This work is funded by the Netherlands Organization for Scientific Research (NWO) (Veni no. 916.86.125), awarded to L. Reneman. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no conflicts of interest.

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We have nothing to disclose.

5-HT phMRI is a promising tool to assess neurotransmitter function in animals in vivo. It visualizes the brain response to a 5-HT challenge with functional MR imaging. MRI has the great advantage to have a high spatial resolution and to not need the injection of contrast-agent or radio-labeled molecules thus avoiding the repetitive exposure to ionizing radiations. This technique is applicable in both human and animal subjects and therefore very suitable for translational research of neurotransmitter systems and psychiatric disorders. Its application is of course not limited to the 5-HT pathway and has already been used extensively to assess effects of dopaminergic drugs in both animals5,15 and humans22.
Nevertheless, phMRI in small animals remains challenging, as already pointed out in review articles by Martin and Sibson11 and Steward20. One of these challenges is the maintenance of stable physiological parameters during image acquisition. Most anesthetics can alter cardiovascular function and given that phMRI is critically dependent on cardiovascular/hemodynamic parameters it is essential to ensure that any hemodynamic changes are solely attributable to the given drug challenge. It is therefore vitally important that pCO2 levels remain constant during baseline acquisition. Mechanical ventilation can to help ensure physiological stability, and is often used in this type of experiments. We however chose to use free-breathing animals to leave open the possibility to perform longitudinal studies in the future. Instead, we extensively monitored (and altered) respiration rate and blood gas values to ensure physiological stability within the normal ranges before start of the functional scan and in this way to preserve stable vascular reactivity and thus T2*/T2 signal. Literature about the effects of general anesthetics on cerebral hemodynamics and metabolism is abundant20 and beyond the scope of this manuscript. We chose to use gas anesthesia with &plusmn;2% isoflurane in this specific protocol, because with inhalation anesthetics, the depth of anesthesia can be rapidly and easily controlled. This is important in our setup to ensure normal range stable pCO2 levels before start of the image acquisition. Isoflurane is the most commonly used inhalant anesthetic today and allows for rapid induction and recovery, which is important for longitudinal studies. It also produces minimal cardiovascular and respiratory depression and induces good relaxation of skeletal muscles.
Secondly, the intravenous administration of the challenging drug is more complicated in small animals than in humans. The surgery that is needed for the cannulation of the femoral artery and vein requires well-trained and experienced staff. Due to these invasive procedures it is at the moment mainly used in terminal procedures. However, non-invasive monitoring of blood homeostasis and tail vein injection could be used for longitudinal studies23.
In addition, there are some more general limitations to the technique, which are not specific for animal phMRI. Additionally, as pointed out by Martin and Sibson11, a potential confound of all fMRI studies is that it is assumed that the changes in brain activity evoked by the challenge reflect changes in neuronal activity rather than peripheral systemic effects. Especially in deeper brain structures, a relatively poor understanding of neurovascular coupling (relationship between neuronal activity changes and hemodynamic changes) remains. Studies of the kind performed by Logothetis 10 to determine neurovascular coupling in the cortex have not yet been performed in other parts of the brain. It is therefore unknown what an increase in BOLD signal in important structures such the striatum or amygdala is telling us about neuronal activity. The best we could say at this moment is that the brain region reacts to the given challenge and that depending on the treatment and/or conditions, we can monitor the significant changes of the brain reactivity. This can largely be verified by looking at both the MRI data and physiological responses. The general pattern of brain activation should be region specific and restricted to areas with, in this case, a high 5-HT innervation, and not as much a general vascular response. Also, a different temporal profile between vascular and hemodynamic changes is expected. Whereas the blood pressure changes return to their baseline values within several minutes, the effect of the drug on BOLD activation is in the case of fluoxetine visible until the end of the image acquisition and correspond to the know pharmacokinetic properties of this drug. Finally, the physiological responses of all animals should be similar in order to make inter-subject comparisons. Nonetheless, it is known that a neurogenic regulation of the local blood flow by 5-HT exist4. Therefore it can not be excluded that local changes of BOLD signal may attribute to vascular changes due to release of 5-HT at the proximity of vessels. Although these effects are not associated to local neuronal activation and can thus be considered as false positive results, it is also an index of the overall specific function of the 5-HT system (see also3).
Critical steps of this technique are therefore to monitor physiological responses extensively and to make sure that the physiological conditions of the animal are stable before and during the image acquisition. Also scanner conditions should be as stable as possible and exactly the same for each animal. Signal stability of your sequence should be checked and confirmed before start of your experiment. Furthermore, make sure to always have large enough statistical power, even with small subject groups. For a nice review on the experimental considerations of animal phMRI in general, see Steward 20 and for an additional example of an experimental protocol for pharmacological fMRI in rats and mice, see Ferrari5.
Possible modifications of technique described here are numerous. One could:
<ol>
	<li>using a different drug for 5-HT challenge, such as another SSRIs or 5-HT receptor (ant)agonists16,13,18,7 or even a double challenge in order to reveal underlying mechanisms of drug action6,19;</li>
	<li>use a different experimental setup, such as a different anesthesia regime, mechanical ventilation, blood-pool contrast agents instead of BOLD15, longitudinal studies (animal needs to be kept alive, so no invasive blood pressure/blood gas measurement and/or mechanical ventilation are possible), or even combinations with other (invasive) methods such as recording of neuronal activity using MR-compatible electrodes10 or PET/SPECT studies4;</li>
	<li>use different MRI data analysis methods such as the 'p-block' method of McKie12 or functional connectivity analysis15.</li>
</ol>
Which choices you make in the experimental setup is highly dependent on the possibilities of and/or the experience within your lab and the type of research question you would like to answer.

<table border="1">
<tbody>
 <tr>
 <td>Name of the reagent/equipment</td>
 <td>Company</td>
 <td>Catalogue number</td>
 <td>Comments </td>
 </tr>
 <tr>
 <td>Isoflurane</td>
 <td>ABBOTT 
 <a href="http://www.abbott.co.uk/" target="_blank">Abbott Laboratories Ltd.,Maidenhead, UK</a></td>
 <td>No B506</td>
 <td>Mix with medical air</td>
 </tr>
 <tr>
 <td>Medical air</td>
 <td><a href="http://www.bochealthcare.co.uk/" target="_blank">BOC Healthcare</a></td>
 <td>&nbsp;</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>Heating pad</td>
 <td><a href="http://www.harvardapparatus.co.uk/" target="_blank">Harvard apparatus</a></td>
 <td> 507223F 
 <a href="http://www.harvardapparatus.co.uk/webapp/wcs/stores/servlet/haisku3_10001_11555_39108_-1_HAUK_ProductDetail_N_37610_37611_37613" target="_blank">Complete Homeothermic Blanket System with Flexible Probe, Medium, 230 VAC, 50 Hz</a></td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>Silk ligature</td>
 <td><a href="http://www.harvardapparatus.com/" target="_blank">http://www.harvardapparatus.com/</a></td>
 <td><a href="http://www.harvardapparatus.com/webapp/wcs/stores/servlet/product_11051_10001_43051_-1_HAI_ProductDetail" target="_blank">2-0 black braided silk non-absorbable</a> 
 Cat Num 51-7631</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>PE-50 Cannula</td>
 <td><a href="http://www.scientificlabs.co.uk/" target="_blank">http://www.scientificlabs.co.uk/</a></td>
 <td><a href="http://www.scientificlabs.co.uk/product/TUB3662" target="_blank">Portex Tubing PE 0.58x0.96mm</a></td>
 <td>0.58 ID 0.96 OD mm</td>
 </tr>
 <tr>
 <td>Heparin sodium</td>
 <td> <a href="http://www.leo-pharma.com/Home/Products/List-of-LEO-Pharma-products.aspx" target="_blank">Leo laboratories Ltd, Bucks., UK</a></td>
 <td>Heparin sodium 1000IU/ml</td>
 <td>15 U/ml</td>
 </tr>
 <tr>
 <td>Vetbond Tissue Adhesive</td>
 <td><a href="http://solutions.3m.co.uk" target="_blank">3M</a></td>
 <td><a href="http://solutions.3m.co.uk/wps/portal/3M/en_GB/HealthCare/Home/ProdInfo/VetProducts/" target="_blank">M&nbsp;Vetbond Tissue Adhesive</a></td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>Monitoring system</td>
 <td><a href="http://www.i4sa.com/" target="_blank">SA Instruments</a></td>
 <td><a href="http://www.i4sa.com" target="_blank">http://www.i4sa.com</a> 
 <a href="http://69.20.42.253/web_app/main/defaultProduct.aspx?ID=16&amp;PT=3" target="_blank">Model 1025L monitoring system</a></td>
 <td>Monitors respiration and temperature</td>
 </tr>
 <tr>
 <td>Pressure transducer</td>
 <td><a href="http://www.biopac.com/" target="_blank">Biopac Systems Corp</a></td>
 <td><a href="http://www.biopac.com/blood-pressure-transducer" target="_blank">BLOOD PRESSURE TRANSDUCER - TSD104A</a> 
 <a href="http://www.biopac.com/data-acquisition-analysis-system-mp150-system-windows" target="_blank">MP150 DATA ACQUISITION SYSTEM - WIN - MP150WSW</a></td>
 <td>Monitors blood pressure</td>
 </tr>
 <tr>
 <td>RapidLab blood gas analyzer</td>
 <td><a href="http://www.medical.siemens.com/" target="_blank">Siemens Diagnostics</a></td>
 <td><a href="http://www.medical.siemens.com/webapp/wcs/stores/servlet/ProductDisplay~q_catalogId~e_-111~a_catTree~e_100001,1023069,1016115~a_langId~e_-111~a_productId~e_172940~a_storeId~e_10001.htm" target="_blank">RAPIDLab 248/348 Systems</a></td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>4.7T animal scanner</td>
 <td>Agilent Technologies (previously Magnex) 
 4.7T frequency 199.845 MHz</td>
 <td>&nbsp;</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>MR compatible stereotactic bed</td>
 <td><a href="http://www.m2mimaging.com/products/preclinical.html" target="_blank">m2m Imaging Corp</a></td>
 <td>Rat bed: PA Multi element AHS 50-72-1003/100</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>Coil</td>
 <td><a href="http://www.m2mimaging.com/products/preclinical.html" target="_blank">m2m Imaging Corp</a></td>
 <td>Volume TH/Rx 
 RQD1 72/112 200</td>
 <td>&nbsp;</td>
 </tr>
 <tr>
 <td>Fluoxetine Hydrochloride</td>
 <td>Sigma-Aldrich</td>
 <td>F-132</td>
 <td>5mg/kg in saline</td>
 </tr>
 </tbody>
</table>

the use of pharmacological-challenge fmri in pre-clinical research: application to the 5-ht system

Pharmacological MRI (phMRI) is a new and promising method to study the effects of substances on brain function that can ultimately be used to unravel underlying neurobiological mechanisms behind drug action and neurotransmitter-related disorders, such as depression and ADHD. Like most of the imaging methods (PET, SPECT, CT) it represents a progress in the investigation of brain disorders and the related function of neurotransmitter pathways in a non-invasive way with respect of the overall neuronal connectivity. Moreover it also provides the ideal tool for translation to clinical investigations. MRI, while still behind in molecular imaging strategies compared to PET and SPECT, has the great advantage to have a high spatial resolution and no need for the injection of a contrast-agent or radio-labeled molecules, thereby avoiding the repetitive exposure to ionizing radiations. Functional MRI (fMRI) is extensively used in research and clinical setting, where it is generally combined with a psycho-motor task. phMRI is an adaptation of fMRI enabling the investigation of a specific neurotransmitter system, such as serotonin (5-HT), under physiological or pathological conditions following activation via administration of a specific challenging drug.
The aim of the method described here is to assess brain 5-HT function in free-breathing animals. By challenging the 5-HT system while simultaneously acquiring functional MR images over time, the response of the brain to this challenge can be visualized. Several studies in animals have already demonstrated that drug-induced increases in extracellular levels of e.g. 5-HT (releasing agents, selective re-uptake blockers, etc) evoke region-specific changes in blood oxygenation level dependent (BOLD) MRI signals (signal due to a change of the oxygenated/deoxygenated hemoglobin levels occurring during brain activation through an increase of the blood supply to supply the oxygen and glucose to the demanding neurons) providing an index of neurotransmitter function. It has also been shown that these effects can be reversed by treatments that decrease 5-HT availability16,13,18,7. In adult rats, BOLD signal changes following acute SSRI administration have been described in several 5-HT related brain regions, i.e. cortical areas, hippocampus, hypothalamus and thalamus9,16,15. Stimulation of the 5-HT system and its response to this challenge can be thus used as a measure of its function in both animals and humans2,11.

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The Use of Pharmacological-challenge fMRI in Pre-clinical Research: Application to the 5-HT System

The goal of this technique is to assess serotonin (5-HT) neurotransmitter function in the live and free-breathing animal with pharmacological magnetic resonance imaging (phMRI) and an intravenous challenge with a selective serotonin reuptake inhibitor (SSRI), fluoxetine.

Pharmacological MRI (phMRI) is a new and promising method to study the effects of substances on brain function that can ultimately be used to unravel ...

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15.3K Views.  Academic Medical Center Amsterdam. The goal of this technique is to assess serotonin (5-HT) neurotransmitter function in the live and free-breathing animal with pharmacological magnetic resonance imaging (phMRI) and an intravenous challenge with a selective serotonin reuptake inhibitor (SSRI), fluoxetine.