Human hippocampal theta oscillations: Distinctive features and interspecies commonalities1

Joshua Jacobs1, Bradley Lega2, Andrew J. Watrous12

1 Department of Biomedical Engineering, Columbia University3

2 Department of Neurosurgery, UT Southwestern4

Correspondence:5

Joshua Jacobs6

Department of Biomedical Engineering7

Columbia University8

351 Engineering Terrace, Mail Code 89049

1210 Amsterdam Avenue10

New York, NY 1002711

212-854-244512

joshua.jacobs@columbia.edu13

1

Abstract14

The hippocampus, along with its characteristic theta oscillation, has been widely implicated in various15

aspects of animal memory and behavior. Given the important roles that hippocampal theta oscillations have16

in theoretical models of brain function, it might be considered surprising that these signals have not been17

reported as often in humans as in animals. In this chapter we review recent research on hippocampal theta18

oscillations in humans, focusing on brain recordings from neurosurgical patients, which provides a key19

opportunity for observing hippocampal oscillations during cognition. The emerging theme of this body of20

work is that humans do indeed have hippocampal oscillations that are similar overall compared to the theta21

oscillation that is commonly found in rodents. Most notably, the human theta oscillation exhibits correlations22

with sensorimotor, navigation, and memory processing in the same general fashion as expected from rodents.23

However, some of the details of theta’s relationship with behavior differ significantly compared to such24

signals in rodents—such as having a lower amplitude, frequency, and duration—which can make this signal25

less readily observable. Thus, theta oscillations are a key component of hippocampal processing in humans,26

but the patterns it exhibits compared to rodents points out distinctive aspects of human brain processes.27

2

Introduction28

In recent years there is growing evidence throughout neuroscience research that neuronal oscillations have29

an important role in how the brain supports behavior and cognition. Brain oscillations with critical functional30

roles are present in many brain regions, in both complex and simple behaviors (Buzsaki & Draguhn, 2004),31

and have even been found to evolve independently through multiple paths during evolution (Shein-Idelson32

et al., 2016). Understanding the roles of neuronal oscillations in brain processing is important on multiple33

levels. In any one neuron, the presence of membrane-potential oscillations can reveal when that cell is34

active (Klausberger et al., 2003). Across a neuronal network, the properties of oscillations reveals that35

rhythmic activations are an important part of neuronal computation (Gray et al., 1989; Fries, 2005). At the36

largest scale, across the brain the patterns of neuronal oscillations illustrates which brain regions are active37

at any particular moment and how information moves between brain areas (Jensen et al., 2007). In addition,38

neuronal oscillations are also useful as a practical research tool in humans because they can be recorded39

easily and because they demonstrate patterns related to high-level cognitive behaviors (Kahana, 2006).40

The hippocampal theta oscillation, in particular, is one brain oscillation that has an especially notable41

role. The hippocampus is a key brain region for high-level cognitive processing, including memory and42

spatial cognition (Burgess et al., 2002; Buzsaki & Moser, 2013). Research has linked theta oscillations to43

virtually every aspect of hippocampal processing throughout these behaviors. Notably, theta oscillations in44

rodents, which generally occur at 4–10 Hz, relate to hippocampal processing at multiple levels, including45

the timing of neuronal spiking, the modulation of synaptic plasticity, the properties of neuronal computation46

within the hippocampus, and the hippocampus’s interactions with other brain structures (Buzsaki, 2002,47

2005). Theta oscillations are also associated with many behavioral processes, including memory, spatial48

navigation, and sensorimotor processing. Owing to the diverse array of neural processes in which theta is49

involved, it seems that understanding theta’s functional role is important for showing how the brain as a50

whole operates, especially including any behavior or neural process that is linked to the hippocampus.51

Historically, our understanding of hippocampal theta oscillations has been primarily derived from studies52

in rodents (e.g., Vanderwolf, 1969). Of course, the general tactic of using research findings from rodents53

to make insights regarding biological processes in other species has traditionally been very successful and54

impactful. However, several key features of rodent theta oscillations have not been observed in humans55

(Jacobs, 2014). Some papers have even suggested that hippocampal theta oscillations may not exist at all in56

3

some species (Halgren et al., 1985; Yartsev et al., 2011)!57

As a result, there currently seems to be a large conceptual disconnect between research in rodents, which58

suggests that theta oscillations underlie most every aspect of hippocampal function (Buzsaki, 2005), versus59

the studies of brain recordings in humans and other species that do not find evidence of theta. In light of60

this uncertainty, it seems important to carefully evaluate the literature regarding human theta oscillations in61

a comparative cross-species manner. The goal of this chapter is to provide this evaluation by describing our62

current understanding of human theta amidst the larger literature on theta oscillations in rodents and other63

simpler animals.64

We organize our review of human data around the main hypothesized functions of theta that were identi-65

fied in rodents. We also discuss data from non-human primates when possible. Our overarching conclusion66

is that humans and monkeys do have hippocampal theta oscillations and that these signals are largely anal-67

ogous in function to the theta oscillations commonly observed in rodents. However, as we explain below,68

human hippocampal oscillations generally are slower in frequency compared with theta oscillations in ro-69

dents. This difference caused some previous studies to refer to them as “delta” oscillations. Nonetheless,70

here we continue to use our preferred term “theta” to refer to human hippocampal oscillations across the71

wider band of 1 to 10 Hz because it emphasizes their important functional similarities with rodent 4–10 Hz72

theta (Jacobs, 2014).73

As we explain, most of the key findings from theta in rodents are relevant for understanding human74

hippocampal neuronal activity and the role of neuronal oscillations. When extending the rodent literature75

towards humans it is important to keep in mind that human behavior is more diverse compared to the be-76

havior of rodents in laboratory experiments. Therefore, as we explore below, there are multiple potential77

causes of differences in theta oscillations between humans and rodents, including both behavior as well as78

brain physiology. Nonetheless, despite these differences in the detailed properties of theta across species—79

which are notable especially in frequency and amplitude—we feel overall that the all-important functional80

similarities outweigh the differences.81

Recording hippocampal theta oscillations in humans82

Until the last couple of decades, the vast majority of research on the electrical activity in the human brain83

recorded electroencephalographic (EEG) signals from the scalp, which primarily measured activity from84

4

the outer layers of the cortex (Niedermeyer & da Silva, 2005). This research was of limited use for under-85

standing activity in deep brain structures such as the hippocampus. Unlike laboratory studies in animals,86

where scientists place electrodes directly in a region of their choosing, for obvious ethical reasons it is not87

straightforward to characterize electrical activity from deep brain structures in humans.88

Neurosurgery provides a unique opportunity to record neuronal activity from deep human brain struc-89

tures because clinicians already placed electrodes in these regions for clinical purposes. A particular type90

of neurosurgery that lends itself well to recording human brain activity is the monitoring of patients who91

have severe epilepsy. These patients have electrodes implanted directly in various brain structures as part92

of a clinical mapping procedure to characterize the brain regions involved in seizures. The hippocampus is93

frequently targeted in this procedure because it plays an important role in seizure propagation (Spencer &94

Spencer, 1994). The electrodes often remain in place for up to several weeks while patients remain in their95

hospital beds. Because patients are usually well functioning cognitively during these periods, it provides a96

unique opportunity to directly measure the human neural signals that underlie cognition (Jacobs & Kahana,97

2010). In time between clinical procedures, researchers can ask patients to perform cognitive tasks and the98

data recorded provides a direct view of the electrical activity underlying human behavior.99

Several types of electrodes that are commonly implanted in the epilepsy patients who undergo this100

procedure: surface grid and strip electrodes, which record from the surface of the neocortex, and depth101

electrodes, which target deep brain structures including the hippocampus. Here our focus is on the depth102

electrodes that target the hippocampus. By incorporating the latest advances in high resolution MR scans, it103

is often possible to localize individual electrodes to small regions within the hippocampus, including small104

regions such as the subiculum and Cornu Ammonis regions (A. Ekstrom et al., 2009; Yushkevich et al.,105

2010).106

Neurosurgical patients are generally limited to their hospital bed while electrodes are implanted. There-107

fore, any cognitive tasks must be performed from their bedside. Generally, this means performing tasks on108

a laptop computer. Many behaviors can be examined using a laptop computer, with the use of computerized109

tasks that measure memory or perception of visually presented stimuli (Sederberg et al., 2003). However,110

some behaviors are more challenging to study in this setting, such as those that require movement or lo-111

comotion. Given this constraint, to study movement and navigation researchers developed video-game-like112

virtual-reality paradigms. In these paradigms patients are presented with a view of a virtual environment113

on a computer screen and use a keyboard or joystick to control movement (A. D. Ekstrom et al., 2003).114

5

Although there are certainly important differences between the brain signals underlying real-world and vir-115

tual navigation (e.g., Taube et al., 2013; Minderer et al., 2016), this approach has proven useful because116

it has identified a number of key similarities between how the brain supports real and virtual navigation117

(A. D. Ekstrom et al., 2003; Jacobs et al., 2013; Jacobs, Kahana, et al., 2010).118

In addition to recordings from neurosurgical patients, magnetoencephalography (MEG) has emerged as119

an alternate approach for studying activity in deep human brain structures (Tesche, 1997). By combining120

extracranial measurements of the brain’s magnetic fields with advanced source localization methods based121

on beamforming, researchers have been able to characterize neuronal oscillations in deep brain structures122

such as the hippocampus (Quraan et al., 2011). In many cases this approach has replicated findings of theta123

oscillations and other signals that appeared in direct brain recordings (Cornwell et al., 2008), as well as124

extending these findings, suggesting that MEG is viable for noninvasively probing deep brain structures.125

Role of theta in sensorimotor processing126

Some of the first work identifying a functional role for hippocampal neuronal oscillations in any species fo-127

cused on the fact that that these signals appeared prominently when animals processed sensory information.128

Green and Arduini (1954) provided seminal evidence in this area by showing that prominent oscillations at129

∼5–7 Hz appear in field potentials from the hippocampus of rabbits, cats, and monkeys when they perceived130

new sensory information. Notably, these signals were fairly “high level” such that they appeared in a sim-131

ilar form regardless of whether the animal received visual or auditory input. In this way, sensory-evoked132

hippocampal oscillations differed dramatically from sensory oscillations in neocortex, which are generally133

limited to a particular modality that is specific to the brain region where they are measured. A further feature134

that distinguished human hippocampal theta is that these signals were linked to arousal or attention, such135

that in drowsy animals sensory-evoked hippocampal theta was sometimes missing or diminished.136

A largely separate line of research linked hippocampal oscillations to movement and motor planning.137

Vanderwolf (1969) found that oscillatory activity in the hippocampus often appeared before animals made138

movements such as walking, jumping, or rearing. In many cases these oscillations were sustained through139

the duration of these movements. These movement-related theta oscillations seem to be distinct from the140

sensory patterns mentioned above because they are driven by internal brain events rather than being re-141

sponses to sensory cues.142

6

It should be noted that even this early research on theta oscillations contained discrepancies regarding143

theta’s sensorimotor role. Although both studies examined theta and sensory processing (Green & Arduini,144

1954; Vanderwolf, 1969), only one of these studies actually found positive evidence for this pattern (Green145

& Arduini, 1954). Later work confirmed that hippocampal theta has a role in perception, but nonetheless146

this type of discrepancy emphasizes the challenges of characterizing theta, foreshadowing issues that would147

be described subsequently (Buzsaki, 2005).148

The emerging theme from early animal research on hippocampal theta oscillations is that theta relates to149

sensory and motor processing in a complex manner that is linked to internal brain events and the relevance150

of external percepts. Owing to these distinctive high-level properties, researchers became interested in151

probing hippocampal theta in humans, in part because it seemed that this distinctive signal could be key for152

demonstrating the neural basis of more complex behaviors.153

In humans, some of the earliest work on theta oscillations was performed by Halgren et al. (1985), who154

examined theta oscillations in a neurosurgical patient during verbal and motor tasks. In contrast to expecta-155

tions from animals of task-related theta elevations, this patient exhibited decreased theta-band oscillations156

when processing new information in a memory task or when performing movements. This patient’s hip-157

pocampus was indeed capable of exhibit hippocampal theta oscillations because these signals were present158

in a baseline rest condition. Therefore, these results were interpreted as suggesting that theta’s functional159

role may be fundamentally different in humans compared to animals (see also Brazier, 1968).160

Although this apparent difference in theta’s properties between humans and animals was noteworthy,161

there was only limited follow-up work in this area for a number of years. In addition to the practical chal-162

lenge of collecting human data from this deep brain structure, the experiments that were performed showed163

a patterns of results that was harder to interpret than expected. One study examined hippocampal brain164

activity during different behaviors and found a divergent pattern of theta signals between behaviors (Meador165

et al., 1991). This study found differences in theta activity between visual and auditory task conditions,166

which was surprising because animal studies showed similar levels of theta activity irrespective of sensory167

modality. A different study examined hippocampal theta activity with MEG during a sensory task and also168

found lower than expected theta rhythmicity (Tesche, 1997).169

A surprisingly complex pattern emerged from this early research, suggesting that human theta oscil-170

lations have a more complex behavioral role compared to analogous signals in rodents. Therefore, to un-171

derstand human theta it would seem to be important to characterize the behavioral correlates of theta more172

7

precisely, rather than the coarser-grained approaches that were used initially (Halgren et al., 1985; Tesche,173

1997). Therefore, later generations of studies used quantitative signal-processing techniques to measure the174

phase and amplitude of theta and their precise relations to the timing of sensorimotor events. These evolved175

methods revealed detailed features of theta’s properties that offered hints to help explain discrepancies from176

earlier research. In one study hippocampal theta oscillations were found to be linked to the onset of eye177

movements during visual search (Hoffman et al., 2013).178

One study in monkeys examined the links between hippocampal theta oscillations, sensory processing,179

and memory (Jutras et al., 2013). Consistent with humans, this work showed that theta phase was modulated180

by processing sensory information and, as we describe below, this pattern correlated with memory. These181

two studies on eye movements therefore show an important new way that hippocampal theta oscillations182

related to sensory processing, by showing precise alterations (resets) in theta phase. Showing that theta183

phase is an important aspect of sensory processing was important because it suggested that oscillatory phase184

rather than amplitude is the critical functional variable for certain behaviors (see also Mormann et al., 2005;185

Lopour et al., 2013). In addition to adding a key new wrinkle towards the challenge of understanding theta’s186

functional role, these phase patterns could be important for understanding theta’s role at the neuronal level187

(see below).188

Although studies of hippocampal theta oscillations in humans and animals usually show some type of189

significant correlation with sensorimotor behavior, there are key inconsistencies across this body of work.190

Therefore, going forward researchers took a richer approach to understanding theta’s behavioral role by191

probing its relation to more complex behaviors. In particular, spatial navigation caught the attention of192

researchers because during navigation rodents exhibit hippocampal theta signals that are extremely robust193

and well studied (Buzsaki, 2005). Given the strength of this signal and the broad literature on this topic,194

it seemed that spatial tasks could provide hope for characterizing theta’s functional role more precisely in195

humans.196

Role of theta in navigation and path integration197

Several findings closely link hippocampal theta oscillations to spatial navigation. (We consider navigation198

to be a particular form of the sensorimotor processing described above.) First, when a rodent runs through199

an environment it reliably elicits theta oscillations that have a large amplitude and that are reliably sustained200

8

for extended periods (Vanderwolf, 1969; Winson, 1978). Second, the hippocampus contains place cells201

that encode an animal’s current spatial location (O’Keefe & Dostrovsky, 1971) and that are modulated by202

ongoing theta activity (O’Keefe & Recce, 1993). Third, hippocampal theta activity is necessary for the203

activation of entorhinal “grid cells” (Bonnevie et al., 2013), which seem to play a role in allowing animals204

to keep track of their location during movement (Steffenach et al., 2005; McNaughton et al., 2006). Spatial205

navigation inherently requires both sensory and motor processes—the planning of movements through an206

environment and the acquisition of sensory information to refine trajectories. Thus, Bland and Oddie (2001)207

suggested that theta was important for navigation by helping to build multimodal networks to link sensory208

and motor processing to support behavior in complex environments and tasks.209

One hypothesis regarding the functional role of theta oscillations is notable because it proposes a specific210

computational role for theta in computing and representing an animal’s spatial location. The oscillatory211

interference (OI) model explains that grid cells in the entorhinal cortex keep track of an animal’s location212

during movement on the basis of differences in the phase of intracellular and extracellular theta oscillations213

(Burgess et al., 2007). This type of theory is innovative because it proposes for the first time that the theta214

oscillation is critically involved in neuronal computation for high-level behavioral information. Given the215

strong interest in this type of model (e.g., Zilli et al., 2009; Domnisoru et al., 2013; Schmidt-Hieber &216

Hausser, 2013), it seems important to test the relevance of the OI model to humans. The OI model relies217

on several specific properties of theta oscillations that are robust in rodents, including a positive correlation218

between theta frequency and movement speed, and the stability of theta phase across time. Below we219

describe the literature on hippocampal theta oscillations in human navigation, focusing on comparing these220

patterns with features of theta in rodents and the needs of the OI model.221

Studies of human hippocampal oscillations during spatial navigation revealed an unexpectedly diverse222

pattern of results compared to findings from animals. Consistent with rodents, there is an overall tendency223

for theta-like oscillations in the human hippocampus during spatial navigation. This was first demonstrated224

by Kahana et al. (1999), who showed the first evidence of theta oscillations from humans in a spatial naviga-225

tion task. However, unlike navigation-related theta in rodents, these oscillations were transient and appeared226

in distinct episodes that generally lasted less than one second (Figure 2). An additional finding from this227

work is that the amplitude and duration of theta episodes was greater in the more challenging task condi-228

tions versus simpler ones (Caplan et al., 2001), which suggested a link between theta oscillations and task229

difficulty that was unexpected from rodent studies. Overall, this research was impactful because not only230

9

did it provide the first link between human theta oscillations and navigation, but it also suggested for the231

first time that in humans these signals may also relate to richer aspects of cognition and behavior.232

Follow-up work in human navigation identified additional distinctive features of hippocampal theta.233

In rodents the link between movement and hippocampal theta is so robust that it can be observed easily by234

visual inspection of raw recordings, in which theta oscillations emerge strongly around the time of movement235

onset (Green & Arduini, 1954). Instead, in humans the link between hippocampal theta and movement is236

less consistent (although still very robust statistically). The first study to quantitatively characterize the237

prevalence of hippocampal oscillations to (virtual) movement found that although theta oscillations were238

more prominent during movement than stillness, they were only present in a fairly small proportion (∼15%)239

of movement trials (A. D. Ekstrom et al., 2005). Furthermore, this signal lacked specificity, as there were240

some moments when the patient was still but electrodes nonetheless exhibited robust theta oscillations.241

Follow-up work demonstrated that theta power correlates with movement speed in humans, but that it also242

correlates with other more abstract task variables (Watrous et al., 2011). Overall, this work illustrated243

the challenge in comparing theta oscillations between humans and rodents. Clearly there is a correlation244

between human hippocampal theta and navigational behavior, but this relation is multifaceted and not as245

strong as it appears in rodents. The fact that the link between movement and theta in humans is imperfect246

would seem to be an issue for OI models, which had proposed that a consistent theta phase pattern was vital247

for path integration. Therefore, one prediction of OI models is that people would become disoriented when248

theta power is low. This could be tested by comparing path integration performance with hippocampal theta249

power on a trial-by-trial basis.250

Perhaps the most surprising difference between findings from human and rodent studies of theta oscil-251

lations in navigation concerns the frequency where these signals are present. In humans hippocampal theta252

oscillations during navigation generally appear at the slower frequency of ∼3 Hz rather than ∼ 8 Hz where253

these signals are present in rodents (Watrous, Lee, et al., 2013). Human hippocampal theta oscillations are254

also seemingly more variable in frequency compared to rodents, with there being some clear examples of255

theta-like activity at frequencies as slow as 1 Hz during navigation (Jacobs et al., 2007; Rutishauser et al.,256

2010). One possibility is that this frequency difference is task-specific: Although most observations of hu-257

man hippocampal theta oscillations occur during navigation at ∼3 Hz (Watrous, Lee, et al., 2013; Jacobs,258

2014), there is evidence for theta in non-spatial tasks at ∼7 Hz (Axmacher et al., 2010).259

An additional surprising set of findings emerging from this work is that hippocampal theta oscillations260

10

related to other aspects of navigational behavior beyond movement. A. D. Ekstrom et al. (2005) found that261

hippocampal theta oscillations were more prevalent when a person searched for particular objects (see also262

Watrous et al., 2011). Other studies found similar findings regarding theta in neighboring brain regions263

(Caplan et al., 2003; Jacobs, Korolev, et al., 2010). These findings parallel work in monkeys showing that264

oscillations were specifically linked to visual perception processes (Jutras et al., 2013). This link between265

theta and visual search seems sensible in virtual-navigation paradigms where vision is the sole source of task266

input, in contrast to real-world navigation where humans receive proprioceptive input or where rodents use267

olfaction to inform navigation (A. D. Ekstrom, 2015). Nonetheless, this pattern underscores the possibility268

that human theta is linked to other types of cognitive processing beyond the neural coding of location. This269

adds to the emerging view that the hippocampus, as well as theta, could have a broad, high-level role in270

cognition that includes other behaviors that have not yet been explored.271

The two most prominent ideas concerning the functional role of theta oscillations point to sensorimotor272

processing (Bland & Oddie, 2001) and path integration (Burgess et al., 2007) during spatial navigation. It273

can be challenging to distinguish which of these processes are more closely coupled to navigation because274

vision and movement are usually active simultaneously during navigation (but see Markus et al., 1994).275

Using an innovative virtual-reality task, a recent study provided new data to elucidate this issue, by distin-276

guishing whether theta was more closely tied to sensory processing or to path integration (Vass et al., 2016).277

Vass et al. (2016) had patients perform a navigation task that included a condition where the screen went278

blank and the patient was “teleported” through an environment without receiving visual information. The279

teleportation condition provided key data to distinguish the role of theta by testing how this signal differed280

between spatial movements that were and were not accompanied by visual information. If theta oscillations281

were present during teleportation then it would indicate that these signals were coupled to the high-level282

behavioral function of path integration. Alternatively, if theta oscillations were absent during teleportation283

then it would indicate that these signals were linked to sensory processing.284

The results from this study support the view that human hippocampal oscillations are involved in path285

integration. At most sites, the level of theta activity did not drop significantly during teleportation (Fig. 3).286

Thus, sensory input is not required to elicit hippocampal theta oscillations. Instead, internal cognitive events287

during navigation are indeed sufficient for activating theta. Together with the work described above, the288

view from this literature is that many types of behaviors are capable of activating human hippocampal theta289

(Watrous et al., 2011). In humans the behaviors that elicit theta include all the signals identified in rodents,290

11

but also extend to a broader range that include some human-specific behaviors.291

Roles of theta in memory encoding292

Building off seminal findings showing a link between hippocampal theta oscillations and synaptic plasticity293

(Huerta & Lisman, 1993; Holscher et al., 1997), a different line of research focused on the link between theta294

and memory. Following a series of groundbreaking experiments into human memory centered around the295

neurosurgical patient HM (who had undergone bilateral temporal lobe resections, including the hippocampi)296

the view emerged that humans utilize a mix of different memory systems (Tulving, 1985). Central figures in297

this work, including Endel Tulving, synthesized phenomenological properties of memory and experimental298

data to propose the existence of episodic memory (“mental time travel” that allows humans to re-experience299

past events within specific temporal units), working memory (items immediately held in consciousness300

and used for decision making), familiarity (knowledge of past events and facts not placed within specific301

temporal context) and semantic memory (knowledge of facts without relevant contextual information). This302

portion of our chapter will discuss the role of theta oscillations in these processes.303

Some of the first and strongest behavioral evidence for the involvement of theta oscillations in memory304

encoding comes from classical conditioning experiments where some stimuli were deliberately presented305

during a “theta state,” which was defined as a period of high-amplitude theta oscillations (Berry & Swain,306

1989; Griffin et al., 2004). This has proven to be a reproducible and robust effect in simpler animals.307

However, pre-stimulus hippocampal theta oscillations in humans have not yet been linked to this type of308

learning (Merkow et al., 2014). There is some evidence for pre-stimulus theta-frequency oscillations that309

predict successful encoding in neocortex (Addante et al., 2015) and oscillatory synchrony related to memory310

between hippocampal–neocortical connections (Haque et al., 2015; Guderian et al., 2009). Nonetheless, it311

remains to be demonstrated whether hippocampal–neocortical synchrony is the same phenomenon as the312

large-amplitude theta oscillations that are closely coupled to memory in rodents.313

Episodic memory is thought to be the most hippocampally dependent memory process: it is most fragile314

in the face of degenerative diseases affecting the mesial temporal structures, it is specifically degraded in315

lesions such as those of HM, and it is cognitively demanding (Tulving, 2002). Given this link, oscillatory316

processes during human episodic memory might be expected to most strongly relate to the theta signals seen317

in rodents, which appear whenever the hippocampus is active (Buzsaki, 2002).318

12

A common paradigm for testing episodic memory is the Free Recall task. Here participants are shown319

a list of stimuli (such as words) and, after a delay, are asked to speak aloud as many items as they can320

remember. If rodent behavior is analogous to episodic memory, successful encoding for items in this task321

should be associated with increases in the amplitude of theta oscillations. An early study examining human322

hippocampal activity during free recall observed robust gamma-band power increases during memory en-323

coding without a memory-related power increase in the theta band (Sederberg et al., 2007). In fact, a large324

fraction of electrodes in the hippocampus exhibit a theta power decrease during successful item encoding.325

This was not an isolated finding. Across many studies encompassing hundreds of human subjects, a sub-326

stantial fraction of hippocampal sites do exhibited rodent–type oscillatory power increases in the theta band,327

but this is generally outweighed by a more widespread oscillatory power decrease for all frequencies below328

24 Hz (Sederberg et al., 2003, 2007; Lega et al., 2012). Further, the electrodes that do exhibit oscillatory329

power increases do so at frequencies lower than that observed in rodents, centered at 3 Hz or even slower, as330

compared to the 4–10-Hz frequency of rodent theta (Lega et al., 2012). Overall, a number of hippocampal331

sites do exhibit memory-related theta signals (Fig. 4A), but they are lower in number than expected.332

A strong link between memory and navigation vis-a-vis theta oscillations was articulated by Buzsaki333

(2005) and later elaborated by Buzsaki and Moser (2013) with additional navigation data. This theory sug-334

gests that there is a direct analogy between item–place associations formed in traversing a two dimensional335

path in space and the resultant item–time and item–place associations that are the basic units of episodic336

memory. The prediction of this theory is that human oscillatory activity during episodic memory should337

demonstrate the same neurophysiological patterns as rodent spatial memory. The view that the hippocampal338

theta oscillations are important for remembering spatial locations was first supported by a study in rodents339

that compared memory performance on a task where the animals were taught to run to a particular spatial340

goal location (Winson, 1978). One set of animals in this task had their theta oscillations disrupted with elec-341

trolytic lesions in their medial septum. Compared to controls, animals with disrupted theta were impaired342

in navigation accuracy. This was the first evidence for theta in remembering spatial locations.343

In recent years similar evidence for hippocampal theta in spatial memory has emerged in humans.344

Cornwell et al. (2008) examined theta activity in patients performing a spatial learning task while they345

underwent MEG scanning. Here the amplitude of theta activity in the posterior hippocampus correlated346

positively with spatial memory performance (Figure 5). A subsequent study by Kaplan et al. (2012) sup-347

ported this finding, and also showed that theta activity in human spatial memory perhaps spanned a broader348

13

set of cortical brain areas rather than being limited to the hippocampus. A key question from this work349

is how closely the theta signal that was measured noninvasively with MEG was specifically localized to350

the hippocampus. Because spatial localization is challenging with MEG data, one possibility is that the351

memory-related theta in these studies was not specifically localized to the hippocampus and was instead352

present in surrounding cortex. To bolster the link between hippocampal theta and memory performance it353

will be helpful for a study with direct hippocampal recordings to examine the link between theta and spatial354

memory. Nonetheless, the pattern of these results bolsters the view that theta oscillations are involved in355

spatial cognition in a general manner that is linked to memory, extending beyond pure path integration or356

sensory processing.357

Aside from power changes, there are several other memory-related patterns of theta oscillations in the358

human hippocampus. One example is phase–amplitude coupling (PAC). PAC is a phenomenon where high-359

frequency oscillations increase in amplitude at particular low-frequency (theta) phases (Bragin et al., 1995;360

Canolty et al., 2006). PAC related to memory and theta appears in numerous human cortical and hippocam-361

pal structures (Canolty & Knight, 2010; Kendrick et al., 2011; Lega et al., 2015). Phase resetting is another362

property of theta oscillations that has been linked to memory encoding in rodents (McCartney et al., 2004).363

Here, memory encoding is enhanced when theta oscillations are organized to reset to a specific phase after364

an observes a stimulus. Memory-related theta phase resetting has been observed in human hippocampus and365

neocortex (Mormann et al., 2005; Rizzuto et al., 2003), as well as in monkeys (Jutras et al., 2013).366

Further evidence for the contribution of theta oscillations to memory processing in humans comes from367

recordings that include measures of single-neuron spiking (Fig. 5B). Rutishauser et al. (2010) found that368

hippocampal neurons that fire at preferred phases of the 3–8 Hz theta oscillation exhibited increased firing369

when participants encoded memory items that were subsequently remembered. This suggests that theta370

oscillations are important for memory and efficient hippocampal processing because they help to temporally371

coordinate neuronal activity (Jacobs et al., 2007).372

Data linking human hippocampal oscillations in the 4–8-Hz frequency range to memory is probably373

most robust in “working memory” behaviors. In rodents, theta oscillations have been observed linking374

hippocampal and frontal lobe activity (Jones & Wilson, 2005; J. M. Hyman et al., 2011). Increases in theta375

amplitude and theta–gamma coupling in the human hippocampus have been observed in the 4–8-Hz range376

during working memory tasks (Mormann et al., 2005; Axmacher et al., 2010). This work on hippocampal377

theta oscillations related to working memory is intriguing because, in fact, some researchers suggested that378

14

working memory occurs entirely independently of the hippocampus (Zarahn et al., 2005). Thus, going379

forward, hippocampal theta oscillations related to working memory performance must be examined further380

to test whether these signals are causally important or epiphenomenalogical.381

Human hippocampal EEG have been recorded for decades now in patients performing cognitive tasks382

(Jacobs & Kahana, 2010). In spite of the numerous experiments looking for evidence of robust theta ac-383

tivation in humans, the properties of human hippocampal theta for episodic, spatial, and working memory384

are not fully understood because they are sometimes weaker than expected and not fully consistent with385

animal models. Although many hippocampal sites exhibit oscillations that increase in power for successful386

memory encoding, this pattern is not present at all sites. Furthermore, it remains unclear if memory-related387

hippocampal oscillations are most closely coupled to oscillations at ∼3 Hz (Lega et al., 2012) or 7 Hz388

(Rutishauser et al., 2010; Axmacher et al., 2010). A further question is which aspects of theta oscillations389

are most important for memory coding, oscillatory power at a single site, interregion phase synchrony, or390

PAC. It will be important to examine these issues going forward with multiple types of memory tasks, as391

well as advanced statistical methods that can dissociate the contributions of these signals towards behavior.392

Theta dynamically coordinates within and across brain regions393

Although research in rodents primarily focused on characterizing the amplitude of theta in relation to behav-394

ior, there is some evidence that theta phase rather than power may have a stronger role in modulating local395

neuronal activity. In both humans and rodents the activity level of individual neurons is modulated by the396

phase of ongoing theta oscillations (Jacobs et al., 2007; Patel et al., 2012; Sirota et al., 2008; Rutishauser et397

al., 2010). To the extent that oscillations such as theta are simultaneously present in multiple brain regions,398

examining the timing of these signals could reveal how neurons in these regions interact on a rapid timescale399

to support cognition.400

Rather than being a unitary signal that is always coherent across a fixed spatial topography, research401

has shown multiple theta sources in the hippocampus and MTL that dynamically coordinate with aspects402

of behaviors (Montgomery et al., 2009; Watrous et al., 2011). Based on empirical findings in rodents,403

we suggest that the phase of hippocampal theta is a rich signal that coordinates both local and distributed404

cell assemblies, dynamically linking hippocampus and neocortical regions to support wide-ranging types of405

cognition. These findings suggest that the hippocampus is part of a network that consists of both large- and406

15

small-scale theta signals that becomes dynamically synchronized to support rich behaviors. Consistent with407

this, rodent slice data provided evidence of theta generators that can operate independently of other brain408

regions (Goutagny et al., 2009), as well as similar data from the human medial temporal lobe (Mormann et409

al., 2008).410

In line with these ideas, in rodents the phase of hippocampal theta modulates firing rates in both the411

parietal and prefrontal cortices of rodents (Sirota et al., 2008; Jones & Wilson, 2005; Siapas et al., 2005;412

J. Hyman et al., 2005; Benchenane et al., 2010). These observations are consistent with the theoretical role413

that low-frequency oscillations have in coordinating neural activity across larger spatial scales (von Stein414

& Sarnthein, 2000; Fries, 2005; Womelsdorf et al., 2007; Fell & Axmacher, 2011). Consistent with this415

animal electrophysiological work, a rich body of human cognitive studies hypothesized that the hippocam-416

pus and neocortex are coordinated to support memory and navigation (Teyler & DiScenna, 1986; Miller,417

1991; McClelland et al., 1995; Buzsaki, 1996; Nadel & Moscovitch, 1997; Eichenbaum, 2000; Norman &418

O’Reilly, 2003). These cognitive studies present a diverse landscape of information processing across the419

hippocampus and surrounding regions that may be coordinated by theta.420

Extending these ideas to human recording data, a few studies in epilepsy patients show phase syn-421

chronization between the hippocampus and extra-hippocampal locations. Recording from surface elec-422

trodes overlying the MTL, Foster et al. (2013) showed that memory retrieval was associated with MTL–423

retrosplenial theta-band connectivity, followed by increased gamma-band activity in the retrosplenial cor-424

tex, putatively reflecting increases in firing rate. Another study by Anderson et al. (2009) also showed425

enhanced theta synchronization between PHG and frontal electrodes during a free recall task. A third study426

by Watrous, Tandon, et al. (2013) observed increased theta phase synchronization between frontal, parietal,427

and PHG during correct memory retrieval of both spatial and temporal information. Interestingly, in this428

latter study, whereas retrieval of spatial information led to synchronization at ∼2Hz, retrieval of temporal429

information led to synchronization at ∼8 Hz. The PHG showed the strongest pattern of connectivity in both430

cases. Taken together, these three studies demonstrate theta oscillations in the human medial temporal lobe431

that coordinate with other cortical sites in a task-dependent manner.432

The observation of frequency-specific information retrieval Watrous, Tandon, et al. (2013) is broadly433

consistent with the notion of frequency-multiplexing. This emerging idea, which has gained increasing434

empirical support in animal experiments (Belitski et al., 2010; Cabral et al., 2014; Colgin, 2016; Panzeri435

et al., 2010; Bieri et al., 2014; Zheng et al., 2016) suggests that distinct, frequency-specific oscillatory436

16

brain states subserve distinct behaviors (Donner & Siegel, 2011; Siegel et al., 2012; Colgin, 2016) Such437

a multiplexed representational scheme could allow multiple processing streams (Giraud & Poeppel, 2012;438

Watrous, Tandon, et al., 2013; Benchenane et al., 2011) to process information with enhanced capacity439

(Akam & Kullmann, 2014; Panzeri et al., 2010). Moreover, during rest the direction of information flow440

between brain areas in humans also shows frequency specificity (Hillebrand et al., 2016). Taken together,441

these studies highlight the possibility that hippocampal coupling at varying slow frequencies may subserve442

distinct behaviors (A. D. Ekstrom & Watrous, 2014), not only including memory but also other domains443

(Schyns et al., 2011; Gross et al., 2013; Daitch et al., 2013; Freudenburg et al., 2014).444

Role of theta oscillations in neuronal coding445

In addition to correlating with high-level behaviors, theta oscillations in rodents have also received substan-446

tial attention because they are involved in the representation of information by single neurons. The strongest447

example of this is the phenomonenon of phase precession in rodents (O’Keefe & Recce, 1993). Here, hip-448

pocampal neurons systematically vary the theta phase of their spiking such that when an animal runs through449

a place field, the cell spikes at earlier phases over successive theta cycles. This phenomenon is viewed as450

an example of phase coding, in which individual neurons represent behavioral information by varying the451

timing of their spiking relative to the peaks and troughs of ongoing oscillations. In many cases the informa-452

tion that is signaled by spike phase is significantly more informative than information conveyed by the cell’s453

overall firing rate (Jensen & Lisman, 2000; Huxter et al., 2003). From rodent models, theta phase coding454

has widely been considered to be a key feature of hippocampal coding, not only because phase-based coding455

is an efficient manner for representing information but also because theta-phase coding causes neurons to456

activate on a timescale consistent with spike-timing-dependent plasticity (Skaggs et al., 1996; Mehta et al.,457

2002). An additional feature of this phenomenon is that spike phase is informative about multiple aspects of458

the animal’s behavior, including the location of the animal relative to the center of a neuron’s place field, as459

well as whether a cell’s place field was traversed in the past or will be encountered in the future (Lubenov460

& Siapas, 2009).461

Although theta phase coding has not been characterized directly in humans, some studies in humans462

provide evidence for related phenomena. Jacobs et al. (2007) examined simultaneous recording of spiking463

and oscillations from the hippocampus and entorhinal cortex of epilepsy patients with implanted micro-464

17

electrodes. Across the brain the firing of many neurons was modulated by the ongoing phase of neuronal465

oscillations. For oscillations at most frequencies individual neurons reliably spiked at the trough of the466

oscillation. However, in the hippocampus at 1–4 Hz, individual neurons fired at a range of phases. The467

phase diversity of this theta pattern suggested that individual human hippocampal neurons robustly use theta468

phase as a mechanism for information coding. Going forward it will be useful to more precisely compare469

this pattern with phase precession in rodents by testing whether individual cells vary the theta phase of their470

spiking on a cycle-by-cycle basis as in place cells that use phase precession to code location.471

The importance of theta oscillations for neuronal coding in humans is bolstered by the new finding that472

human hippocampal oscillations are travelling waves. In rodents theta oscillations are not a static signal473

that exists identically across the whole hippocampus, but instead they move gradually along the long axis474

of the hippocampus (Lubenov & Siapas, 2009; Patel et al., 2012). Because individual hippocampal neurons475

use theta phase as a mechanism for encoding the timing of behavioral events (Lubenov & Siapas, 2009),476

these travelling waves have been interpreted as allowing sections of the hippocampus to simultaneously477

represent different times. In this way, travelling theta waves can be thought of as encoding time across478

the hippocampus, in much the same way that separate parts of the world exist in different time zones.479

A recent study provided evidence that hippocampal theta oscillations in humans also behave as travelling480

waves (Zhang & Jacobs, 2015). This study found that theta oscillations move across the hippocampus in481

a posterior-to-anterior direction, which is analogous to the dorsal-to-ventral movement in rodents (Fig. 6).482

However, this work went further and compared the properties of hippocampal travelling waves between483

theta oscillations at different frequencies, providing information on how these waves propagate.484

Individual theta waves move through the hippocampus at a rate that correlates with the oscillation’s485

temporal frequency. This link indicated that theta oscillations travel along the hippocampus by following486

the principals of coupled oscillator models (Ermentrout & Kleinfeld, 2001). Following these models, phase487

differences are continually preserved across space in the hippocampus, regardless of the oscillation’s tempo-488

ral frequency. The distinctive phase pattern in these data suggests that phase-based coding exists in humans489

despite the different properties of theta oscillations in our species. Thus, these findings support the idea that490

individual neurons in the human hippocampus support oscillatory phase coding based on theta oscillations.491

18

Theta oscillations and internal thought dynamics492

The research reviewed above related to sensorimotor, memory, and navigation characterized neural corre-493

lates of theta that involve cognitive processes with clearly defined relations to external events. As one probes494

further into this literature, it seems clear that theta oscillations relate to even richer aspects of the human495

experience including internal brain patterns with no outwardly visible behavioral correlate.496

A surprising feature of early work on human hippocampal theta oscillations is that not only was theta497

activity increased by listening to auditory stimuli, but there were also theta elevations in a section of a task498

when patients were asked to closed their eyes and rest (Meador et al., 1991). One possibility is that subjects499

were attending to aspects of their own thoughts during this period (e.g., “day dreaming”). This finding was500

interpreted to suggest that theta oscillations in humans could be important for internal thought dynamics and501

volition.502

Some evidence that theta oscillations related to internal thought processes was also provided by Caplan503

et al. (2001), who studied brain signals underlying maze learning. Here the amplitude and duration of504

medial-temporal theta oscillations increased on task trials that were generally more difficult. Interestingly,505

these signals seemed to be neural correlates of high-level cognitive processing, because they only related to506

the trial’s high-level difficulty rather than varying with the patient’s trial-by-trial reaction time.507

Other evidence for the involvement of theta oscillations in high-level cognitive processing comes from508

patients performing self-initiated memory recall tasks. Foster et al. (2013) showed that prior to the moment509

of peak neural activity there was a transient burst of 1–3-Hz oscillations that synchronized the medial-510

temporal lobe and retrosplenial cortex. Because this theta burst occurred before the primary neuronal acti-511

vation, it indicates that hippocampal theta oscillations were involved in the dynamics of successful memory512

search. These findings suggest that theta oscillations could be involved in a diverse set of purely internal513

neural processes akin to dreaming, as similar patterns of hippocampal theta oscillations were also observed514

during sleep in rodents (Montgomery et al., 2008) and humans (Bodizs et al., 2001). Recent work in ro-515

dents has found evidence for hippocampal theta oscillations in tasks where animals attentively wait for fixed516

periods of time (Pastalkova et al., 2008; MacDonald et al., 2013). Because rodents in timed waiting tasks517

initiate their own movements on the basis of internal brain dynamics, it suggests that hippocampal theta os-518

cillations could be a general correlate of internal thought dynamics. In the same way that theta oscillations519

support the hippocampal representation of space during navigation, it might also allow the hippocampus to520

19

represent cognitive representations of time (Eichenbaum, 2014) during both fixed-interval timing tasks as521

well as free-ranging time progression during day dreaming.522

Conclusion523

The literature on human hippocampal theta oscillations is complex because it contains a combination of sim-524

ilarities and differences compared to similar signals in rodents. Whereas there is evidence that the strongest525

features of theta from rodents are preserved in humans—the increases in theta amplitude during sensorimo-526

tor and memory tasks—some of these effects are smaller in magnitude (although still robust statistically).527

These types of differences make it challenging to understand which features of theta properties from rodent528

studies are relevant in humans.529

Whereas we have a good grasp of human behavior in many of the memory and cognitive tasks where530

hippocampal theta appears, we currently have only a coarse understanding of the core electrophysiological531

properties of human theta, including its spatial, temporal, and spectral properties. Perhaps the biggest mys-532

tery concerning theta in the human literature is that whereas the amplitude of these oscillations positively533

correlates with navigational behavior (A. D. Ekstrom et al., 2005), this link is weaker compared to the tight534

coupling between theta and movement found in rodents (Vanderwolf, 1969). One possibility is that human535

hippocampal theta is spatially diverse, with signals in a subset of the hippocampus that behave as expected536

from animal studies and with oscillations in other subregions that behave differently, perhaps relating to537

non-spatial behaviors. Supporting this idea, there is evidence from rodent studies that hippocampal theta538

oscillations consist of many separable components, including both Type 1 and Type 2 theta at different fre-539

quencies (Kramis et al., 1975), as well as spatially distinct theta generators across hippocampal subfields540

(Sirota et al., 2008). To identify multiple theta sources it will be useful to measure the spatial extent of theta541

in detail using high-resolution methods for mapping hippocampal substructures (A. Ekstrom et al., 2009;542

Yushkevich et al., 2010). Research in rodents had suggested that dorsal and ventral theta oscillations behave543

very differently (Sabolek et al., 2009; Royer et al., 2010). This result could be relevant to understanding544

human theta given that the primate posterior and anterior hippocampi are analogous structurally to the dor-545

sal and ventral hippocampi of rodents (Strange et al., 2014). Thus, to test this pattern it would be useful546

to compare the properties of theta more fully along the anterior–posterior axis of the human hippocampus547

expanding on an approach used recently(Mormann et al., 2008; Zhang & Jacobs, 2015).548

20

A distinctive feature of human hippocampal theta oscillations is that these signal exist in short episodes549

(Kahana et al., 1999; Watrous, Lee, et al., 2013). In this way human theta seems to be qualitatively different550

compared to the long-lasting and consistent theta oscillations in rodents (Vanderwolf, 1969). A possibility551

is that the shorter, transient nature of human theta oscillations is the result of human multitasking, such552

that humans periodically switch the target of their attention, in contrast to rodents that stay focused on a553

single task (usually spatial processing). Theta oscillations exhibit phase resets when a person processes new554

attended events (Rizzuto et al., 2003; Mormann et al., 2005). These disruptions could cause human theta555

oscillations to have a shorter duration. It seems likely that epilepsy patients performing a rich behavioral556

task in a virtual setting on a laptop computer would have more distractions and interruptions compared to a557

rodent performing a simpler navigation task and who has weaker vision. If each distraction caused a theta558

phase reset, then it could cause short, disrupted theta oscillations. To characterize this potential explanation559

for human theta’s short duration, it would be helpful for human behavioral studies to use video- and eye-560

tracking (Hoffman et al., 2013) to monitor shifts in attention and multitasking and test for correlations with561

theta pauses or resets.562

One reason that the hippocampal theta oscillation is so strongly visible in rodents seems to be that this563

signal is expressed synchronously across a large number of neurons that have aligned dipoles (Buzsaki,564

2002). If the intracellular oscillations at each neuron were not perfectly synchronized, then the theta oscilla-565

tion in the aggregate extracellular field potential would be smaller. One recent study in rodents showed that566

hippocampal theta oscillations involve complex spatial patterns of phase shifts that encode cognitively rele-567

vant information (Agarwal et al., 2014). Thus, one possibility towards explaining theta’s complex structure568

in humans is that human behavior, with its heavy information content, requires a more diverse set of electro-569

physiological processes to organize incoming information into neural assemblies. The human hippocampus570

receives projections from a broader range of diverse brain areas compared to rodents (Strange et al., 2014).571

As a result, individual hippocampal neurons could be involved in coding a very broad range of cognitive572

variables, and this may require their theta signals to express a larger range of spatial phase patterns. Accord-573

ing to this idea, the smaller apparent amplitude of theta oscillations in extracellular recordings could be the574

result of these neurons expressing a diverse range of theta phases. To test this idea it will be necessary to575

analyze the coding properties of human hippocampal theta with high resolution multi-contact recordings.576

21

Future directions. A key challenge going forward is to understand how the theta oscillation underlies577

such a broad range of behaviors in humans. One possibility is that the theta oscillation represents a single578

general computational and electrophysiological process. Alternatively, it is possible that theta is not a single579

phenomenon and that many distinct hippocampal electrophysiological and computational processes produce580

theta oscillations.581

To address these issues as hippocampal theta research in humans moves forward, it seems research in this582

will fall into two categories: 1. Interspecies comparisons of the properties of hippocampal theta oscillations583

between humans and rodents and 2. Characterizing theta in humans performing advanced behaviors where584

comparable animal data are rare. One way of performing work in the first category would be to measure the585

physiological characteristics of human theta oscillations in a relatively simple task with similar demands as586

rodent navigation. Although it is impossible to perfectly match human and rodent behavior, by comparing587

human and rodent brain activity in similar tasks it will provide useful data for distinguishing whether ap-588

parent interspecies differences in theta stem from behavioral or physiological differences. Then, it will be589

important to characterize the electrophysiology of these datasets in precise spatial, temporal, and spectral590

detail to reveal whether human and animal theta signals have similar properties. It will also be useful to use591

single-neuron recordings to compare across species the nature of theta oscillations’ use for phase coding.592

Equally important to comparing rodent and human theta is to understand features of theta oscillations593

that underlie complex behaviors that are specific to humans. One example of this is episodic memory594

retrieval, which exhibits some characteristics that are human-specific (Tulving, 1985). A growing number595

of researchers suggested that the hippocampus performs a general computational process that underlies596

both memory and navigation (Eichenbaum, 1999; Howard et al., 2005), so testing whether human theta’s597

properties differ between these behaviors is an important step. Future work on episodic memory and other598

types of cognition should test the degree to which the properties of theta in these behaviors is consistent with599

one core set of principles of theta oscillations that underlie both navigation and memory (Buzsaki, 2005).600

This can be done by comparing the phase, frequency, amplitude, and spatial topography of hippocampal601

theta oscillations in periods before and during the retrieval of episodic (autobiographical) memory episodes602

and comparing the results with analogous signals in navigation.603

Studying theta oscillations in humans provides several new avenues for research tasks that could not be604

performed in rodents. The teleportation study by Vass et al. (2016) provides an example of a particularly605

powerful approach for assessing the fundamental functional nature of human theta oscillations. This study606

22

took advantage of humans’ ability to understand a complex type of behavior—teleportation—that might607

not be intuitive to animals. Vass et al. study used this manipulation to dissociate whether theta was linked608

to high-level (path integration) or low-level (sensory) processing. Future experiments might build off this609

approach by using richer, human-specific experimental manipulations to identify the specific aspects of be-610

havior that contribute most directly to theta, such as dissociating between theta contributions from motor,611

sensory, or internal brain processes. A different possibility for probing theta is to take advantage of humans’612

language and introspective abilities. One could envision an experiment whereby patients are asked to ver-613

bally describe their brain states during periods when different types of theta oscillations were evident. This614

approach, if applied in a careful and rigorous fashion, could provide unique data to distinguish unexpected615

variations in human theta signals.616

An aspect of hippocampal theta oscillations that bears further investigation is the existence of inter-617

hemispheric differences. For some time now researchers have hypothesized that the the right and left brain618

hippocampi support spatial and language processing, respectively (O’Keefe & Nadel, 1978). This notion619

is important theoretically because it suggested that the two hippocampi operate independently, at least in620

certain situations. The theta oscillation would seem to be a prime mechanism for testing this notion, if it621

was possible to compare data between the two hippocampi of one patient who performed both spatial and622

non-spatial tasks. An existing study in this area was inconclusive (Jacobs, Korolev, et al., 2010), but it seems623

possible that with an improved dataset that included both spatial and nonspatial tasks theta oscillations could624

shed key light on this laterality hypothesis.625

Some of the strongest evidence for the importance of theta oscillations comes from animal studies show-626

ing that theta has a causal functional role (Seager et al., 2002). If hippocampal theta oscillations are shown627

to have this type of direct mechanistic role in cognition then it could lay the groundwork for key transla-628

tional work to improve human behavior by modulating theta oscillations, perhaps with neural manipulation629

methods based on optogenetic (Sohal et al., 2009; Pastoll et al., 2013) or electrical stimulation (Wetzel et al.,630

1977; Kim et al., 2016). Researchers and engineers have tried many approaches to create devices to human631

cognition. It seems challenging to meaningfully alter human behavior by manipulating individual neurons,632

due to the large number of cells in the brain. However, owing to the large-scale nature of the human theta633

oscillation, this network signal may indeed have the potential for being modified with external methods to634

achieve meaningful behavioral outputs. Large-scale network manipulations, including theta alterations, be635

one of the best short-term hopes we have for achieving human cognitive enhancement (Kim et al., 2016).636

23

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B

B CA

Figure 1: Methods for examining human hippocampal brain signals. A. Epilepsy patient with implantedelectrodes performing a cognitive task on a bedside laptop computer. B. Magnetic resonance image ofa patient’s brain showing depth electrodes targeting the hippocampus. C. Screen image from a patientperforming a virtual spatial navigation task. Images with permission from Jacobs, Kahana, et al. (2010);Jacobs et al. (2012).

36

A

B

C

D

Figure 2: Theta is less continuous and occurs at a lower frequency in humans compared to rodents duringspatial navigation. A) Example of human hippocampal raw LFP trace over 3 seconds (upper) and averageproportion of time oscillatory activity was detected as a function of frequency and increasing P-episode du-ration criteria for 284 human hippocampal recordings (lower). B) Similar to A, but for 30 rodent recordingsduring a Barnes maze. Note the difference in color scale for humans and rodents. C) Proportion of timeoscillatory activity was detected at the human peak frequency of 3.4 Hz and the rodent peak frequency of 8Hz. Gray dashed lines correspond to the half-maximum P-episode duration criteria at the human and rodentpeak frequency. D) Average number of cycles for each detected oscillatory event for humans and rodents.Error bars indicate the standard error of the mean across electrodes. (Figure modified with permission fromWatrous, Lee, et al. (2013).)

37

Figure 3: Data from a hippocampal electrode that exhibited similar levels of theta activity during (virtual)navigation (top) and during teleportation (bottom). Figure from Vass et al. (2016).

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A B

5 10 15 20 25Frequency (Hz)

SFC(%

)Forgotten (FN)Remembered (TP)

1.0

1.5

2.0

2.5* * * * * * * * *

Figure 4: Theta oscillations and episodic memory encoding. A. Data from Lega et al. (2012) showing thecount of electrodes where increased oscillatory power correlates with successful memory encoding. Notethe peak in the theta band. B. Analysis of coupling between hippocampal spiking and neuronal oscillationsfrom Rutishauser et al. (2010). Spike-field coherence (SFC) reveals the temporal coordination betweenspike timing and oscillatory phase, separately computed for trials of good or bad memory. Figures obtainedwith permission.

39

A B

Figure 5: Theta oscillations and spatial memory. Data from Cornwell et al. (2008) showing theta signalsrelated to spatial memory accuracy. A. Spatial localization of memory-related theta signals to the hippocam-pus. B. Relation between excess path length in a spatial memory task and theta power. Figures obtainedwith permission.

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Figure 6: Theta oscillations in the human hippocampus are travelling waves. Example data from one patient.Figure from Zhang and Jacobs (2015), with permission. A. & B. Images depicting electrode locations. C.Raw recordings from several hippocampal contacts. Inset shows mean power spectrum with peak in thetheta band. Circles on left side of plot denote electrode correspondence with panels A & B. D. Theta-filteredsignal from these contacts. Red asterisks denote oscillatory peaks. Note the progressively positive phaseshift as one moves from posterior to anterior sites, which is the key indication of a travelling wave. E. Phaseanalysis of the theta signals at these electrodes. Color denotes cosine of theta phase.

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