Comparison of fMRI BOLD Response Patterns by Electrical Stimulation of the Ventroposterior Complex and Medial Thalamus of the Rat

et al. (2013) Comparison of fMRI BOLD Response Patterns by Electrical Stimulation of the Ventroposterior Complex and Medial Thalamus of the Rat. PLoS ONE 8(6): e66821. doi:10.1371/journal.pone.0066821 Comparison of fMRI BOLD Response Patterns by Electrical Stimulation of the Ventroposterior Complex and Medial Thalamus of the Rat Pai-Feng Yang 0 You-Yin Chen 0 Der-Yow Chen 0 James W. Hu 0 Jyh-Horng Chen 0 Chen-Tung Yen 0 Ching-Po Lin, National Yang-Ming University, Taiwan 0 1 Interdisciplinary MRI/MRI Lab, Department of Electrical Engineering, National Taiwan University , Taipei, Taiwan , 2 Department of Biomedical Engineering, National Yang- Ming University , Taipei, Taiwan , 3 Department of Psychology, National Cheng Kung University , Tainan City, Taiwan , 4 Faculty of Dentistry, University of Toronto , Toronto , Canada , 5 Neurobiology and Cognitive Science Center, National Taiwan University , Taipei, Taiwan , 6 Institute of Zoology, National Taiwan University , Taipei , Taiwan The objective of this study was to compare the functional connectivity of the lateral and medial thalamocortical pain pathways by investigating the blood oxygen level-dependent (BOLD) activation patterns in the forebrain elicited by direct electrical stimulation of the ventroposterior (VP) and medial (MT) thalamus. An MRI-compatible stimulation electrode was implanted in the VP or MT of a-chloralose-anesthetized rats. Electrical stimulation was applied to the VP or MT at various intensities (50 mA to 300 mA) and frequencies (1 Hz to 12 Hz). BOLD responses were analyzed in the ipsilateral forelimb region of the primary somatosensory cortex (iS1FL) after VP stimulation and in the ipsilateral cingulate cortex (iCC) after MT stimulation. When stimulating the VP, the strongest activation occurred at 3 Hz. The stimulation intensity threshold was 50 mA and the response rapidly peaked at 100 mA. When stimulating the MT, The optimal frequency for stimulation was 9 Hz or 12 Hz, the stimulation intensity threshold was 100 mA and we observed a graded increase in the BOLD response following the application of higher intensity stimuli. We also evaluated c-Fos expression following the application of a 200mA stimulus. Ventroposterior thalamic stimulation elicited c-Fos-positivity in few cells in the iS1FL and caudate putamen (iCPu). Medial thalamic stimulation, however, produced numerous c-Fos-positive cells in the iCC and iCPu. The differential BOLD responses and c-Fos expressions elicited by VP and MT stimulation indicate differences in stimulus-response properties of the medial and lateral thalamic pain pathways. - Funding: This work was supported by grants from National Science Council, Taiwan (NSC100-2311-B002-002-MY3), from National Health Research Institutes, Taiwan (NHRI-EX101-10104NI), and from National Taiwan University (101R892102). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Nociceptive sensory processing within the thalamus involves 2 distinct and parallel systems: the lateral and medial systems [1]. Lateral regions of the thalamus project to the primary (S1) and secondary (S2) somatosensory cortices, which are considered important in the sensory-discriminative aspects of pain. Medial regions of the thalamus transmit processed nociceptive signals to the anterior cingulate cortex, insular cortex, and other limbic brain areas, which might be involved in the affective-motivational aspects of pain [25]. Most primary studies of these 2 systems used recording and tracing methods to investigate the anatomical and electrophysiological interconnections of these brain regions. However, it remains unclear if fundamental differences in signal processing exist between the medial and lateral thalamic pathways. A global comparison using direct stimulation and functional brain imaging is, therefore, needed. Functional magnetic resonance imaging (fMRI) uses blood oxygenation level-dependent (BOLD) contrasts to correlate neural activities with neurovascular changes [68]. Although fMRI measures neural activity indirectly, it has the advantages of being noninvasive and capable of detecting whole-brain activation patterns. It is, therefore, a preferred method for evaluating human cognitive function. In addition, fMRI technique can be used for the investigation of functional changes of specific brain pathways in animal models. For examples, several studies combined fMRI with direct brain microstimulation to identify functional neural connections and BOLD responses, including in the visual system of the monkey [9], and hippocampal formation [10], the thalamocingulate pathway [11], and in Parkinson disease [12,13]. To test the hypothesis that medial and lateral thalamic pathways have differential sensory processing properties, we monitored the BOLD responses in the forebrain following application of electrical stimulation to the ventroposterior (VP) or the medial (MT) thalamus. In addition, we investigated the functional activation areas associated with VP or MT stimulation by evaluating early-gene Fos expression in cortical and subcortical structures. Results indicated that the 2 thalamocortical pathways have distinct activation areas and c-Fos activation patterns, as well as different intensity- and frequency-dependent stimulationresponse properties. Materials and Methods All experimental procedures were approved by the Institutional Animal Care and Use Committee of National Taiwan University and adhered to guidelines established by codes for the experimental use of animals by the Council of Agriculture, Taiwan. In this study, all efforts were made in order to minimize both the number and suffering of the animals. Thirty female Long Evans rats weighing 250 g to 350 g were used, including 12 rats for fMRI experiments (6 for VP stimulation and 6 for MT stimulation), and 18 rats for c-Fos immunohistochemistry. Rats were kept in a 12-h dark/light cycle environment at a temperature of 22uC with food and water available ad libitum. Electrode Implantation and Recordings A head mask was applied to each rat, providing an anesthetic of 4% isoflurane in 100% O2. A cannula was inserted into the rat femoral vein for administering anesthetic and the anesthetic was then changed to a-chloralose (80 mg/kg) and medetomidine hydrochloride (0.05 mg/kg). The addition of a low dosage of medetomidine (regular dose is 0.250.5 mg/kg) was to keep the rat under a suitable anesthesia level for surgery. On the basis of pharmacokinetic study of medetomidine hydrochloride in blood is about 1 hour [14]. We started deep brain stimulation 2 hr later. Therefore, there should be minimal lingering medetomidine effect during the stimulation experiment. After 1 h, a continuous infusion of a-chloralose was provided at a rate of 30 mg/kg/h. Each animal was positioned in a stereot (...truncated)