Phase of neuronal activity encodes 2-dimensional space in the human entorhinal cortex

Abstract

19The entorhinal cortex plays a vital role in our spatial awareness. Much focus has been placed on the spatial 20 activity of its individual neurons, which fire in a grid-like pattern across an environment 1 . On a population 21 level, however, neurons in the entorhinal cortex also display coherent rhythmic activity known as local field 22 potential. These local field oscillations have been shown to correlate with behavioural states but it remains 23 unclear how these oscillations relate to spatial behaviour and the spatial firing pattern of individual neurons. 24 To investigate this, we recorded entorhinal cortical neurons in the human brain during spatial memory tasks 25 performed in virtual environments. We observed a spatial modulation of the phase of action potentials relative 26 to the local field potentials. In addition, the spike phase modulation displayed correlation with the movement 27 of the avatar, displayed discrete phase tuning at the cellular level, rotated phase between electrodes, and 28 expressed spatially coherent phase maps that scaled with the virtual environment. Using surrogate data, we 29 demonstrated that spike phase coherence is dependent on the spatial phase dynamics of gamma oscillations. 30 We argue that the spatial coordination of spike generation with gamma rhythm underlies the emergence of 31 grid cell activity in the entorhinal cortex. These results shed a new light on the intricate interlacing between 32 the spiking activity of neurons and local field oscillations in the brain. 33 1 The medial entorhinal cortex (EC) is found in the medial temporal lobe of the mammalian brain and plays a 34 critical role in spatial awareness in rodents 1 as well as in humans [2][3][4] . The activity of grid cells and border cells 35 in the EC, together with place cells and head direction cells in the hippocampus and subiculum, respectively, 36 constitute key components of the allocentric navigation system enabling individuals to localize themselves 37 relative to the environment. The spatially periodic activity, a hallmark of grid cells 1 and displayed by about 38 50% in the human brain 4 , is hypothesized to support spatial navigation as an internal coordinate system. 39 In addition to their spatial tuning, EC neurons generate a broad frequency range of local field potentials 40 (LFPs) with two prominent harmonic components: theta and gamma 5 . Theta and gamma are predominant 41 in the rodent and human hippocampus and EC during active exploratory behaviour and REM-sleep 2,6 42 and hippocampal theta tend to phase-couple with slow gamma (30-50 Hz) from EC 7,8 . Theta-spike and 43 theta-gamma phase coherence are instrumental for memory encoding 9,10 . Although grid cells represent the 44 allocentric coordinate system for spatial navigation in a number of mammalian species 1,11,12 , the role of 45 oscillations in the generation of this spatially periodic activity is unknown. 46A grid of 16 extracellular microelectrodes ( Fig. 3a) was implanted in the EC of two human subjects...

Phase coding of spatial representations in the human entorhinal cortex

“…The 1-ms precise intersections of spike times with the two phase transforms defined two phase vectors converting the spike times to spike phases (ϕ), one vector relative to theta and the other vector relative to gamma, referred herein as gamma phases and theta phases, respectively (Fig. 1E) ( 13 ). While the distributions of spike phases for most cells were nonuniform, three times as many (19%) neurons expressed deviation from uniform phase distribution relative to gamma as to theta (6.21%) [Fig.…”

“…4, A to E). Single units were verified by their high isolation coefficients [Mahalanobis distance between nearest clusters d n > 50 ≥ 20 corresponds with >99% confidence ( 6 , 13 , 64 )] and >5-ms refractory period in their ISI histograms. The second column of fig.…”

“…By comparing phases of the same spikes when referencing them to gamma versus theta band LFPs, we found that 3 to 10 times as many neurons expressed significant environment-specific phase nonuniformity relative to gamma than to theta ( 13 ). In addition, gamma phase tuning showed an increased polarization (Figs.…”

“…Moreover, we observed that gamma phases from both multiple neurons recorded from the same electrode and single neurons resulted in discrete multimodal phase distributions (Figs. 3, B to E, and 4, A to D, respectively) ( 13 ).…”

“…Before experimental data were collected, subjects were allowed to practice playing the game until they were accustomed to the game controls. The subjects’ virtual trajectory and heading (relative to the north-south axis in each game environment) were recorded ( 6 , 13 ).…”