"Методологические подходы к оценке роли гиппокампа в формировании ассоциативной эпизодической памяти" тема диссертации и автореферата по ВАК РФ 00.00.00, кандидат наук Воробьева Алисия Нуньес

• Воробьева Алисия Нуньес
• кандидат наук
• 2023

Оглавление диссертации кандидат наук Воробьева Алисия Нуньес

Table of contents

PUBLICATIONS AND APPROBATION OF RESEARCH

List of abbreviations

INTRODUCTION

Research problem

Research goals

OVERVIEW

Study

Study

Theoretical novelty

Methodological novelty

Empirical novelty

Contribution of the author

KEY RESULTS

Study 1 (Methodological TES study)

Study 2 (iEEG study)

Provisions for the defense

CONCLUSION

ACKNOWLEDGEMENTS

REFERENCES

APPENDICES

Appendix A. Research article " Transcranial direct current stimulation effects on memory consolidation: timing matters"

Appendix B. Research article "Online and offline effects of transcranial alternating current stimulation of the primary motor cortex"

Appendix C. Research article "Hippocampus-located processing speed of contextual information is associated with its congruence to the previously developed schemas"

Введение диссертации (часть автореферата) на тему «"Методологические подходы к оценке роли гиппокампа в формировании ассоциативной эпизодической памяти"»

INTRODUCTION

Research problem and its significance

One of the most important cognitive mechanisms that provides flexible regulation of behavior is the ability to compare and integrate the subject's background information about the world with novel information constantly coming from outside. The importance of prior knowledge or schema representation in facilitating memory encoding, consolidation, and retrieval has been well-established in research. The hippocampus (HC) plays a crucial role in integrating information across different brain networks during memory processes (Geib et al., 2017; Moscovitch et al., 2016; Nadel & Moscovitch, 1997; Squire & Zola-Morgan, 1991). Recent studies have also highlighted the involvement of the medial prefrontal cortex (mPFC) in establishing connections between object representations based on their congruence with prior knowledge or similarity to each other, thereby enhancing memory functions.

In this study, we aimed to investigate the potential of non-invasive brain stimulation (NIBS) techniques to modulate the functioning of the episodic memory network. Specifically, our focus was on suppressing the activity of the mPFC, which is a core hub within this network, in an attempt to downregulate deeper brain structures otherwise inaccessible for NIBS. NIBS techniques are largely used for studying cognitive processes and their neural underpinning in a causal manner by allowing a transient and reversible modulation of neural activity in a given brain region. Indeed, such techniques as transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES) allow to establish causal relationship between cognitive function and particular cortical regions.

TMS, however, came out inefficient to bring evidence to reject or support our hypothesis about causal involvement of the mPFC to associative memory processing. As a next step, we considered TES for the same purpose of mPFC activity modulation. Transcranial direct current stimulation (or micropolarization) is a widely used method to study neurocognitive functions. However, according to the findings of a recent meta-analysis, transcranial direct

current stimulation (tDCS) studies on long-term memory in healthy subjects have demonstrated statistically non-significant or weak effects (Galli et al., 2019). This can be attributed to the high heterogeneity of tDCS protocols employed, such as variations in stimulation intensity and duration, as well as potential temporal mismatches between the tDCS effect and the process under investigation (Vorobiova et al., 2019).

On the other hand, the usage of transcranial alternating current stimulation (tACS) allowing for modulation of endogenous oscillatory activity, was very appealing. Online effects of tACS are well known, however, our experimental paradigm required for an offline stimulation technique, for there is no evidence for time-locked tACS effects. It is a rather novel method, and we explored its possibilities in a full-scale combined TMS-tACS methodological study on motor cortex excitability. This precursory part was necessary as a groundwork, because testing tACS effects on motor cortex excitability allows to record direct electrophysiological response from muscle to check for reliability of tACS effects per se, which is impossible with cognitive tasks. Our study did not reveal any significant offline effects of tACS on motor cortex excitability. This result, though of high methodological value per se, leaned us to disclose the usage of tACS in our study of associative memory. Thus, we have decided to adopt a challenging but more accurate technique, such as stereoelectroencephalography (sEEG) as the most suitable alternative method for investigating a deep structures like the hippocampus.

To date, sEEG remains the number one provider of detailed information about dynamics of electrophysiological activity of the human HC involved in the memory functions (Johnson et al., 2020; Johnson & Knight, 2015). However, the implementation of this method for the purposes of a fundamental neurocognitive research has a number of potential limitations and disadvantages (Henin et al., 2019; Parvizi & Kastner, 2018; Youngerman et al., 2019). We reviewed the main results in the field of episodic memory mechanisms obtained with the stereo-electroencephalography (sEEG) method, as well as its basic principles, advantages

and limitations. Finally, using sEEG, we recorded the hippocampal local field potential in human subjects performing an associative memory encoding task.

Episodic memory

Episodic memory is a memory for person's own life events in a specific spatial and temporal context (Ranganath, 2010; Tulving, 1993). Starting from Bechterev's description of clinical cases (Бехтерев, 1994) and Milner and Scoville's seminal study of patients with hippocampal resection (Milner, 1972; Milner et al., 1968, 1998; Scoville, 1954; Scoville & Milner, 1957), clinical and neurophysiological evidence served as a foundation for the theoretical inferences about structure and mechanisms of episodic memory. Further development of neuroimaging techniques gave rise to the new insights about neural underpinning of the long-term memory system. Nowadays the episodic memory is assumed to be supported by the distributed network of cortical and subcortical structures, including hippocampal formation, prefrontal and posterior parietal cortices (Buckner et al., 1998; Buckner & Koutstaal, 1998; Burke et al., 2014; Kim, 2011; Long & Kahana, 2015; Paller & Wagner, 2002). It is suggested that the medial temporal lobes (MTL) structures (including the hippocampus, rhinal cortex, amygdala and parahippocampal gyrus) are responsible for the initial formation of the memory trace (Damasio et al., 1985; Milner et al., 1968; Preston & Eichenbaum, 2013; Scoville & Milner, 1957), whereas the neocortex, specifically the medial prefrontal cortex (mPFC) is involved in the binding of details and events into coherent memory trace within a given context (Brodt et al., 2016; Eichenbaum, 2017; Moscovitch et al., 2016; Sestieri et al., 2017; Squire, 1992). Moreover, cortico-hippocampal circuits allow for the construction and reconstruction of episodic events based in semantic structures and within its detail-rich context, i.e. providing an access to the interrelated representations (Behrens et al., 2008; Blumenfeld & Ranganath, 2007; Ghosh & Gilboa, 2014; Moscovitch & Winocur, 2002; Preston & Eichenbaum, 2013).

Cognitive neuroscience of memory is a challenging area of research, for various reasons. Episodic memory is a reconstructive process unfolding in time and charging a large network

of brain areas. For this reason, it requires for the research methods with high temporal and spatial resolution. Due to technical limitations for studying the human MTL, this brain area is not yet investigated at the same level of specificity as for the non-human animal models.

Non-invasive brain stimulation

NIBS techniques, such as transcranial magnetic stimulation (TMS) and transcranial electric stimulation (TES) are well-established methods for studying cognitive processes and their neural underpinning. NIBS is an umbrella term for methods which, by virtue of different non-invasive mechanisms, allow a transient and reversible modulation of neural activity in a particular brain region. Thus, they have advantage over other neuroimaging techniques, moving from correlative approach to establishing of causal relationship between a given brain region and its function. TMS affects brain tissue by generating strong electric field which elicits an electric current depolarizing neuronal membranes, thus inducing action potentials in cortical structure directly under the induction area (Wagner et al., 2007). A series of TMS pulses of specific frequency allows for safe short-term stable modulation (facilitation or inhibition) of cortical excitability (Huang et al., 2005; Rossi et al., 2009). TES, in turn, uses weak electric current to modulate brain activity, shifting its excitability by direct current stimulation, or entraining endogenous rhythmical activity by alternating current (tACS).

Intracranial EEG

Intracranial EEG (iEEG) is the main technique that provide high spatial and temporal resolution human memory data from the MTL. This method provides research opportunities that are inaccessible for non-invasive neuroimaging techniques (Chiong et al., 2018). Typically, iEEG involves patients with implanted stereotaxic electrodes due to the drug-resistant epilepsy. The number of electrodes in non-epileptic tissues depends on the total amount of electrodes and their position. Generally, it is assumed that up to 80% of contacts are located in non-epileptic brain tissue (Parvizi & Kastner, 2018). A stereo-EEG electrodes records local field potentials, i.e. compiled neuronal (and other electrophysiological) activity

with millimeter spatial and millisecond temporal resolution (Buzsaki et al., 2012; Parvizi & Kastner, 2018). High signal to noise ratio (compared to the scalp EEG and magnetoencephalography (MEG)) increases observed effect sizes and allows to conduct studies with relatively small sample size. However, this method presents several difficulties proceeding from the participants' clinical state. Typical limitations of an iEEG research include:

1) suboptimal physical and psychological state and engagement of participants due to seizures, pain, medication intake, fatigue, disturbances in the sleep-wake cycle, which only allow to conduct cognitive studies with a low amount of trials and relatively simple experimental design.

2) the experimenter's lack of full control over the environmental conditions during the experiment;

3) artifacts caused by the hospital equipment, patient's movements, or interictal activity that results in significant data leakage;

4) limited time of patients' availability due to the risk of infection and signal deterioration over time (Henin et al., 2019);

5) limited access to patients and small sample size (Youngerman et al., 2019);

6) heterogeneity of samples by diagnosis, age, sex, handedness, etc.;

7) influence of focal epileptic activity on the normal physiological activity (Henin et al., 2021), as well as possible functional (Alessio et al., 2013; Sidhu et al., 2013; Wilson et al., 2015; Witt et al., 2014; Witt & Helmstaedter, 2012) or structural (Bonilha et al., 2015; Buckmaster, 2010; Taylor et al., 2015; van Diessen et al., 2013) abnormalities in the epileptic brain;

8) limited spatial coverage of the brain by the implantation scheme (Johnson et al., 2020; Parvizi & Kastner, 2018);

9) additional massive data leakage due to an ambiguous status of the hippocampus: on the one hand, it is often a target for the stereo-electroencephalography (sEEG) as a potential candidate for the seizure onset zone, on the other hand, only data from the

non-epileptic hippocampi could be used for the research purposes, whereas an assumption of the hippocampus as a source of epileptic activity can be rejected only after surgery.

Therefore, an additional experimental control, as well as customized approach to data analysis and interpretation are required at all stages of iEEG-research, from study design to the data interpretation.

In summary, we identified the following gaps in this field of research, which we addressed in a series of studies: 1) previous studies robustly demonstrated the role of stimuli congruence to their memorization, but no studies causally addressed underlying brain mechanisms of this process; 2). Results of the NIBS memory studies are mixed and controversial, so additional methodological study is required to identify optimal stimulation parameters allowing to modulate memory functions; 3) no study of the human hippocampal electrophysiological activity was performed to investigate its involvement in the processing of information of various congruence.

Research goals and tasks

1) To perform a methodological study to identify an optimal protocol for tACS memory modulation;

2) To identify the patterns of electrophysiological activity associated to the memorization of information of varying congruence:

- To perform a review of iEEG studies of episodic memory aimed to identify known patterns of hippocampal oscillatory activity related to episodic memory processing, as well as predominant methodological problems in this field of research;

- To perform a study with sEEG and to analyze the difference in hippocampal evoked response potentials (ERP) depending on the congruence of encoding material.

Заключение диссертации по теме «Другие cпециальности», Воробьева Алисия Нуньес

ВЫВОДЫ

1. Прямая регистрация электрофизиологической активности гиппокампа человека указывает на вовлеченность гиппокампа в когнитивную обработку сложной контекстуальной информации, как конгруэнтной, так и неконгруэнтной ранее сформированному семантическому знанию.

2. Обработка информации, конгруэнтной сформированному ранее семантическому знанию, сопровождается более ранней активацией гиппокампа по сравнению с обработкой информации, требующей установления новых ассоциативных связей.

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A. N. Vorobiova"' b- #, T. Fedeleb, |E. F. Pavone}', J. Sarnthein^, L. Imbach", M. Feurra"' b

aCentre for Cognition and Decision Making, Institute for Cognitive Neuroscience, HSE University, Moscow, Russia

bHSE University, Moscow, Russia cBraintrends Ltd., Rome, Italy dUniversity Hospital Zurich, Zurich, Switzerland e University of Zurich, Zurich, Switzerland #e-mail: [e-mail]