The neural response to deep brain stimulation of the anterior nucleus of the thalamus: A MEMRI and c-Fos study

Christiane Gimenes; Jackeline Moraes Malheiros; Harsha Battapady; Alberto Tannus; Clement Hamani; Luciene Covolan

doi:10.1016/j.brainresbull.2019.01.011

The neural response to deep brain stimulation of the anterior nucleus of the thalamus: A MEMRI and c-Fos study

Brain Res Bull. 2019 Apr:147:133-139. doi: 10.1016/j.brainresbull.2019.01.011. Epub 2019 Jan 15.

Authors

Christiane Gimenes¹, Jackeline Moraes Malheiros¹, Harsha Battapady², Alberto Tannus³, Clement Hamani⁴, Luciene Covolan⁵

Affiliations

¹ Department of Physiology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
² Renovo Neural Inc., Cleveland, OH, USA.
³ Physics Institute of Sao Carlos, Universidade de Sao Paulo, Sao Paulo, Brazil.
⁴ Harquail Centre for Neuromodulation, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁵ Department of Physiology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: lucovolan@gmail.com.

PMID: 30658130
DOI: 10.1016/j.brainresbull.2019.01.011

Abstract

Background: Deep brain stimulation (DBS) refers to the delivery of electric current to specific deep brain structures through implanted electrodes. Recently approved for use in United States, DBS to the anterior nucleus of thalamus (ANT) is a safe and effective alternative treatment for medically refractory seizures. Despite the anti-seizure effects of ANT DBS, preclinical and clinical studies have failed to demonstrate it actions at a whole brain level.

Objective: Here, we used a magnetic resonance imaging (MRI)-based approach in healthy adult rats to investigate the effects of ANT DBS through the circuit of Papez, which has central role in the generation and propagation of limbic seizures, in temporal lobe epilepsy (TLE).

Methods: After ANT electrode implantation and recovery, ANT DBS and SHAM (sham animals had electrodes implanted but were not stimulated) rats received one single injection of the contrast enhancer, manganese chloride (60 mg/kg, ip). Twelve hours after, rats underwent the baseline scan using the MEMRI (Manganese-Enhanced Magnetic Resonance Imaging) technique. We used the same MEMRI and parvalbumin sequence to follow the DBS delivered during 1 h (130 Hz and 200 μA). Perfusion was followed by subsequent c-Fos and parvalbumin immunostaining of brain sections.

Results: Acute unilateral ANT DBS significantly reduced the overall manganese uptake and consequently, the MEMRI contrast in the circuit of Papez. Additionally, c-Fos expression was bilaterally increased in the cingulate cortex and posterior hypothalamus, areas directly connected to ANT, as well as in amygdala and subiculum, within the limbic circuitry.

Conclusion: Our data indicate that MEMRI can be used to detect whole-brain responses to DBS, as the high frequency stimulation parameters used here caused a significant reduction of cell activity in the circuit of Papez that might help to explain the antiepileptic effects of ANT DBS.

Keywords: Anterior thalamus; Deep brain stimulation; Hippocampus; Manganese enhanced MRI; c-Fos.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amygdala / metabolism
Animals
Anterior Thalamic Nuclei / metabolism*
Cell Nucleus / metabolism
Deep Brain Stimulation / methods
Electrodes, Implanted
Epilepsy / metabolism
Epilepsy / therapy
Epilepsy, Temporal Lobe / therapy
Hippocampus / metabolism
Limbic System
Magnetic Resonance Imaging / methods
Male
Proto-Oncogene Proteins c-fos / metabolism
Rats
Rats, Wistar
Seizures / metabolism
Seizures / therapy*
Thalamus / metabolism

Substances

Proto-Oncogene Proteins c-fos