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Invited Symposium 2 - Neuromodulation of cognitive circuits – from animal models to human translation

Chair: Dr. Sabine Kastner¹; ¹Princeton University
Presenters: Rober Boshra, Thilo Womelsdorf, Christina Kim, Peter Rudebeck

Cognition results from computations within and across nodes of large-scale networks that span areas of the cerebral cortex, basal ganglia, and thalamus. Using non-invasive and invasive methods in humans, non-human primates and rodents much has been learned about the neuroanatomical organization, functional characteristics and mechanistic underpinnings of circuit elements in relation to cognitive behaviors. The field is now at a point where local circuits and large-scale networks can be manipulated to influence cognitive behaviors in predictable ways. In this symposium, we will introduce precision tools and their application to cognitive circuits at the molecular, cellular and systems level that have been developed in animal models but hold the promise for direct and indirect translation to neuropsychiatric disease treatments. The emerging field of precision neuromodulation will be represented by four speakers presenting their cutting edge research. Rober Boshra will present studies showing behavioral improvements induced by electrical microstimulation of key nodes of the monkey attention network. Thilo Womelsdorf will report on influences induced by low intensity focused ultrasound stimulation on several cognitive behaviors in monkeys. Tina Kim will report on studies in mice using precision tools to manipulate cell-type specific neurons to impact behavior. And Peter Rudebeck will report on deep brain stimulation studies in monkeys to identify structural and functional network changes. Together, the symposium will showcase how basic research in animal models utilizing precision neuromodulation can impact neural circuits and behavior with significant translational potential to improve human health.

Presentations

Electrical microstimulation of pulvinar for modulation of thalamo-cortical activity and behavior

Rober Boshra¹; ¹Princeton University

The pulvinar, largest nucleus of the primate visual thalamus, is a critical node for cognitive behavior, where prior evidence has shown its role in gating cortical activity and dynamically regulating cortico-cortical interactions. However, a mechanistic understanding of thalamo-cortical interactions and how their dynamic moment-to-moment changes are causally linked to behavior remains lacking. In this talk, I will present a series of experiments where we used combined electrical microstimulation (EMS) and dense neural recordings to probe the macaque pulvinar and its dynamic response properties through perturbing its local ensembles. To investigate the propagation of pulvinar-initiated signals, we simultaneously recorded from the lateral intraparietal area and posterior inferotemporal cortex, both reciprocally connected with pulvinar, as well as interconnected with one another. Across these experiments, we showed that pulvinar EMS robustly initiated a neural response cascade, starting with brief excitation, prolonged inhibition, and lastly shifting to rapid spike sequences (i.e. bursts). Further, we found that a single stimulation train could trigger a rhythmic modulation of local spiking in the theta-alpha range (4-12 Hz) and that rhythmic pulvinar EMS entrained cortical spiking activity. Using combined EMS and recording during a spatial attention task, we found that EMS-induced bursting improved attentional performance in a manner that was both spatially and temporally specific. Together, these results demonstrate that precisely timed thalamic stimulation can modulate cortex and influence behavior. Notably, the neural cascade we identified following pulvinar stimulation may offer translational potential in cognition-targeted human deep brain stimulation (e.g. in closed-loop designs).

Event-related focused ultrasound (eFUS) of cognitive-thalamic nuclei enhances set shifting, working memory updating and sequence learning

Thilo Womelsdorf¹; ¹Vanderbilt University

The talk surveys a novel transcranial, event-related focused ultrasound stimulation (eFUS) protocol that has a likely net-excitatory effect on local circuit using a multi-phase transducer array that allows non-invasive targeting the mediodorsal thalamus or the anterior nucleus of the thalamus. We show in nonhuman primates the high precision and consistency of FUS pressure fields within these nuclei and apply focal FUS sonication during brief periods when subjects fixate task relevant objects in different cognitive tasks: In a probabilistic set shifting task, eFUS of the anterior portion of the mediodorsal thalamus enhanced subjects’ overall accuracy amongst others. In a working memory updating task eFUS increased the saliency of recently updated objects reflecting an enhanced WM recency effect. In an object sequence learning task subjects showed reduced perseverative errors and better retention of object sequences. Some of these effects showed session-by-session correlations with the actual sonication pressure arriving in the thalamic nucleus. In summary, this multitask assessment of noninvasive, gaze contingent eFUS provides a new test-bed for network-specific modulation of higher cognitive functioning and circuit-level understanding of attentional control operations - and possibly for using non-invasive neuromodulation to enhance cognitive flexibility in neuropsychiatric conditions.

Genetically encodable tools for tagging, reactivating, and sequencing cells undergoing neuromodulation

Christina Kim^1,2; ¹Princeton University, ²Howard Hughes Medical Institute

Probing the molecular and functional properties of neuronal ensembles is essential for understanding how these networks give rise to circuit function and animal behavior. Our group specializes in developing molecular and optical approaches to study different types of neuronal signaling in the brains of awake, behaving mice. We utilize real-time, cellular-resolution imaging techniques for recording activity during behavior, in addition to next-generation molecular activity integrators for tagging and stimulating activated neuronal circuits. To allow investigations into the molecular cell-types of these neurons, we engineer technologies that encode the cellular activity history into the transcriptome of individual neurons. This activity tag is read-out during single-cell RNA sequencing, and can then be linked to specific set of relevant cell-types. Alternatively, the activity tag can encode an optogenetic channel, to enable subsequent manipulation of the tagged neurons. Here I will discuss our work using a family of light- and calcium-dependent transcription reporters and proximity enzymes to tag and manipulate neurons that respond to psychoactive drugs in mice.

Stimulate, Disrupt, or Rewire? Rethinking the Neural Mechanisms of Deep Brain Stimulation for Psychiatric Disorders

Peter Rudebeck¹; ¹Icahn School of Medicine at Mount Sinai

Treatment-resistant depression affects millions of people worldwide and remains one of psychiatry's most pressing challenges. Deep brain stimulation targeting the subcallosal anterior cingulate cortex (SCC-DBS) has emerged as a promising intervention, achieving meaningful symptom reduction in 60–70% of patients who have failed to respond to other therapies. Despite this, the neural mechanisms engaged by SCC-DBS remain almost entirely unknown, largely because they cannot be directly interrogated in the human brain. To address this, we modeled SCC-DBS in macaques using parameters matched to those proven to be effective in humans. SCC-DBS produced a selective increase in fractional anisotropy in the cingulum bundle distant from the stimulation site, reflecting structural white matter remodeling. At the cellular level, this was accompanied by increased myelination and oligodendrocyte density in the mid-cingulum bundle. In parallel, SCC-DBS altered brain-wide functional connectivity, changing interactions between the SCC and multiple brain networks, most notably the default mode network that has been implicated in depression. These effects were specific to active stimulation and not attributable to lead placement. Together, these findings reveal that SCC-DBS drives coordinated structural and functional reorganization of large-scale brain networks, identifying white matter remodeling as a previously unrecognized mechanism of therapeutic neuromodulation.