Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.

JNJ-42491293 is a metabotropic glutamate 2 (mGlu2) positive allosteric modulator (PAM) that was radiolabelled with [11C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [11C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [11C]-JNJ-42491293 did not modify the SUVs obtained with [11C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human.

Anatomical variability, multi-modal coordinate systems, and precision targeting in the marmoset brain.

Localising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and posterior commissures (AC-PC) and CIFTI grayordinates. We found that the horizontal plane of the stereotactic coordinate was significantly rotated in pitch relative to the AC-PC coordinate system (10 degrees, frontal downwards), and had a significant bias and uncertainty due to positioning procedures. We also found that many common cranial and brain landmarks (e.g., bregma, intraparietal sulcus) vary in location across subjects and are substantial relative to average marmoset cortical area dimensions. Combining the neuroimaging-based targeting pipeline with robot-guided surgery enabled proof-of-concept targeting of deep brain structures with an accuracy of 0.2 mm. Altogether, our findings demonstrate substantial intersubject variability in marmoset brain and cranial landmarks, implying that subject-specific neuroimaging-based localization is needed for precision targeting in marmosets. The population-based templates and atlases in grayordinates, created for the first time in marmoset monkeys, should help bridging between macroscale and microscale analyses.

Co-registration of Imaging Modalities (MRI, CT and PET) to Perform Frameless Stereotaxic Robotic Injections in the Common Marmoset.

The common marmoset has emerged as a popular model in neuroscience research, in part due to its reproductive efficiency, genetic and neuroanatomical similarities to humans and the successful generation of transgenic lines. Stereotaxic procedures in marmosets are guided by 2D stereotaxic atlases, which are constructed with a limited number of animals and fail to account for inter-individual variability in skull and brain size. Here, we developed a frameless imaging-guided stereotaxic system that improves upon traditional approaches by using subject-specific registration of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) data to identify a surgical target, namely the putamen, in two marmosets. The skull surface was laser-scanned to create a point cloud that was registered to the 3D reconstruction of the skull from CT. Reconstruction of the skull, as well as of the brain from MR images, was crucial for surgical planning. Localisation and injection into the putamen was done using a 6-axis robotic arm controlled by a surgical navigation software (Brainsight™). Integration of subject-specific registration and frameless stereotaxic navigation allowed target localisation specific to each animal. Injection of alpha-synuclein fibrils into the putamen triggered progressive neurodegeneration of the nigro-striatal system, a key feature of Parkinson's disease. Four months post-surgery, a PET scan found evidence of nigro-striatal denervation, supporting accurate targeting of the putamen during co-registration and subsequent surgery. Our results suggest that this approach, coupled with frameless stereotaxic neuronavigation, is accurate in localising surgical targets and can be used to assess endpoints for longitudinal studies.

Neuronavigated Repetitive Transcranial Ultrasound Stimulation Induces Long-Lasting and Reversible Effects on Oculomotor Performance in Non-human Primates.

Since the late 2010s, Transcranial Ultrasound Stimulation (TUS) has been used experimentally to carryout safe, non-invasive stimulation of the brain with better spatial resolution than Transcranial Magnetic Stimulation (TMS). This innovative stimulation method has emerged as a novel and valuable device for studying brain function in humans and animals. In particular, single pulses of TUS directed to oculomotor regions have been shown to modulate visuomotor behavior of non-human primates during 100 ms ultrasound pulses. In the present study, a sustained effect was induced by applying 20-s trains of neuronavigated repetitive Transcranial Ultrasound Stimulation (rTUS) to oculomotor regions of the frontal cortex in three non-human primates performing an antisaccade task. With the help of MRI imaging and a frame-less stereotactic neuronavigation system (SNS), we were able to demonstrate that neuronavigated TUS (outside of the MRI scanner) is an efficient tool to carry out neuromodulation procedures in non-human primates. We found that, following neuronavigated rTUS, saccades were significantly modified, resulting in shorter latencies compared to no-rTUS trials. This behavioral modulation was maintained for up to 20 min. Oculomotor behavior returned to baseline after 18-31 min and could not be significantly distinguished from the no-rTUS condition. This study is the first to show that neuronavigated rTUS can have a persistent effect on monkey behavior with a quantified return-time to baseline. The specificity of the effects could not be explained by auditory confounds.

Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model.

Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200-800 µL) and rates (0.5-5 µL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for ∼1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 µL (2 × the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 µL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 µL/min at a volume ∼1/3 of the thalamus (400-600 µL) appears to be well tolerated in sheep both clinically and histopathologically.

Frameless Stereotactic Targeting of the Cerebellar Dentate Nucleus in Nonhuman Primates: Translatable Model for the Surgical Delivery of Gene Therapy.

BACKGROUND: Stereotactic targeting techniques in nonhuman primate (NHP) models are often utilized in the preclinical investigation of new drug therapies with the goal of demonstrating accurate and reliable delivery of a therapy to the target tissue. However, targeting certain neuroanatomical structures can be challenging. The deep cerebellar nuclei, specifically the dentate nucleus, are potential stereotactic targets for the treatment of certain ataxias. Currently, there are no detailed techniques describing frameless targeting of these structures in a NHP model. A well-defined, accurate, and reliable stereotactic surgical approach to the dentate in these animal models is critical to prove the feasibility and safety of drug delivery in order to develop clinical protocols. METHODS: Frameless stereotactic neuronavigation was employed to target the bilateral dentate nuclei of the cerebellum in four healthy juvenile Cynomolgus monkeys via a suboccipital, transcerebellar approach. The precision and accuracy of the targeting were evaluated radiologically and histologically. RESULTS: Using the described surgical methodology, we were successful in hitting the target deep cerebellar nuclei seven out of eight times. CONCLUSION: Frameless stereotactic targeting of the cerebellar dentate nuclei in NHPs for future investigational drug delivery is feasible, safe, and accurate as described by this report. Potential areas for improving the technique are discussed.

Improved methods for MRI-compatible implants in nonhuman primates.

BACKGROUND: Neuroscientists commonly use permanently implanted headposts to stabilize the head of nonhuman primates (NHPs) during electrophysiology and functional magnetic resonance imaging (fMRI). Here, we present improved methodology for MRI-compatible implants without the use of acrylic for head stabilization in NHPs. NEW METHOD: MRI is used to obtain a 3D-reconstruction of NHP skulls, which are used to create customized implants by modeling intersections with the bone. Implants are manufactured from PEEK using computer numerical control machining and coated with hydroxyapatite to promote osseointegration. Surgically, implants are attached to the skull with ceramic screws, while the skin flap is pulled over the implant and closed subcutaneously. RESULTS: Quality of blood oxygen level dependent (BOLD) fMRI signal is improved in animals implanted with our method as compared to traditional acrylic implants. Additionally, implants are well-integrated with the skull, remain robust for more than a year and without granulation tissue around the skin margin. COMPARISON WITH EXISTING METHOD(S): Previous improvements on NHP implants (Chen et al., 2017; McAndrew et al., 2012; Mulliken et al., 2015; Overton et al., 2017) lacked fMRI-compatibility, as they relied on titanium headposts and/or titanium screws. Thus, most fMRI studies in NHPs today still rely on the use of acrylic-based headposts for stabilization and the use of contrast-enhanced agents to improve MRI signal. CONCLUSIONS: Our method preserves fMRI-compatibility and results in measurable improvement in BOLD signal without the use of contrast-enhanced agents. Furthermore, the long-term stability of our implants contributes positively to the wellbeing of NHPs in neuroscience research.

Transsphenoidal surgery: accuracy of an image-guided neuronavigation system to approach the pituitary fossa (sella turcica).

OBJECTIVE: To determine the accuracy of locating the pituitary fossa with the Brainsight neuronavigation system by determining the mean target error of the rostral (tuberculum sellae) and caudal (dorsum sellae) margins of the pituitary fossa. STUDY DESIGN: Experimental cadaveric study. ANIMALS: Ten canine cadavers. METHODS: Computed tomography (CT) and MRI were performed on each cadaver with fiducials in place. Images were saved to the neuronavigation computer and used to plan the drilling approach. The cadavers were placed in the surgical head clamp of the Brainsight system and positioned for a transsphenoidal approach. On the basis of the planning, 2 localization points were drilled, 1 each at the rostral and caudal margins of the pituitary fossa, and CT was repeated. Error was assessed from the difference in millimeters between the targets identified during Brainsight planning and the actual location of the 2 points drilled on each cadaver skull as identified by postdrilling CT. RESULTS: The rostral and caudal margins of the pituitary fossa provided 2 target points per cadaver. The median target error (interquartile range) for all target sites (n = 20) was 3.533 mm (range, 2.013-4.745). CONCLUSION: This stereotactic system allowed the surgeon to locate the rostral and caudal margins of the pituitary fossa with clinically acceptable accuracy and confidence. CLINICAL SIGNIFICANCE: Using the Brainsight neuronavigation system for localization during transsphenoidal hypophysectomy may decrease morbidity and surgical time.

Accuracy and Precision of a Veterinary Neuronavigation System for Radiation Oncology Positioning.

Conformal radiation treatment plans such as IMRT and other radiosurgery techniques require very precise patient positioning, typically within a millimeter of error for best results. CT cone beam, real-time navigation, and infrared position sensors are potential options for success but rarely present in veterinary radiation centers. A neuronavigation system (Brainsight Vet, Rogue Research) was tested 22 times on a skull for positioning accuracy and precision analysis. The first 6 manipulations allowed the authors to become familiar with the system but were still included in the analyses. Overall, the targeting mean error in 3D was 1.437 mm with SD 1.242 mm. This system could be used for positioning for radiation therapy or radiosurgery.

Bifeprunox versus placebo for schizophrenia.

BACKGROUND: Bifeprunox is a novel antipsychotic drug designed to treat schizophrenia. However, research into the drug was ceased in 2009 due to rejection of licence to go to market by the US Food and Drug Administration (FDA), who could not approve the drug for acute or long-term symptoms of schizophrenia because more research was required to demonstrate convincing effects "beyond those already achieved" with currently licenced drugs. There were also concerns expressed over one death of a person whilst on the drug. OBJECTIVES: To investigate the clinical and adverse effects of bifeprunox for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register on 23 October 2015, which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and clinical trials registries. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: All randomised clinical trials focusing on bifeprunox versus placebo for schizophrenia. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included four randomised controlled trials (RCTs). We found evidence of missing data and poor reporting. When bifeprunox 20 mg was compared with placebo for schizophrenia, the drug resulted in a reduction of the Positive and Negative Syndrome Scale (PANSS) positive subscale score regarding positive symptoms (n = 549, 2 RCTs, MD -1.89, 95% CI -2.85 to -0.92, low-quality evidence) and the PANSS negative subscale regarding negative symptoms (n = 549, 2 RCTs, MD -1.53, 95% CI -2.37 to -0.69, low-quality evidence). There was a clear improvement regarding deterioration in the bifeprunox 20 mg group (n = 231, 1 RCT, RR 0.71 95% CI, 0.54 to 0.93, very low-quality evidence). The total number of participants with equal to or greater than 7% weight increase was similar between bifeprunox and placebo (n = 483, 1 RCT, RR 1.02 95% CI 0.31 to 3.33 moderate-quality evidence). There were no useable data for quality of life, economic outcomes, and service use. AUTHORS' CONCLUSIONS: Our results showed some positive effects and a favourable adverse effect profile for bifeprunox, although there were few data overall and none were of high quality. It would seem that these data alone would not have been enough for the FDA to decide to halt progress of the drug to market. We can only assume that we are missing important data. Both the FDA and the relevant pharmaceutical companies have not made all relevant data accessible. As some of these trials also involved an additional haloperidol, olanzapine, quetiapine, or risperidone arm, these data are not only relevant to evaluation of bifeprunox. In not making all data accessible, it is hard to see how the FDA and the drug companies have fulfilled their full obligations to people with schizophrenia or their clinicians.

Quantitative analysis of the myelin g-ratio from electron microscopy images of the macaque corpus callosum.

We provide a detailed morphometric analysis of eight transmission electron micrographs (TEMs) obtained from the corpus callosum of one cynomolgus macaque. The raw TEM images are included in the article, along with the distributions of the axon caliber and the myelin g-ratio in each image. The distributions are analyzed to determine the relationship between axon caliber and g-ratio, and compared against the aggregate metrics (myelin volume fraction, fiber volume fraction, and the aggregate g-ratio), as defined in the accompanying research article entitled 'In vivo histology of the myelin g-ratio with magnetic resonance imaging' (Stikov et al., NeuroImage, 2015).

A stereotaxic, population-averaged T1w ovine brain atlas including cerebral morphology and tissue volumes.

Standard stereotaxic reference systems play a key role in human brain studies. Stereotaxic coordinate systems have also been developed for experimental animals including non-human primates, dogs, and rodents. However, they are lacking for other species being relevant in experimental neuroscience including sheep. Here, we present a spatial, unbiased ovine brain template with tissue probability maps (TPM) that offer a detailed stereotaxic reference frame for anatomical features and localization of brain areas, thereby enabling inter-individual and cross-study comparability. Three-dimensional data sets from healthy adult Merino sheep (Ovis orientalis aries, 12 ewes and 26 neutered rams) were acquired on a 1.5 T Philips MRI using a T1w sequence. Data were averaged by linear and non-linear registration algorithms. Moreover, animals were subjected to detailed brain volume analysis including examinations with respect to body weight (BW), age, and sex. The created T1w brain template provides an appropriate population-averaged ovine brain anatomy in a spatial standard coordinate system. Additionally, TPM for gray (GM) and white (WM) matter as well as cerebrospinal fluid (CSF) classification enabled automatic prior-based tissue segmentation using statistical parametric mapping (SPM). Overall, a positive correlation of GM volume and BW explained about 15% of the variance of GM while a positive correlation between WM and age was found. Absolute tissue volume differences were not detected, indeed ewes showed significantly more GM per bodyweight as compared to neutered rams. The created framework including spatial brain template and TPM represent a useful tool for unbiased automatic image preprocessing and morphological characterization in sheep. Therefore, the reported results may serve as a starting point for further experimental and/or translational research aiming at in vivo analysis in this species.

In vivo histology of the myelin g-ratio with magnetic resonance imaging.

The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment.

Auditory properties in the parabelt regions of the superior temporal gyrus in the awake macaque monkey: an initial survey.

The superior temporal gyrus (STG) is on the inferior-lateral brain surface near the external ear. In macaques, 2/3 of the STG is occupied by an auditory cortical region, the "parabelt," which is part of a network of inferior temporal areas subserving communication and social cognition as well as object recognition and other functions. However, due to its location beneath the squamous temporal bone and temporalis muscle, the STG, like other inferior temporal regions, has been a challenging target for physiological studies in awake-behaving macaques. We designed a new procedure for implanting recording chambers to provide direct access to the STG, allowing us to evaluate neuronal properties and their topography across the full extent of the STG in awake-behaving macaques. Initial surveys of the STG have yielded several new findings. Unexpectedly, STG sites in monkeys that were listening passively responded to tones with magnitudes comparable to those of responses to 1/3 octave band-pass noise. Mapping results showed longer response latencies in more rostral sites and possible tonotopic patterns parallel to core and belt areas, suggesting the reversal of gradients between caudal and rostral parabelt areas. These results will help further exploration of parabelt areas.

Cortico-cortical connections of areas 44 and 45B in the macaque monkey.

In the human brain, areas 44 and 45 constitute Broca's region, the ventrolateral frontal region critical for language production. The homologues of these areas in the macaque monkey brain have been established by direct cytoarchitectonic comparison with the human brain. The cortical areas that project monosynaptically to areas 44 and 45B in the macaque monkey brain require clarification. Fluorescent retrograde tracers were placed in cytoarchitectonic areas 44 and 45B of the macaque monkey, as well as in the anterior part of the inferior parietal lobule and the superior temporal gyrus. The results demonstrate that ipsilateral afferent connections of area 44 arise from local frontal areas, including rostral premotor cortical area 6, from secondary somatosensory cortex, the caudal insula, and the cingulate motor region. Area 44 is strongly linked with the anterior inferior parietal lobule (particularly area PFG and the adjacent anterior intraparietal sulcus). Input from the temporal lobe is limited to the fundus of the superior temporal sulcus extending caudal to the central sulcus. There is also input from the sulcal part of area Tpt in the upper bank of the superior temporal sulcus. Area 45B shares some of the connections of area 44, but can be distinguished from area 44 by input from the caudal inferior parietal lobule (area PG) and significant input from the part of the superior temporal sulcus that extends anterior to the central sulcus. Area 45B also receives input from visual association cortex that is not observed in area 44. The results have provided a clarification of the relative connections of areas 44 and 45B of the ventrolateral frontal region which, in the human brain, subserves certain aspects of language processing.

A method for actively tracking excitability of brain networks using a fully implantable monitoring system.

This paper introduces a new method for estimating the excitability of brain networks. The motivation for this research was to develop a system that can track pathological changes in excitability, in diseases such as epilepsy. The ability to track excitability may provide a method for anticipating seizures and intervening therapeutically. Four normally healthy canines were implanted with the Medtronic Activia PC+S deep brain stimulation and sensing system. The devices were used to probe the circuit of Papez, with electrical stimulation in the anterior nucleus of the thalamus to measure evoked potentials in the hippocampus. The canines were given three different dosage levels of anti-convulsant medication in an attempt to manipulate the excitability of the network. The results showed changes in the morphology of the evoked potentials, following a circadian profile and reflecting times of drug delivery.

Description and validation of a magnetic resonance imaging-guided stereotactic brain biopsy device in the dog.

A stereotactic brain biopsy system that is magnetic resonance (MR) imaging-guided has not been validated in dogs. Our purpose was to determine the mean needle placement error in the caudate nucleus, thalamus, and midbrain of a canine cadaver brain using the modified Brainsight stereotactic system. Relocatable reference markers (fiducial markers) were attached to the cadaver head using a dental bite block. A T1-weighted gradient echo three-dimensional (3D) sequence was acquired using set parameters. Fiducial markers were used to register the head to the acquired MR images in reference to a 3D position sensor. This allowed the planning of trajectory path to brain targets in real time. Coordinates (X, Y, Z) were established for each target and 0.5 microl of diluted gadolinium was injected at each target using a 26-gauge needle to create a lesion. The center of the gadolinium deposition was identified on the postoperative MR images and coordinates (X', Y', Z') were established. The precision of this system in bringing the needle to target (needle placement error) was calculated. Seventeen sites were targeted in the brain. The mean needle placement error for all target sites was 1.79 +/- 0.87 mm. The upper bound of error for this stereotactic system was 3.31 mm. There was no statistically significant relationship between needle placement error and target depth (P = 0.23). The ease of use and precision of this stereotactic system support its development for clinical use in dogs with brain lesions > 3.31 mm.

An MRI based average macaque monkey stereotaxic atlas and space (MNI monkey space).

In studies of the human brain, a standard stereotaxic space such as the Montreal Neurological Institute (MNI space) is widely used to provide a common reference for the three-dimensional localization of functional activation foci and anatomical structures, enabling the comparison of results obtained across different studies. Here we present a standard macaque monkey brain MRI template that offers a common stereotaxic reference frame to localize anatomical and functional information in an organized and reliable way for comparison across individual monkeys and studies. We have used MRI volumes from a group of 25 normal adult macaque monkeys (18 cynomolgus and 7 rhesus) to create a common standard macaque monkey brain as well as atlases for each of these species separately. In addition, the digital macaque monkey volume was subjected to 3D volumetric analysis and comparison of brain structures between the individual brains and the average atlas. Furthermore, we provide a means of transforming any macaque MRI volume into MNI monkey space coordinates in 3D using simple web based tools. Coordinates in MNI monkey space can also be transformed into the coordinate system of a detailed neuroanatomical paper atlas (Paxinos et al., 2008), enabling researchers to identify and delineate cortical and subcortical structures in their individual macaque monkey brains.

Encoding touch and the orbitofrontal cortex.

Lesion studies on nonhuman primates utilizing recognition memory tests have shown that the orbitofrontal cortex is critical for the encoding of novel information, and anatomical studies have shown that the orbitofrontal cortex forms part of a mnemonic circuit that connects limbic medial temporal areas with higher-order lateral frontal cortical regions. Furthermore, functional neuroimaging studies have demonstrated increased activity in the orbitofrontal cortex of the human brain during the encoding of novel visual and auditory information. The present positron emission tomography study examined brain activity related to the encoding of tactile information. Cerebral blood flow (CBF) in normal human subjects during the tactile exploration of novel stimuli from a related set of textures and patterns, as well as from a set of aversive tactile stimuli, was compared with CBF during a control condition involving familiar tactile stimuli. The results demonstrate that the right rostral orbitofrontal cortex is involved in the active encoding of novel tactile information, while a more caudal region of the orbitofrontal cortex, which is more closely connected with limbic and autonomic regions of the brain, was activated when subjects explored novel aversive tactile stimuli. These results suggest that the orbitofrontal cortex, through its connections with the limbic areas of the medial temporal lobe, influences the processing of incoming information and thus contributes to its encoding.