Causal investigation of the functional interactions of theta and alpha neural oscillations in output-gating

PROJECT SUMMARY – UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH
Cognitive control requires the brain to dynamically allocate limited resources to manipulate internal
representations as a function of behavioral demands, a process referred to as output-gating. Output-gating
comprises two intertwined cognitive processes: the selection of relevant information and the suppression of
irrelevant information. These two cognitive processes have been correlated with oscillatory neuronal network
activity in two distinct frequency bands and network locations: theta oscillations (4-7 Hz) in prefrontal cortex
(PFC) for selection and alpha oscillations (8-12 Hz) in posterior parietal cortex for suppression. However, the
causal role of these oscillations and their interactions in output-gating has yet to be established. To address this
gap, this proposal examines the causal role of theta and alpha oscillations in output-gating across multiple scales
with individualized brain stimulation paradigms to provide a mechanistic delineation of how these oscillations
support behavior, coordinate network activity, and regulate neuronal spiking activity. The objective of AIM 1 is to
demonstrate the causal role of theta and alpha oscillations in selection and suppression, respectively. To
accomplish this, theta and alpha frequency rhythmic transcranial magnetic stimulation is applied in healthy
participants to frontal and parietal sites with simultaneous electroencephalography (EEG) during a working
memory task with a retrospective cue that drives output-gating. The hypothesis of AIM 1 is that frontal theta
activity coordinates the selection of relevant information, while parietal alpha activity coordinates the suppression
of irrelevant information. The objective of AIM 2 is to spatially resolve the theta and alpha network dynamics that
support selection and suppression, respectively. To achieve this objective, direct cortical stimulation combined
with invasive EEG will be used in epilepsy patients with implanted electrodes for clinical purposes. The
hypothesis of AIM 2 is that connectivity between frontal and parietal regions establishes oscillatory dynamics
critical for selection and suppression. The objective of AIM 3 is to determine how oscillatory network dynamics
regulate neuronal spiking activity. This is examined by applying theta and alpha frequency rhythmic optogenetic
stimulation to frontal and parietal sites in the ferret with simultaneous electrophysiology recordings during an
attentional task that modulates theta and alpha oscillations. The hypothesis of AIM 3 is that theta oscillations
increase spiking and alpha oscillations decrease spiking activity. The proposed work is significant since it will
provide a multi-scale mechanistic understanding of how theta and alpha oscillations coordinate output-gating.
The proposed aims are innovative since they employ synergistic causal perturbations through targeted brain
stimulation paradigms with concurrent electrophysiology, enabling the manipulation of oscillatory dynamics and
the delineation of their role in coordinating neuronal spiking, network organization, and behavior. This work will
provide the foundation for the future development of brain stimulation interventions that target impaired brain
network oscillations for the restoration of cognitive deficits in psychiatric illnesses.