Distressing reactions to perceived threats in safe environments is a hallmark feature of anxiety-related disorders such as post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The development of novel targeted neural circuit therapies requires an understanding of how neurophysiological activity relates to behavior and subjective emotional experience. To determine electrophysiological signatures related to emotionally negative and clinically relevant states, we characterize intracranial oscillatory changes within the amygdala and other fear circuitry nodes (including the hippocampus and ventromedial Prefrontal Cortex), during a range of aversive experiences in humans with and without treatment-resistant post-traumatic stress disorder (TR-PTSD) in support of clinical trial (NCT04152993). Additionally, we present pilot neural and behavioral data during a novel virtual reality fear conditioning task compatible with simultaneous intracranial electroencephalography and fear behavior recordings in naturalistically behaving humans. We found increases in amygdala theta activity during unpleasant portions of six separate paradigms (emotional image task, fear conditioning task, script driven imagery task, virtual reality fear conditioning task, and at home recordings during symptomatic TR-PTSD states). Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms and changes in amygdala theta activity following one year of treatment. Altogether, our findings connect decades of rodent literature to clinical symptoms and intracranial neurophysiology in humans and demonstrate the viability of responsive neurostimulation in TR-PTSD.

Parkinson disease is a common neurodegenerative disorder characterized by deficits of balance, resting tremor and voluntary movement. The study of this dopamine-depleted state has come to focus upon the role of beta oscillations (12-35 Hz) as a means of explaining the movement deficits that feature prominently in the constellation of symptoms. It remains unclear what the precise role of beta oscillations is in the healthy state and why they feature so prominently in the pathophysiology of Parkinson disease. Deep brain stimulation in movement disorders affords a valuable opportunity to invasively record from cortical and subcortical structures in patients undergoing the procedure. This dissertation embarks upon an in-depth analysis of beta oscillations in the motor cortices of Parkinsonian patients undergoing deep brain stimulation and contrasts the findings in this cohort with those observed in the dopamine-intact state of essential tremor patients. The findings detailed here show that in both cohorts, transient increases in beta power (beta bursts) constitute periods of high interregional cortical synchrony and that these episodes are associated with stereotyped changes in waveform morphology. Beta bursts are furthermore characterized by high beta-phase to broadband gamma amplitude coupling. Beta bursting is preceded by increases in cortico-cortical synchrony which is proposed here to act as a driver for beta burst episodes in the motor cortex. Parkinson patients display disordered temporal patterns of beta bursting compared with essential tremor patients. Correlation between the duration of beta bursts and Unified Parkinson's Disease Rating Scale (UPDRS) scores of bradykinesia and rigidity suggests that electrophysiological dysfunction in the timing of beta bursts has direct relevance to clinical manifestations of the dopamine-depleted state. Waveform analysis shows that, when compared with Parkinson disease patients, essential tremor patients exhibit greater degrees of waveform change during bursting compared with non-burst epochs. The extent of waveform morphology change also correlates inversely with severity of bradykinesia and rigidity as measured by UPDRS scores. Analysis of movement onset in patients shows that beta oscillations are transiently suppressed at the time of movement initiation in both Parkinson disease and essential tremor cohorts. Only essential tremor patients demonstrated a significant reduction in cortico-cortical synchrony prior to movement onset. The probability of beta transients immediately following movement onset was reduced for both cohorts however this beta burst suppression occurred earlier for the essential tremor cohort and could be identified a full second prior to movement initiation. Waveform morphology during beta bursting was significantly altered during movement compared to rest and initial changes in waveform morphology occurred as early as three seconds prior to movement onset. Beta-phase to broadband gamma amplitude during bursting was reduced during movement but there was no difference between the cohorts in absolute levels of burst-associated phase-amplitude coupling. The findings presented are consistent with a model of hypersynchrony across cortico-basal ganglia loops driving disordered beta bursting in motor cortices, resulting in impairments of voluntary movement. Evidence is presented to show that burst timing pathology occurs as a direct result of synchrony abnormalities and acts to impair movement via phase-amplitude coupling and waveform morphology changes noted to occur therein. Higher burst synchrony and extended burst durations may be acting as a physiological tamponade on development and updating of movement plans. This interpretation offers a unified explanatory framework for a body of literature that has uncovered seemingly contradictory findings regarding beta oscillations and lays the groundwork for targeted therapies directed towards restoring the dopamine-intact electrophysiological features of voluntary movement.

Our ability to recall memories of personal experiences is an essential part of daily life. These episodic memories often involve movement through space and thus require continuous encoding of one’s position relative to the surrounding environment. Formation of successful episodic memories (of personal events) requires the integration of contextual information within a spatial environment. Memory decline accompanies numerous neurological and psychiatric diseases. To inform the development of effective therapies, understanding how complex memories are encoded in the medial temporal lobe (MTL) is critical. To examine how MTL neural representations flexibly encode spatial memories, rare recordings in humans were collected from two complementary cohorts: (1) freely moving participants with chronic intracranial electroencephalographic (iEEG) electrodes and (2) stationary participants with single neuron recording electrodes. All participants completed an ecologically meaningful 3D immersive virtual reality (VR) spatial memory task. Our results highlight the utility of an immersive VR behavioral paradigm to interrogate multi-scale neurophysiology of episodic memory and spatial navigation in humans. We found that MTL theta oscillations dynamically represent memory and spatial variables to support momentary cognitive task demands. Theta oscillations were modulated by (i) memory performance during memory retrieval immediately before conscious recall, (ii) proximity to spatial boundaries or (ii) latently accessed memory representations of previously learned positions. We found that the immersive VR spatial memory paradigm elicited hexadirectional modulation of theta bandpower and also grid cell-like population activity. Interestingly, these hexadirectional modulation spatial representations exhibited putative grid axes reorientation during changing environmental contexts, and preliminary findings suggest that grid cells also may exhibit similar reorientation, suggesting that spatial codes may be context-specific. Altogether, these results demonstrate how human MTL oscillations and single neurons can represent both memory and space in a temporally flexible manner during interactive spatial navigation and memory retrieval. These findings advance our understanding of medial temporal lobe representations of spatial navigation, memory, and the effect of contextual changes that will together serve as a scientific foundation for development of neurological therapies for disorders of memory.

Decades of accumulated scientific evidence has demonstrated that vital factors (e.g., amyloid-β (Aβ) and the gene apolipoprotein E (APOE) ε4) contribute to the neuropathological changes and memory deficits observed in Alzheimer's disease (AD) and related dementias. Identifying these factors prior to disease onset could facilitate earlier access to disease-modifying treatments or promote healthy lifestyle modifications that might reduce neuropathology or cognitive deficits. However, the relationship between plasma-derived Aβ, APOE ε4, and brain atrophy in older adults before the manifestation of clinically relevant memory loss remains unclear. Furthermore, brain stimulation has emerged as a powerful approach for developing novel neuromodulatory therapies for those with deficits in cognition. Thus, these techniques may be used as potential treatments for those at risk for AD and other severe memory impairments.

The studies from this dissertation investigated the neural correlates and causal outcomes of cognitive and memory-related systems in the aging human brain. The first study examined the relationship between plasma-derived Aβ, APOE ε4, and brain atrophy in a large sample of 160 healthy older adults (ages 50+). The second and third studies showed promising effects on memory using invasive and non-invasive brain stimulation in cognitively healthy adults without memory impairments. Together these findings suggest that genetic, biological, and neural determinants could be combined with neuroimaging-guided brain stimulation to better identify individuals at risk for AD and improve their hippocampal-related memory.

Future studies of brain aging in healthy and memory-impaired older adults should monitor the molecular and neurobiological markers indicative of cognitive function and study novel methods like brain stimulation therapies. Since cognition is detrimentally influenced by these factors ensuring memory-enhancing therapies are effective despite indicators of impairment is necessary for the development of clinically viable treatments of benign senescence or more advanced impairment. Using different MRI modalities, the structural and microstructural properties of the brain can be used to predict treatment response or optimize hippocampal network targeting to restore aberrant function and alleviate the deficits associated with progressive memory loss.