulation in a precise temporal regime, allows for the investigation of motor cortical plasticity in particular. To this end, an electrical stimulation of the median nerve is temporally paired with a TMS pulse over the contralateral primary motor cortex (M1). In one variant of PAS, median nerve stimulation is applied 25 ms before the TMS pulse, a protocol that is referred to as PAS25. As the afferent input from the median nerve needs 21–23 ms to reach M1, the electrically-induced neural signal arrives at M1 immediately before the TMS pulse (Wolters et al., 2003). Hence, the PAS25 protocol is known to enhance excitability within M1, where excitability evolves rapidly and remains present for an extended duration, inducing long-term potentiation (LTP) of synaptic efficacy (PAS25LTP). Conceptually, an increase in excitability is interpreted as spike timing dependent plasticity (STDP), which is considered as one of the core mechanisms driving LTP (Stefan et al., 2002, Stefan et al., 2000). Consistently, long-term depression (LTD) effects are also known to occur when the afferent input from the median nerve arrives at M1 after the TMS pulse (Di Lazzaro et al., 2009, Wolters et al., 2003).
While the PAS25 protocol offers an established and mechanistically well understood option to non-invasively study motor cortical plasticity in healthy subjects and patient populations (Golaszewski et al., 2016), motor cortical plasticity has been investigated with various different TMS protocols, e.g., PAS21.5 (Hamada et al., 2012) or intermittent theta-burst stimulation (Huang et al., 2005). Although both PAS21.5 and PAS25 induce LTP-like changes in the motor cortex, subsequent studies have highlighted different pathways underlying these effects (Hamada et al., 2012, Popa et al., 2013, Strigaro et al., 2014). Whereas PAS21.5 is thought to rely on signal transduction by means of a direct sensory pathway to the motor cortex, PAS25 is mediated by comparatively complex circuits (Hamada et al., 2012), including slow extra-lemniscal relays and cerebellar inputs (Butler et al., 1992, Popa et al., 2013). In the present study, we selected the PAS25 protocol as it represents the most frequently used PAS protocol variant to elicit LTP-like effects (reviewed in Wischnewski and Schutter, 2016). Furthermore, the complex circuit dynamics involved in PAS25 allow for investigation of a wide range of plasticity mechanisms potentially impaired in HE. Such a global approach is motivated by the broad symptom spectrum associated with HE.
Although PAS protocols offer an intriguing possibility to non-invasively study motor cortical plasticity in patient populations (Golaszewski et al., 2016), earlier reports describe considerable inter-individual variability in responses to PAS. Regarding PAS25 for example, about half of the subjects are known to not respond to the study protocol (López-Alonso et al., 2014). Because of this high variability, it is possible that up to 50% of the subjects even develop signs of LTD (PAS25LTD), opposing general protocol expectations (Müller-Dahlhaus et al., 2008).
Here, we investigated synaptic plasticity of M1 in patients with manifest HE in different stages of disease severity and healthy controls. We hypothesized that healthy participants demonstrate LTP-like effects after PAS25 intervention, while such effects would be diminished or absent in HE patients.
Section snippets
Participants
23 patients (15 male, 8 female; age: 60.83 ± 1.35 (mean ± SEM)) with hepatic encephalopathy (HE) and 23 healthy volunteers (13 male, 10 female; age: 61.45 ± 1.46) participated in the present study (see Table 1 for details). All participants provided written informed consent prior to study participation. The study was performed in accordance with the Declaration of Helsinki (World Medical Association, 2013) and was approved by the ethics committee of the Medical Faculty, Heinrich Heine
Demographic data
Seven of the 23 HE-patients enrolled in the study exhibited minimal hepatic encephalopathy (mHE); 13 were in grade one (HE1), and three in grade two (HE2) according to West-Haven criteria. All patients in the study were diagnosed with a liver cirrhosis for at least two months prior inclusion. There was no significant difference in age, as well as perceptual threshold, and RMT between HE-patients and healthy controls (p > 0.05 for all comparisons). Age and perceptual threshold of both patients
Discussion
Our study has two main findings. First, significant PAS-induced long term-potentiation (LTP) in M1 could not be observed in HE patients, but exclusively in healthy controls. In addition, MEP change post PAS25 was significantly higher in healthy controls than in HE patients. Second, MEP amplitudes of recruitment curves in HE patients were significantly smaller, as compared to those of healthy controls, which indeed confirmed our previous findings. Taken together, we could demonstrate reduced
Conclusion
Our study shows a reduced long-term plasticity over M1 in patients with HE, including manifest HE, compared to healthy controls of the same age. Further research is needed to determine the relation between altered plasticity and both motor and non-motor symptoms in HE.
Funding
This research was funded by “Deutsche Forschungsgemeinschaft” (DFG), as part of the project SFB974 B07. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 795,998 (MSCA-IF-GF MSC GF awarded to T.J.B.).
Data availability
Data is available from the corresponding author on a reasonable request.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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These authors contributed equally to this manuscript.