Using non-invasive neuroimaging to enhance the care, well-being and experimental outcomes of laboratory non-human primates (monkeys)

Abstract

Over the past 10-20 years, neuroscience witnessed an explosion in the use of non-invasive imaging methods, particularly magnetic resonance imaging (MRI), to study brain structure and function. Simultaneously, with access to MRI in many research institutions, MRI has become an indispensable tool for researchers and veterinarians to guide improvements in surgical procedures and implants and thus, experimental as well as clinical outcomes, given that access to MRI also allows for improved diagnosis and monitoring for brain disease. As part of the PRIMEatE Data Exchange, we gathered expert scientists, veterinarians, and clinicians who treat humans, to provide an overview of the use of non-invasive imaging tools, primarily MRI, to enhance experimental and welfare outcomes for laboratory non-human primates engaged in neuroscientific experiments. We aimed to provide guidance for other researchers, scientists and veterinarians in the use of this powerful imaging technology as well as to foster a larger conversation and community of scientists and veterinarians with a shared goal of improving the well-being and experimental outcomes for laboratory animals.

Fig. 1.

Example axial (horizontal) CT image from a human showing the hyperdense signal arising from the bony skull and an intraparenchymal hemorrhage.

Fig. 2.

Example horizontal sections showing a T1 (left) and T2 (right) weighted images from a human brain. Note CSF hyperintensity in the T2 image and hypointensity in the T1 weighted image.

Fig. 3.

Coronal T1 weighted post contrast image of an intraparenchymal abscess in a human brain.

Fig. 4.

a. Planning software allows researchers to identify a region of interest on the MRI and reconstructed surfaces of the brain; b. simulation of an electrophysiology chamber over the planned target location at the appropriate angle; c) visualization of the x-y electrode placements. The lower image shows a grid positioned and superimposed on the brain MRI. Adapted from Frey et al., 2007.

Fig. 5.

Functional imaging data in frontal lobe of the NHP used to help place recording chamber (arrow). Adapted from Frey et al., 2007

Fig. 6.

Distortion from a titanium implant and screws that are centered over the frontal bone in a NHP. Note the deviation of the midline from center (arrow) as well as the signal voids (black spots) caused by the titanium in the magnetic field during a T1 MPRAGE image acquisition.

Fig. 7.

In the case of custom designed shapes, simulated stress testing can be done with standard CAD software to judge the strength of a given design.

Fig. 8.

CAD files are superimposed on 3D reconstructed skull models and the intersection of the two images are used to generate new CAD files. The CAD files can then be used to create the parts on a 3D printer or manufactured on a CNC machine for higher precision. Pictured above is a custom chamber that is designed to sit over the hippocampus (in red).

Fig. 9.

Example of an experimental set-up for the anesthesia fMRI studies using a 3T MRI scanner: Representation of an EEG-fMRI set-up for anesthesia experiments in macaques. Red, MRI room with MR compatible devices around the monkey; blue, non-MR devices connected to the MRI room through the wall. TTL, transistor-transistor logic; TxRx, transmit/receive head coil. For this MR compatible anesthesia set-up, most of the material and equipment used (ventilator, physiology monitor, EEG system) match the human clinical regulations, and are commercially available.

Fig. 10.

Schematic representation of the cerebral activations in the macaque cerebral cortex for the auditory “local-global” paradigm in the awake state and under anesthesia (ketamine, propofol) (Uhrig et al., 2016). A: First-order auditory violations (local novelty effect) in the awake state and under ketamine and propofol anesthesia: The local effect is shifted during ketamine anesthesia compared to the parietal cortex and disappears during propofol anesthesia. B: Second-order sequence violations (global novelty effect) in the awake state and under ketamine and propofol anesthesia: Complete suppression of the global effect under ketamine and disorganization of the global effect under propofol anesthesia.

Fig. 11.

MRI with liquid-filled grid (arrow) indicates penetration trajectories into the brain. Image courtesy of Dr. Aidan Murphy.

Fig. 12.

A CT and B MR images showing inserted electrodes in the brain.

Fig. 13.

MRI-based localization by directly visualizing inserted electrode A, B and marking recording sites with metal deposition C, D. Adapted from Matsui et al. (2007) and Koyano et al. (2011) with modification.

Fig. 14.

T2-weighted anatomical MRI of macaque containing examples of two types of extracranial tissue growth that can be identified early through routine anatomical scans. On the left, light tissue (yellow arrows) has appeared between the skull and overlying acrylic, both of which appear as black. On the right, tissue or fluid from outside the skull (green arrow) communicates with the intracranial epidural space (red arrow). T2 weighted image acquired with fast spin echo (FSE) or rapid acquisition with relaxation enhancement (RARE) sequence.

Fig. 15.

SPECT-CT images of the cranium from a rhesus macaque with a long-standing cranial implant. A. Coronal slice of SPECT-CT image just anterior and B. posterior to head post (asterisk), and C. composite image showing strong SPECT signal (arrow) corresponding to exudate beneath the implant (Reprinted with permission from Guerriero et al, 2019).

Fig. 16.

Extracranial infection communicating with epidural space detected using routine MRI scan. Systemic antibiotic treatment (TMS + CTX) was initiated on the day of detection. The infection was tracked over the next week and was much reduced in time for a corrective surgery carried out on Dec. 6. T2 weighted image acquired with fast spin echo (FSE) or rapid acquisition with relaxation enhancement (RARE) sequence.

Fig. 17.

A large abscess was detected on Apr. 1 and was treated immediately with systemic antibiotics. A subsequent scan 10 days later demonstrated that the antibiotic treatment was ineffective, as the abscess volume increased. Following the second scan, an emergency surgery was performed, in which the abscess was drained and the implant completely removed. Subsequent scanning demonstrated a complete clearing of the intracranial infection, with scar tissue visible at the previous site of the abscess. T2 weighted image acquired with fast spin echo (FSE) or rapid acquisition with relaxation enhancement (RARE) sequence.

Fig. 18.

Example of large zone of edema in the white matter detected during a routine scan on Sep 26, in association with a chronically implanted deep electrode and prior to overt clinical symptoms. Upon detection, the patient was treated immediately with systemic antibiotics (chloramphenicol and doxycycline), which were effective at treating the infection. T2 weighted image acquired with fast spin echo (FSE) or rapid acquisition with relaxation enhancement (RARE) sequence.

Fig. 19.

Example of an incidental finding from an anatomical scanning session in a macaque. T2 weighted image acquired with fast spin echo (FSE) or rapid acquisition with relaxation enhancement (RARE) sequence.