The Caudate Is a Promising Neuromodulation Target for Disorders of Learning and Memory
Key findings
- In this study of patients with refractory epilepsy who had implanted electrodes, caudate stimulation delivered in conjunction with an associative learning task improved learning
- Caudate and dorsolateral prefrontal cortex had learning-related beta power changes during the associative learning task
- Caudate stimulation appeared to modulate learning-related activity in the dorsolateral prefrontal cortex
- The caudate thus appears to be a potential target for neuromodulation to treat disorders of learning and memory
Deep brain stimulation is a promising treatment for disorders of learning and memory, because it has the potential to alter activity in disordered neural circuits in a spatially and temporally precise way. So far, though, no optimal target or stimulation paradigm has been identified.
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Previous research demonstrated that during the reinforcement period of an associative learning task, caudate neural activity in primates correlated with the learning rate. Moreover, high-frequency stimulation of the caudate following correct trials enhanced learning. In Brain, Sarah K. Bick, MD, clinical fellow in the Department of Neurosurgery at Massachusetts General Hospital, Sydney S. Cash, MD, PhD, associate in the Department of Neurology, Emad N. Eskandar, MD, at the Albert Einstein College of Medicine, and colleagues have reported similar findings in humans.
The dorsolateral prefrontal cortex (DLPFC) is also important in associative learning and may work in conjunction with the caudate. The researchers further found feedback-related beta power changes in the caudate and DLPFC. In the DLPFC these changes correlate with learning and may be modulated by caudate stimulation.
Study Design
The researchers recorded local field potentials from intracranial depth electrodes that had been placed in six patients with medically refractory epilepsy for seizure localization. The areas targeted included the DLPFC and the posterior orbitofrontal cortex via a trajectory passing through the striatum. To identify caudate and DLPFC electrode contacts, the researchers co-registered the postoperative computed tomography scan for each patient with preoperative magnetic resonance imaging.
The patients participated in a task that required them to learn an association between a presented image and a specific button press on a keyboard. Three patients completed stimulated sessions and five patients completed non-stimulated sessions.
The study design was that during stimulated sessions, three of the six images presented in each block would be associated with bilateral high-frequency stimulation of the caudate during the one-second feedback period following correct responses. The other three images were never to be associated with stimulation.
Results of Stimulated Sessions
The researchers were able to perform bilateral caudate stimulation sessions in two patients. Learning performance varied by session, but caudate stimulation significantly improved learning.
In the third patient, the right electrode trajectory passed through the right putamen and left caudate. Stimulation in this patient significantly impaired learning.
Results of Non-stimulated Sessions
The researchers conducted the non-stimulated sessions in order to identify neurophysiological correlates of stimulation-induced behavioral changes. First, they examined changes in beta power in the caudate and DLPFC, to understand the role of those structures in associative learning. Beta power (15–30 Hz) has been linked to learning, and it is also known to play an important role in motor planning and execution.
When averaged over all trials, caudate beta power increased during feedback, and the increase was significantly greater after correct trials than incorrect trials. Similarly, average DLPFC beta power during feedback following correct trials was significantly greater than that following incorrect trials. Unlike in the caudate, this difference persisted into the post-feedback period.
Because of the latter result, the researchers decided to examine the post-feedback period of the stimulated sessions. They determined that DLPFC beta power was greater following correct stimulated trials than correct non-stimulated trials, which suggests that caudate stimulation may alter DLPFC learning-related activity.
Toward the Future
The caudate appears to be a therapeutic target worth testing in new neuromodulation strategies. Caudate pathology has been linked to memory dysfunction in several disease states, including Huntington's disease and Parkinson's disease, and caudate stimulation might prove to be particularly useful for treating memory dysfunction in those disorders.
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