Utilizing Invasive Recording and Stimulating Opportunities in Humans to Advance Neural Circuitry Understanding of Mental Health Disorders

Presenter:

David McMullen, M.D.
Division of Translational Research

Goal:

The goal of this initiative is to encourage researchers to utilize invasive neural recording opportunities in humans to study the neural circuity underlying mental health disorders.

Rationale:

Invasive neural recordings provide an unparalleled window into the human brain to explore the neural circuitry underlying complex moods, emotions, and behaviors with high spatial and temporal precision. Additionally, the ability to stimulate, via the same electrodes, allows for direct causal tests by modulating network dynamics. Understanding what circuits are involved in complex behaviors in humans, and how to manipulate the circuits into preferred states, can inform both invasive and non-invasive brain stimulation therapies of the future. Although early deep brain stimulation (DBS) studies for treatment-refractory depressed patients showed potential, the inability of two large pivotal studies to demonstrate efficacy highlights the need to deepen our understanding of the neural circuitry of mental health disorders.

Invasive neural recordings provide an excellent opportunity to explore the circuitry underlying complex human behavior and to translate lessons from animal research. These opportunities arise during the normal treatment course of a variety of clinical conditions. These can include intra-operative micro-electrode or strip recordings during DBS surgery, sub-acute epilepsy monitoring electrocorticography (ECoG) or depth electrode recordings, or chronic deep brain stimulation/responsive neural stimulation (DBS/RNS) devices capable of recording and stimulating. Many of these opportunities arise in patients being implanted for non-mental health related conditions. However, many relevant patient populations (e.g., epilepsy and Parkinson’s patients) represent an enriched sample of mental health comorbidities. Careful study of fluctuating mood patterns of both patients with and without mental health disorders can provide unique insights into behavioral network dynamics. Direct neural stimulation will complement invasive recordings by enabling researchers to test mechanistic hypotheses and explore therapeutic options. Networks correlated with mood changes (using dense behavioral assessments) can be modulated to assess for behavioral improvements. While current DBS and non-invasive brain stimulation therapies target localized areas, this research may demonstrate the distributed nodes involved in disorders, and therefore inform the design of new devices and therapies.

This initiative would target a gap in the scientific knowledge of neural circuits related to mental health disorders. Research related to this initiative may include, but is not limited to, studies of:

• Intra-operative DBS placement cases where a strip electrode is placed through the burr hole or single neuron recordings are made in a relevant brain area. Acute mood evaluations or behavioral tasks could be completed.
• sEEGs placed in epilepsy patients. During their weeklong hospital stay, researchers could conduct a variety of tasks, depending on the placement of the electrodes (e.g., a fear extinction paradigm if there is amygdala coverage). Areas of coverage could include amygdala, hippocampus, and distributed frontal networks.
  • Mood variations could be assessed using EMA and other tools to correlate mood fluctuations with neural circuitry changes.
  • Researchers could stimulate portions of the network to assess the effect on network dynamics and behavior.
• Chronic recordings. There are various long-term DBS/RNS systems that include the ability to record. Some patients with mental health disorders are implanted with these devices. The proposed initiative may support scientific studies of these patient’s neural circuits, beyond the clinical trial focus of the original funding.
• RDoC-based circuit assessments. Researchers could use RDoC-inspired paradigms to assess the neural circuits involved at a higher spatial and temporal precision than previously possible.