Current Studies

Willie Lab

Modulation of Memory and Emotional Reactivity Through Deep Brain Stimulation of the Amygdala

Across studies of rodents, non-human primates and humans, the amygdala has been established as a key brain region involved in the experience of emotions and the encoding of emotional memories into long-term storage. The amygdala exerts modulatory effects on multiple neural systems of the brain including episodic memory, attentional control and autonomic arousal networks. In this project, we modulate amygdala activity through deep brain stimulation in patients undergoing intracranial monitoring for treatment-resistant epilepsy. In particular, we are exploring the effects of deep brain stimulation to the amygdala on affective bias, a task which objectively quantifies patient mood, and examining the extent to which stimulation-induced changes in affective bias can predict post-operative neuropsychiatric complications. Thus far we have shown amygdala stimulation is safe and effective for modulating various aspects of autonomic arousal. We concurrently measure intracranial electromyography (EEG), electrocardiography (ECG), electrodermal activity (EDA), and respiration during amygdala stimulation as patients perform the memory and emotional reactivity tasks. We will continue expanding this line of research as we establish these cognitive effects of amygdala stimulation. 

Deep Brain Stimulation of the Amygdala: A Potential Surgical Intervention for Narcolepsy with Cataplexy

Narcolepsy with cataplexy is a disabling sleep-wake disorder characterized by the inability to maintain a prolonged awake state and abrupt episodes of muscle paralysis (called cataplexy).  Cataplexy is triggered by strong emotions such as laughter, reward and surprise. Cataplexy is more broadly defined as the sudden loss of postural tone with preserved consciousness that can be elicited by laughter in patients with narcolepsy. Even in normal subjects, laughter is associated with brief periods of postural instability (“weak with laughter”).  Laughter coincides with increased activity in the amygdala, an integrator for emotional-motor networks and sustained activation of the amygdala has been observed during cataplexy.  Thus, amygdala activity may induce or maintain cataplexy.

We hypothesized that deep brain stimulation (DBS) of the amygdala would modulate Hoffman-reflex (an electromyography metric of postural tone) and cataplexy.  For this study, we utilize inpatients with epilepsy that have depth electrodes surgically implanted into their amygdala for temporary clinical monitoring of seizures. In addition to measuring the Hoffman-reflex, we are measuring a variety of electrophysiological and psychophysiological parameters. These parameters include electrophysiological changes as a result of amygdala stimulation and changes in autonomic arousal (heart rate, respiration and palm sweat) produced by amygdala stimulation. The short-term goal of this project is to determine the safety and efficacy of using human amygdala stimulation to modulate neural systems potentially involved in cataplexy. The long-term goal of this project is to consider amygdala stimulation as a potential surgical and therapeutic intervention for cataplexy. 

Deep Brain Recording and Stimulation in Mouse Models of Sleep Disorders

Deep Brain Stimulation (DBS) can promote arousal-related behaviors in deep brain regions of mice with sleep disorders (narcolepsy with cataplexy, Parkinsonism, etc.).  In mice with sleep disorders, we surgically implant electrodes in muscle, brain surface and deep brain regions (e.g. the prefrontal cortex, amygdala, and hypothalamus), while recording electrophysiological signals such as electromyography (EEG), electromyogram (EMG) and local field potential (LFP) in freely behaving mice. We measure behavior and locomotion using video camera recordings and infrared beam beaks. We are testing the hypothesis that various DBS parameters of areas involved in regulating arousal can alter sleep-wake patterns. These results will have therapeutic implications for treating sleepiness in patients with narcolepsy, hypersomnia and insomnia. We will next utilize optogenetic approaches to further examine the neuronal specificity of brain nucleus-targeted interventions.

Characterization of Sleep-Wake Disturbances in a Novel Mouse Model of Parkinson's Disease

Parkinson’s disease (PD) affects about 1 million individuals in the US and the secondary non-motor symptoms can be debilitating.  PD patients suffer nocturnal insomnia and excessive daytime sleepiness. Studies of such patients exhibit excessive motor activity during sleep and fragmented nocturnal sleep, despite relatively normal latency to sleep during daytime nap opportunities.  Mice deficient in the vesicular monoamine transporter 2 (VMAT2LO) exhibit insufficient monoamines, display PD pathology in the brain and develop age-dependent motor and non-motor signs of Parkinsonism.  Our lab is characterizing VMAT2LO sleep-wake patterns using electroencephalogram (EEG) and electromyogram (EMG) recordings and sleep latency tests. We have observed that VMAT2LO mice exhibit abnormal muscle activity during sleep and disrupted sleep-wake patterns, mirroring the form of insomnia found in PD patients. We will utilize this model to test novel interventions (e.g. DBS, optogenetics) to improve these sleep-wake abnormalities.

Surgical Neuroimaging for Electrode Localization and Modeling of Tissue Engaged By Stimulation

We are developing novel neuroimaging approaches to provide fine-grained anatomical detail on the brain structures in which depth electrodes are implanted, using high-field imaging, novel applications of histological atlas data, state-of-the-art diffusion tensor imaging fiber tracking, and automated neural nets to estimate the volume of neural tissue activated by the application of particular electrical stimulation parameters to different tissue types.

Cingulum-Induced Euphoria, Mirth and Analgesia

Stimulation to the dorsal anterior cingulum bundle has been observed by our team to evoke euphoria, smiling, laughter, relaxation, and analgesia, as well as evoking dose-responsive changes to autonomic functions such as skin conductance and heart rate. Our team is examining the extent to which these effects are dependent on the white matter architecture of the dorsal anterior cingulum bundle, the impacts of stimulation on local field potentials and single unit recordings elsewhere in the limbic system, and the extent to which affective bias, an objective measure of emotional state, tracks with stimulation-induced behavioral changes.