Exploring the Neural Basis of Cognitive Processing in the Human Brain:
Single Neuron Recordings in Depth-electrode Candidates for Epilepsy Surgery

The present project proposes to investigate the cellular basis of cognitive
functions (such as memory and visual information processing) using
single-neuron activity recorded via micro-wires implanted in different brain
areas of patients undergoing treatment for intractable epilepsy. Significant
research at the cellular level in animals, and with fMRI, PET and clinical
cases in humans has revealed aspects of cognitive processing. However, studies
of the mechanisms underlying various cognitive processes at the single neuron
level in awake behaving humans are scarce. The recording of activity from
single neurons is the gold standard for neuroscientific research, giving
insight into the neural mechanisms underlying cognitive processes ranging from
visual perception to memory formation. However, until recently, single-neuron
recordings were only possible in animal models. Recent work (e.g. protocol
2009/194) has shown that it is possible to record from single human neurons
during treatment for intractable epilepsy. The activity of single neurons and
local field potentials will provide unique, direct evidence (contrary to
imaging techniques such as PET and fMRI) on the functioning of different brain
areas and their interplay during cognitive processing in awake behaving humans.
Moreover, it will be possible to study elements of cognition which are
impossible to study in animals, such as visual imagery. Therefore, these
experiments will not only verify previous findings from the animal literature
in the human brain, but will also provide unique data for which there is no
alternative method available.

The main objective of this study is to investigate the neural basis of
cognitive processing in awake behaving patients. The main focus will be on
memory processes in the medial temporal lobe (MTL), emotional processing in the
insular cortex and visual processing.
The secondary objective of this study is to measure single neuron activity
during stimulation of macro-electrode contacts to measure in vivo connectivity
between different cortical areas.

This is a prospective observational study. We will record from both macro- and
microelectrodes implanted in the brains of fifty epileptic patients while they
perform simple cognitive tasks. The neuronal data will be analyzed according to
standard procedures employed in both human and non-human primate
electrophysiology.

This project uses patients who have been selected to be implanted with depth
electrodes as part of their treatment for intractable epilepsy. In a subset of
these patients we will select between 4-8 depth electrodes to receive hybrid
macro/micro-electrodes. This combination of a depth electrode (macro-electrode)
and the micro-wire tetrodes is known as MME depth electrode. This type of
electrode has also been used successfully in previous studies in other centers
(Despouy et al., 2019; Despouy et al., 2020). The use of a hybrid electrode
instead of a standard depth electrode does not impact on the clinical data
obtained from the macro-electrode in any way and the volume occupied by the
micro-wires is negligible in comparison to the volume occupied by the
macro-electrode. As such the only risks that should considered here are any
additional risks posed by implanting hybrid electrodes rather than the standard
depth electrodes.
Recently, a study was published in the Journal of Neuroscience Methods that
specifically looked at the safety of hybrid macro-microelectrodes (Despouy et
al., 2020). They reported the characteristics, safety and compatibility of
clinical intracranial recordings in 28 patients, implanted with 240 standard
clinical macroelectrodes and 102 hybrid electrodes. They concluded that the
hybrid electrode is safe, easy to use, and works satisfactorily for conducting
multi-scale seizure and physiology analyses. Therefore, to the best of our
knowledge, no health risks are involved due to the implementation of
microelectrodes. We expect no additional burden and/or risks associated with
the use of micro-macro-electrodes (hybrid electrodes) compared to the use of
standard macro-electrodes. Moreover, we have no reason to expect any additional
burden and/ or risks from recording single neuron activity during macro-contact
stimulation.

The burden for patients in this study consists of a short screening session and
on average three sessions of simple cognitive tests per day during their stay
at the Epilepsy Monitoring Unit. The individual experiments will take on
average 10 minutes. Individual sessions will consist of multiple experiments
with breaks in-between. We design our tasks so as not to overtire the patients
and to maintain their enthusiasm and interest. We have found in a previous
study (protocol 2009/194) that most patients are very willing to take part in
the study and very enthusiastic about the research and see the tasks as a
welcome distraction. Experimental sessions will be scheduled according to the
wishes and needs of the patients, hospital staff and visitors.

The burden for a small group of patients who undergo MRI consists of one fMRI
session and traveling to the MRI location in Amsterdam.