Theta burst transcranial magnetic stimulation of fronto-parietal networks: Modulation by mental state

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Abstract The recent growth of non-invasive brain stimulation has provided new technologies to probe neural function and treat diverse neuropsychiatric conditions, but much remains to be learned about how stimulation interacts with brain networks. We will address this question for transcranial magnetic stimulation (TMS), a powerful and flexible type of non-invasive brain stimulation that directly stimulates neurons and can induce persisting effects and neuroplastic changes which outlast the period of stimulation. We will examine a particular type of TMS, known as theta burst stimulation (TBS), which induces longer lasting effects than other forms of TMS, making TBS an important tool for therapeutic applications. While TBS provides relatively focal stimulation, effects on the brain occur through interconnected networks in ways that are poorly understood. Moreover, stimulation is highly state-dependent, and the use of TMS in most therapeutic settings, such as the treatment of depression, leaves mental state uncontrolled. Augmenting TMS by pairing it with psychological interventions is an attractive idea for improving therapeutic TMS, but the relevant knowledge base is sparse. To address this critical gap, this exploratory R21 proposal will examine the effects of TBS on specific brain networks and the interaction between TBS and mental state. We will test the broad hypothesis that when TBS is applied during a controlled mental state, network changes will be facilitated, compared to stimulation when mental state is uncontrolled. We will focus on the dorsolateral prefrontal cortex (dlPFC) and the associated fronto- parietal network (FPN), which subserves cognitive control -- the ability to flexibly adapt and regulate behavior, an ability known to be impaired in neuropsychiatric conditions such as depression and dementia. We will use an ‘n-back’ task tapping cognitive control and the FPN. We will comprehensively assess brain activity with three functional magnetic resonance imaging (fMRI) modalities: blood oxygenation level-dependent (BOLD) activation will measure FPN activity with the n-back task, resting state BOLD fMRI will measure connectivity and resting state arterial spin labeling (ASL) MRI will measure cerebral perfusion. TBS will be applied to 40 healthy subjects in 3 conditions, each followed by an fMRI session. Analysis will utilize powerful within-subject comparisons. In Aim 1, we will show that persisting neural changes induced by TBS to the dlPFC, compared to TBS to the vertex, will affect the FPN. In Aim 2, we will demonstrate modulation of the effect of dlPFC TBS administered when subjects are performing the n-back task, compared to when their mental state is unconstrained. In Aim 3, we will test predictions that n-back performance will improve following TBS to dlPFC, but not to the cortical vertex, and will improve even more following TBS during n-back performance. Impact: Results will provide insights into the effect of TMS on the brain, identifying a network target manipulated by TBS and interacting with mental state. Demonstrated this interaction will lay critical groundwork for future studies to show how controlling mental state during TMS can improve therapeutic effects.