Electrochemical and Electrophysiological Study

This study will utilize computerized algorithms in combination with real-time intracranial neurophysiological and neurochemical recordings and microstimulation to measure cognitive and affective behavior in humans. Questionnaires or simple behavioral tasks (game-like tasks on a computer or an iPad) may also be given to additionally characterize subjects on related cognitive or affective components. Importantly, for the purposes of understanding the function of the human brain, neural activity can be recorded and probed (i.e. microstimulation) while subjects are performing the same computerized cognitive and affective tasks. These surgeries allow for the in vivo examination of human neurophysiology and are a rare opportunity for such research. In addition to computerized testing, the investigators plan to characterize subjects' behavior on related cognitive or affective components. Some neuropsychological questionnaires, many of which are administered for clinical reasons (listed below under study population), may also be given to patients and healthy control subjects. All patients undergoing epilepsy surgery (the population from which subjects will be selected) undergo a standard clinical neuropsychological battery to assess aspects of cognitive function. This is a regular aspect of their clinical assessment carried out prior to consideration for study inclusion. All participants are selected uniformly because they are undergoing surgery for subdural electrode implantation. No particular ethnic group or population is targeted by or excluded from the study. Those to be considered for inclusion in the proposed study performing more than 2 standard deviations below the mean on any aspect of cognitive functioning as determined by standard preoperative neuropsychological testing will be excluded from the study. No additional neuropsychological testing will be necessary as part of the study itself.

Dysfunction in neurotransmission and neurophysiology can result in a range of psychiatric conditions including depression, anxiety, chronic pain, addiction disorders, and problems with attention (attention deficit disorder) and arousal (narcolepsy). Despite the clear importance of these neuromodulatory systems, practically nothing is known about how these systems act in real time (at sub-second timescales) in the human brain. This temporal resolution has proven to be important in basic research in rodent model organisms, where it has been shown that the extracellular concentration of neurotransmitters and neural electrophysiology changes within 100s of milliseconds of interacting with relevant stimuli while navigating moment-to-moment changes in the environment. Measurements with this kind of precision are necessary to be able to investigate how rapid changes in each of these signals modulate brain function, cognition, learning, mood, and behavior in humans. Cognitive processing occurs very rapidly over functionally organized networks that can be distributed among multiple brain areas. Consequently, understanding such complex functions requires the ability to map neuronal activity with high spatial and temporal resolution. Unfortunately, most noninvasive methodologies for recording neuronal activity have either high spatial or temporal resolution, but not both. However, electrocorticography (ECoG) offers the unique ability to record neuronal activity with both high spatial resolution (single-cell activity) and high temporal resolution (sub-millisecond time-scale). Additionally, certain behaviors are uniquely human, including complex motor control, executive function, language processing, and speech generation. Many of these behaviors and their neural underpinnings are impossible to study in other species. If we are to improve treatments for human neurological and psychiatric conditions, it is critical to study them directly in humans. Patients already undergoing neurological surgery for functional brain mapping (Phase II epilepsy monitoring) offer the rare opportunity to test the neural underpinnings of these uniquely human behaviors via direct neurophysiological recordings. Moreover, ECoG and MER offer the ability to stimulate and record from multiple cortical and subcortical regions. Microstimulation allows for a more complete assessment of both the functional connectivity among isolated brain regions and the causal role(s) of these regions in cognition and behavior. Here, the investigators propose to deploy a new recording protocol in combination with an FDA approved micro-sensor assembly that will enable simultaneous measurements dopamine, serotonin, and norepinephrine micro-fluctuations with subsecond temporal resolution in the human brain. If successful, the proposed work could provide a significant technological advance for neuroscience research in human brain function and behavior, with potential translational impact in areas including in neurosurgery, neurology, and psychiatry. The clinical importance of investigating the action of the neurotransmitters dopamine, serotonin, and norepinephrine is perhaps best highlighted by the pharmaceuticals used to treat major psychiatric conditions like depression, anxiety disorders, chronic pain, attention deficit disorders, and nicotine addiction. Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression and anxiety; Norepinephrine and Serotonin reuptake inhibitors (NSRIs) are used to treat depression and chronic pain; Norepinephrine and dopamine reuptake inhibitors are used to treat depression, attention deficit disorders, and have been used as an aid to smoking cessation; and Norepinephrine reuptake inhibitors (NRIs) have been used to treat depression, narcolepsy, attention deficit hyperactivity disorder, as an aid to weight loss, and anxiety disorders characterized by low arousal. Furthermore, abused substances (e.g., cocaine, nicotine, alcohol, and opiates) are known to alter the subtle balance between neurotransmitter release and reuptake in model organisms. From a basic science perspective, the investigators believe that dopamine is critical for reward processing and motivated behavior, serotonin for processing aversive stimuli and mood regulation, and norepinephrine for regulating states of arousal and attention. These neurotransmitters are released from neurons located in the brain stem (serotonin and norepinephrine) and midbrain (dopamine) whose axon terminals distribute and broadcast these signals throughout the brain including targets throughout the cortex (dopamine, serotonin, and norepinephrine), basal ganglia (dopamine and serotonin), hippocampus (dopamine and serotonin), and amygdala (dopamine, serotonin, and norepinephrine). While it is clear that these systems are critical, most of what is known comes from model organism research at timescales too slow to understand how rapid, real-time fluctuations in these signals contribute healthy human cognition, decision-making, and behavior. Also, there is a very limited understanding of how dopamine, serotonin, and norepinephrine systems interact. In any given brain region, it may be expected that there are one, two, or all three of these neurotransmitter systems contributing to the local neural information processing. In the human brain (and non-human primate brain) we know little about how the density of release sites or the dynamics of release change with psychiatric conditions or the medications used to treat them. This lack of knowledge does not stem from a lack of interest in the neuroscience, neurology, psychiatry, or neurosurgery disciplines; rather, the necessary technology and research paradigm has not been available. This proposal seeks to take the first steps in developing.

epilepsy monitoring, seizure localization, neurotransmitters, electrophysiological parameters, Electrochemical gradients, Fast Scan Cyclic Voltammetry, SEEG

Recordings will be obtained from intracranial electrodes placed for clinical or approved research purposes during neurosurgical procedures, and/or thereafter, while patients are followed in the epilepsy monitoring unit (EMU). Electrodes approved for human use may be placed on the cortex or within subcortical structures. Recordings may be obtained during passive conditions and task-based recordings designed to study particular regions of interest will be carried out in the EMU, as well as passive without task performance. Patients undergoing surgery for invasive functional brain mapping may also undergo electrical microstimulation in addition to neurophysiological recording. Stimulation is typically delivered in 2-5 second bursts (25-50 Hz, 0.3 ms pulse width, 1-15 mA). Recording and microstimulation may take place either intra-operatively and/or post-operatively in the EMU.

After standard of care surgery to implant the electrodes is complete and patients have have recovered satisfactorily from the procedure, they will be asked to perform some computer based tasks to answer questions about pretend financial decisions, pay attention to certain images, watch videos, look at images, listen to sounds, or move a joystick.

Neurotransmitter concentrations will be recorded through Fast Scan Cyclic Voltammetric methods during cognitive psychological tasks for visual memory administered on a laptop.

Neurotransmitter concentrations will be recorded through Fast Scan Cyclic Voltammetric methods and and pupillary diameter will be observe with a pupillometer during cognitive psychological tasks for sustained attention administered on a laptop.

Neurotransmitter concentrations will be recorded through Fast Scan Cyclic Voltammetric methods during cognitive psychological tasks for neuroeconomics administered on a laptop.

Inclusion Criteria: Age 18 to 80 years, inclusive. Patients who are candidates for electrode implantation due to pharmacologically intractable epilepsy, or other neurological/psychological disorders for which subdural electrode implantation may be clinically required for treatment. Patients competent to give informed consent/assent for the research protocol and parents of children under 18 who are competent to give informed consent on behalf of the child. Fluency in English (necessary for uniform cognitive testing). Committee approved candidates for brain surgery. Medications must be at stable doses for at least 1 month before surgery Exclusion Criteria: Clinically significant cognitive dysfunction. Terminal illness associated with <12 month survival. Contraindication to MRI imaging, e.g., morbid obesity, metallic devices such as cardiac pacemakers, some aneurysm clips, or shrapnel. Current pregnancy or pregnancy planned during the course of the study. Cognitive function less than 2 standard deviations below normal on preoperative neuropsychological testing

Data will be stored and collected on the University of Arizona REDCap and deidentified data will be shared with Arizona State University (ASU) and Virginia Tech (VT) researchers.

Data will be available for ASU and VT from initiation of the project, all the way through data analysis.

Virginia Tech and ASU will have access to the de-identified data via encrypted email or the University of Arizona's REDCap EDM.