The baboon in epilepsy research: Revelations and challenges.

The baboon offers a natural model for genetic generalized epilepsy with photosensitivity. In this review, we will summarize some of the more important clinical, neuroimaging, and elctrophysiological findings form recent work performed at the Southwest National Primate Research Center (SNPRC, Texas Biomedical Research Institute, San Antonio, Texas), which houses the world's largest captive baboon pedigree. Due to the phylogenetic proximity of the baboon to humans, many of the findings are readily translatable, but there may be some important differences, such as the mutlifocality of the ictal and interictal epileptic discharges (IEDs) on intracranial electroencephalography (EEG) and greater parieto-occipital connectivity of baboon brain networks compared to juvenile myoclonic epilepsy in humans. Furthermore, there is still limited knowledge of the natural history of the epilepsy, which could be transformative for research into epileptogenesis in genetic generalized epilepsy (GGE) and sudden unexpected death in epilepsy (SUDEP).

Resting-state functional connectivity in the baboon model of genetic generalized epilepsy.

OBJECTIVE: The baboon provides a natural model of genetic generalized epilepsy (GGE). This study compares the intrinsic connectivity networks of epileptic and healthy control baboons using resting-state functional magnetic resonance imaging (rs-fMRI) and data-driven functional connectivity mapping. METHODS: Twenty baboons, matched for gender, age, and weight, were classified into two groups (10 epileptic [EPI], 10 control [CTL]) on the basis of scalp electroencephalography (EEG) findings. Each animal underwent one MRI session that acquired one 5-min resting state fMRI scan and one anatomic MRI scan-used for registration and spatial normalization. Using independent component analysis, we identified 14 unique components/networks, which were then used to characterize each group's functional connectivity maps of each brain network. RESULTS: The epileptic group demonstrated network-specific differences in functional connectivity when compared to the control animals. The sensitivity and specificity of the two groups' functional connectivity maps differed significantly in the visual, motor, amygdala, insular, and default mode networks. Significant increases were found in the occipital gyri of the epileptic group's functional connectivity map for the default mode, cingulate, intraparietal, motor, visual, amygdala, and thalamic regions. SIGNIFICANCE: This is the first study using resting-state fMRI to demonstrate intrinsic functional connectivity differences between epileptic and control nonhuman primates. These results are consistent with seed-based GGE studies in humans; however, our use of a data-driven approach expands the scope of functional connectivity mapping to include brain regions/networks comprising the whole brain.

Neuroimaging in the Epileptic Baboon.

Characterization of baboon model of genetic generalized epilepsy (GGE) is driven both electroclinically and by successful adoption of neuroimaging platforms, such as magnetic resonance imaging (MRI) and positron emission tomography (PET). Based upon its phylogenetic proximity and similar brain anatomy to humans, the epileptic baboon provides an excellent translational model. Its relatively large brain size compared to smaller nonhuman primates or rodents, a gyrencephalic structure compared to lissencephalic organization of rodent brains, and the availability of a large pedigreed colony allows exploration of neuroimaging markers of diseases. Similar to human idiopathic generalized epilepsy (IGE), structural imaging in the baboon is usually normal in individual subjects, but gray matter volume/concentration (GMV/GMC) changes are reported by statistical parametric mapping (SPM) analyses. Functional neuroimaging has been effective for mapping the photoepileptic responses, the epileptic network, altered functional connectivity of physiological networks, and the effects of anti-seizure therapies. This review will provide insights into our current understanding the baboon model of GGE through functional and structural imaging.

Cerebral blood flow differences between high- vs low-frequency VNS therapy in the epileptic baboon.

PURPOSE: Cerebral blood flow (CBF) tracks physiological effects of ictal or interictal epileptic discharges (IEDs) and neurostimulation. This study compared CBF changes between high-frequency (HF; 300 Hz) microburst, and standard, low-frequency (LF; 30 Hz) vagal nerve stimulation (VNS) Therapy in 2 baboons with genetic generalized epilepsy (GGE), including one with photosensitivity. METHODS: The baboons were selected based on video recordings and scalp EEG studies. They were both implanted with Sentiva™ 1000 devices capable of stimulating at standard and microburst frequencies. Nine H215O (10-20 mCi) positron emission tomographic (PET) scans were performed each session (two PET sessions acquired for each animal). The baboons were sedated with ketamine, paralyzed, and monitored with scalp EEG. CBF changes were compared between the two modes of stimulation and resting scans in the first study, while in the second, VNS Therapy trials were combined with intermittent light stimulation (ILS) at 25 Hz and compared to CBF changes induced by ILS alone. RESULTS: ILS-associated IED rates were slightly reduced by HF- and LF-VNS Therapies in B1, while spontaneous IEDs were completely suppressed by HF-VNS Therapy in B2. Regional CBF changes were consistent between the two modes of therapy in each baboon, in particular with respect to the activation of the superior colliculus and cerebellum. Neither VNS mode suppressed the photoepileptic response in B1. In B2, IED suppression was associated with bilateral deactivations of the frontal and temporal cortices, cingulate and anterior striatum, as well as bilateral cerebellar activations. CONCLUSIONS: This pilot study reveals similar activation/deactivation patterns between LF- and HF-VNS Therapies, but the most pronounced CBF differences between the two baboons and the two modes of stimulation may have been driven by the suppression of the epileptic network by HF-VNS Therapy in B2. Some therapeutic targets appear to be subcortical, including the putamen, superior colliculus, brainstem nuclei, as well as the cerebellum, all of which modulate corticothalamic networks, which is particularly reflected by CBF changes associated with HF-VNS Therapy. These findings need to be replicated in larger samples and correlated with long-term clinical outcomes.

Functional neuroimaging of the baboon during concurrent image-guided transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. However the underlying mechanisms of TMS-induced alterations in brain function are not well understood. As a result, treatment design parameters are determined ad hoc and not informed by any coherent theory or model. Once the mechanisms underlying TMS's modulatory effects on brain systems are better understood and modeled, TMS's potential as a therapeutic and/or investigative tool will be more readily explored and exploited. An animal model is better suited to study different TMS variables, therefore we developed a baboon model to facilitate testing of some of the current theoretical models of TMS interactions with brain regions. We have demonstrated the feasibility of this approach by successfully imaging cerebral blood flow (CBF) changes with H(2)(15)O positron emission tomography imaging during high-frequency, suprathreshold repetitive TMS in the primary motor cortex of five healthy, adult baboons.

Cardiac changes in epileptic baboons with high-frequency microburst VNS therapy: A pilot study.

The epileptic baboon provides a natural model of idiopathic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). We sought to evaluate autonomic differences, including heart rate (HR), heart rate variability (HRV) and corrected QT-duration (QTc) between two epileptic (EB1, EB2) and one control (CB) baboon, and the autonomic effects of high-frequency (HF) microburst Vagal Nerve Stimulation (VNS) Therapy in the epileptic baboons. At baseline, EB2's HR was increased over both EB1 and CB, and EB1's HRV was decreased compared to the others. QTc-intervals were significantly prolonged in both epileptic baboons. EB1 became free of generalized tonic-clonic seizures (GTCS) with VNS therapy, whereas EB2's GTCS were reduced by a third. HR decreased in both epileptic baboons, but while HRV improved in EB1, it decreased in EB2. EB2 succumbed to SUDEP after 9 months. This pilot study demonstrates abnormalities in HR, HRV and QTc-intervals in epileptic baboons. HF VNS Therapy demonstrated different effects on HRV in the two epileptic baboons, which, in addition to persistent GTCS and elevated HR, may have contributed to SUDEP risk in EB2. Future studies are needed to establish normative values for HRV and determine variability of HR, HRV and QTc-intervals in epileptic baboons.

A resting-state network comparison of combat-related PTSD with combat-exposed and civilian controls.

Resting-state functional connectivity (rsFC) is an emerging means of understanding the neurobiology of combat-related post-traumatic stress disorder (PTSD). However, most rsFC studies to date have limited focus to cognitively related intrinsic connectivity networks (ICNs), have not applied data-driven methodologies or have disregarded the effect of combat exposure. In this study, we predicted that group independent component analysis (GICA) would reveal group-wise differences in rsFC across 50 active duty service members with PTSD, 28 combat-exposed controls (CEC), and 25 civilian controls without trauma exposure (CC). Intranetwork connectivity differences were identified across 11 ICNs, yet combat-exposed groups were indistinguishable in PTSD vs CEC contrasts. Both PTSD and CEC demonstrated anatomically diffuse differences in the Auditory Vigilance and Sensorimotor networks compared to CC. However, intranetwork connectivity in a subset of three regions was associated with PTSD symptom severity among executive (left insula; ventral anterior cingulate) and right Fronto-Parietal (perigenual cingulate) networks. Furthermore, we found that increased temporal synchronization among visuospatial and sensorimotor networks was associated with worse avoidance symptoms in PTSD. Longitudinal neuroimaging studies in combat-exposed cohorts can further parse PTSD-related, combat stress-related or adaptive rsFC changes ensuing from combat.

Resting-state functional connectivity changes due to acute and short-term valproic acid administration in the baboon model of GGE.

Resting-state functional connectivity (FC) is altered in baboons with genetic generalized epilepsy (GGE) compared to healthy controls (CTL). We compared FC changes between GGE and CTL groups after intravenous injection of valproic acid (VPA) and following one-week of orally administered VPA. Seven epileptic (2 females) and six CTL (3 females) baboons underwent resting-state fMRI (rs-fMRI) at 1) baseline, 2) after intravenous acute VPA administration (20 mg/kg), and 3) following seven-day oral, subacute VPA therapy (20-80 mg/kg/day). FC was evaluated using a data-driven approach, while regressing out the group-wise effects of age, gender and VPA levels. Sixteen networks were identified by independent component analysis (ICA). Each network mask was thresholded (z > 4.00; p < 0.001), and used to compare group-wise FC differences between baseline, intravenous and oral VPA treatment states between GGE and CTL groups. At baseline, FC was increased in most cortical networks of the GGE group but decreased in the thalamic network. After intravenous acute VPA, FC increased in the basal ganglia network and decreased in the parietal network of epileptic baboons to presumed nodes associated with the epileptic network. After oral VPA therapy, FC was decreased in GGE baboons only the orbitofrontal networks connections to the primary somatosensory cortices, reflecting a reversal from baseline comparisons. VPA therapy affects FC in the baboon model of GGE after a single intravenous dose-possibly by facilitating subcortical modulation of the epileptic network and suppressing seizure generation-and after short-term oral VPA treatment, reversing the abnormal baseline increases in FC in the orbitofrontal network. While there is a need to correlate these FC changes with simultaneous EEG recording and seizure outcomes, this study demonstrates the feasibility of evaluating rs-fMRI effects of antiepileptic medications even after short-term exposure.

Voxel-based morphometry in epileptic baboons: Parallels to human juvenile myoclonic epilepsy.

The epileptic baboon represents a natural model for genetic generalized epilepsy (GGE), closely resembling juvenile myoclonic epilepsy (JME). Due to functional neuroimaging and pathological differences between epileptic (SZ+) and asymptomatic control (CTL) baboons, we expected structural differences in gray matter concentration (GMC) using voxel-based morphometry (VBM). Standard anatomical (MP-RAGE) MRI scans using a 3T Siemens TIM Trio (Siemens, Erlangen, Germany) were available in 107 baboons (67 females; mean age 16±6years) with documented clinical histories and scalp-electroencephalography (EEG) results. For neuroimaging, baboons were anesthetized with isoflurane 1% (1-1.5 MAC) and paralyzed with vecuronium (0.1-0.3mg/kg). Data processing and analysis were performed using FSL's VBM toolbox. GMC was compared between CTL and SZ+ baboons, epileptic baboons with interictal epileptic discharges on scalp EEG (SZ+/IED+), asymptomatic baboons with abnormal EEGs (SZ-/IED+), and IED+ baboons with (IED+/PS+) and without (IED+/PS-) photosensitivity, and the subgroups amongst themselves. Age and gender related changes in gray matter volumes were also included as confound regressors in the VBM analyses of each animal group. Significant increases in GMC were noted in the SZ+/IED+ subgroup compared to the CTL group, including bilaterally in the frontopolar, orbitofrontal and anterolateral temporal cortices, while decreases in GMC were noted in the right more than left primary visual cortices and in the specific nuclei of the thalamus, including reticular, anterior and medial dorsal nuclei. No significant differences were noted otherwise, except that SZ+/IED+ baboons demonstrated increased GMC in the globus pallidae bilaterally compared to the SZ-/IED+ group. Similar to human studies of JME, the epileptic baboons demonstrated GMC decreases in the thalami and occipital cortices, suggesting secondary injury due to chronic epilepsy. Cortical GMC, on the other hand, was increased in the anterior frontal and temporal lobes, also consistent with human JME studies. This VBM study may indicate a combination of developmental and acquired structural changes in the epileptic baboon.

Relationship Between Epilepsy and Colpocephaly in Baboons (Papio hamadryas).

Brain MRI scans revealed various occipital horn variants in a pedigreed baboon colony consisting of Papio hamadryas anubis and its hybrids. We retrospectively characterized these variants and evaluated their relationships to epilepsy phenotypes and scalp EEG findings. MRI scans (3D, T1-weighted) from 208 baboons (female, 134 female; male, 74; age [mean ± 1 SD], 16 ± 5 y) were reviewed; 139 (67%) of these animals also underwent scalp EEG previously. Occipital horn variants included elongation (extension of the occipital ventricle behind the mediobasal origin of the calcarine fissure), which affected 23 baboons (11%; 7 bilateral, 9 left, 7 right), and elongation with enlargement (colpocephaly), which occurred in 30 baboons (14%; 7 bilateral, 11 left, 12 right). The incidence of the occipital horn variants did not differ according to age or prenatal or perinatal history. Colpocephaly was associated with craniofacial trauma but not with witnessed seizures. Abnormal scalp EEG findings, including interictal epileptic discharges, did not differ significantly among the occipital horn morphologies. This study is the first radiologic description of occipital horn variants, particularly colpocephaly, in baboons. Whereas colpocephaly is frequently associated with other radiologic and neurologic abnormalities in humans, it is mostly an isolated finding in baboons. Because craniofacial trauma can occur in the setting of seizure-related falls, its increased association with colpocephaly may reflect an increased risk of seizures or of traumatic brain injuries due to seizures. Colpocephaly in baboons needs to be characterized prospectively radiologically, neurologically, histopathologically, and genetically to better understand its etiology and clinical significance.

Repetitive Transcranial Magnetic Stimulation Educes Frequency-Specific Causal Relationships in the Motor Network.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has the potential to treat brain disorders by modulating the activity of disease-specific brain networks, yet the rTMS frequencies used are delivered in a binary fashion - excitatory (>1 Hz) and inhibitory (≤1 Hz). OBJECTIVE: To assess the effective connectivity of the motor network at different rTMS stimulation rates during positron-emission tomography (PET) and confirm that not all excitatory rTMS frequencies act on the motor network in the same manner. METHODS: We delivered image-guided, supra-threshold rTMS at 3 Hz, 5 Hz, 10 Hz, 15 Hz and rest (in separate randomized sessions) to the primary motor cortex (M1) of the lightly anesthetized baboon during PET imaging. Each rTMS/PET session was analyzed using normalized cerebral blood flow (CBF) measurements. Path analysis - using structural equation modeling (SEM) - was employed to determine the effective connectivity of the motor network at all rTMS frequencies. Once determined, the final model of the motor network was used to assess any differences in effective connectivity at each rTMS frequency. RESULTS: The exploratory SEM produced a very well fitting final network model (χ(2) = 18.04, df = 21, RMSEA = 0.000, p = 0.647, TLI = 1.12) using seven nodes of the motor network. 5 Hz rTMS produced the strongest path coefficients in four of the seven connections, suggesting that this frequency is the optimal rTMS frequency for stimulation the motor network (as a whole); however, the premotor cerebellum connection was optimally stimulated at 10 Hz rTMS and the supplementary motor area caudate connection was optimally driven at 15 Hz rTMS. CONCLUSION(S): We have demonstrated that 1) 5 Hz rTMS revealed the strongest path coefficients (i.e. causal influence) on the nodes of the motor network, 2) stimulation at "excitatory" rTMS frequencies did not produce increased CBF in all nodes of the motor network, 3) specific rTMS frequencies may be used to target specific none-to-node interactions in the stimulated brain network, and 4) more research needs to be performed to determine the optimum frequency for each brain circuit and/or node.

Modeling the effective connectivity of the visual network in healthy and photosensitive, epileptic baboons.

The baboon provides a model of photosensitive, generalized epilepsy. This study compares cerebral blood flow responses during intermittent light stimulation (ILS) between photosensitive (PS) and healthy control (CTL) baboons using H 2 (15) O-PET. We examined effective connectivity associated with visual stimulation in both groups using structural equation modeling (SEM). Eight PS and six CTL baboons, matched for age, gender and weight, were classified on the basis of scalp EEG findings performed during the neuroimaging studies. Five H 2 (15) O-PET studies were acquired alternating between resting and activation (ILS at 25 Hz) scans. PET images were acquired in 3D mode and co-registered with MRI. SEM demonstrated differences in neural connectivity between PS and CTL groups during ILS that were not previously identified using traditional activation analyses. First-level pathways consisted of similar posterior-to-anterior projections in both groups. While second-level pathways were mainly lateralized to the left hemisphere in the CTL group, they consisted of bilateral anterior-to-posterior projections in the PS baboons. Third- and fourth-level pathways were only evident in PS baboons. This is the first functional neuroimaging study used to model the photoparoxysmal response (PPR) using a primate model of photosensitive, generalized epilepsy. Evidence of increased interhemispheric connectivity and bidirectional feedback loops in the PS baboons represents electrophysiological synchronization associated with the generation of epileptic discharges. PS baboons demonstrated decreased model stability compared to controls, which may be attributed to greater variability in the driving response or PPRs, or to the influence of regions not included in the model.

Computational and experimental analysis of TMS-induced electric field vectors critical to neuronal activation.

OBJECTIVE: Transcranial magnetic stimulation (TMS) represents a powerful technique to noninvasively modulate cortical neurophysiology in the brain. However, the relationship between the magnetic fields created by TMS coils and neuronal activation in the cortex is still not well-understood, making predictable cortical activation by TMS difficult to achieve. Our goal in this study was to investigate the relationship between induced electric fields and cortical activation measured by blood flow response. Particularly, we sought to discover the E-field characteristics that lead to cortical activation. APPROACH: Subject-specific finite element models (FEMs) of the head and brain were constructed for each of six subjects using magnetic resonance image scans. Positron emission tomography (PET) measured each subject's cortical response to image-guided robotically-positioned TMS to the primary motor cortex. FEM models that employed the given coil position, orientation, and stimulus intensity in experimental applications of TMS were used to calculate the electric field (E-field) vectors within a region of interest for each subject. TMS-induced E-fields were analyzed to better understand what vector components led to regional cerebral blood flow (CBF) responses recorded by PET. MAIN RESULTS: This study found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and nonactive. Specifically, active regions had significantly higher E-field components in the normal inward direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high gradient. In contrast, nonactive regions had higher E-field vectors in the outward normal direction suggesting inhibitory responses. SIGNIFICANCE: These results provide critical new understanding of the factors by which TMS induces cortical activation necessary for predictive and repeatable use of this noninvasive stimulation modality.

Optical characterization of bovine retinal tissues.

An in-depth characterization of the optical properties of bovine retinal and retinal pigment epithelium-choroidal tissues has been performed. The indices of refraction of these ocular tissues were determined by applying Brewster's law. The inverse adding doubling method based on the diffusion approximation and radiative transport theory is applied to the measured values of the total diffuse transmission, total diffuse reflection, and collimated transmission to calculate the optical absorption, scattering, and scattering anisotropy coefficients of the bovine retinal and retinal pigment epithelium-choroidal tissues. The values of the optical properties obtained from the inverse adding doubling method are compared with those generated by the Monte Carlo simulation technique. Optical polarization measurements are also performed on bovine retinal tissues. Our studies show that both retina and retinal pigment epithelium-choroid possess strong polarization characteristics.

Repetitive transcranial magnetic stimulation elicits rate-dependent brain network responses in non-human primates.

BACKGROUND: Transcranial magnetic stimulation (TMS) has the potential to treat brain disorders by tonically modulating firing patterns in disease-specific neural circuits. The selection of treatment parameters for clinical repetitive transcranial magnetic stimulation (rTMS) trials has not been rule based, likely contributing to the variability of observed outcomes. OBJECTIVE: To utilize our newly developed baboon (Papio hamadryas anubis) model of rTMS during position-emission tomography (PET) to quantify the brain's rate-response functions in the motor system during rTMS. METHODS: We delivered image-guided, suprathreshold rTMS at 3 Hz, 5 Hz, 10 Hz, 15 Hz and rest (in separate randomized sessions) to the primary motor cortex (M1) of the lightly anesthetized baboon during PET imaging; we also administered a (reversible) paralytic to eliminate any somatosensory feedback due to rTMS-induced muscle contractions. Each rTMS/PET session was analyzed using normalized cerebral blood flow (CBF) measurements; statistical parametric images and the resulting areas of significance underwent post-hoc analysis to determine any rate-specific rTMS effects throughout the motor network. RESULTS: The motor system's rate-response curves were unimodal and system wide--with all nodes in the network showing highly similar rate response functions--and an optimal network stimulation frequency of 5 Hz. CONCLUSION(S): These findings suggest that non-invasive brain stimulation may be more efficiently delivered at (system-specific) optimal frequencies throughout the targeted network and that functional imaging in non-human primates is a promising strategy for identifying the optimal treatment parameters for TMS clinical trials in specific brain regions and/or networks.

PET-based confirmation of orientation sensitivity of TMS-induced cortical activation in humans.

BACKGROUND: Currently, it is difficult to predict precise regions of cortical activation in response to transcranial magnetic stimulation (TMS). Most analytical approaches focus on applied magnetic field strength in the target region as the primary factor, placing activation on the gyral crowns. However, imaging studies support M1 targets being typically located in the sulcal banks. OBJECTIVE/HYPOTHESIS: To more thoroughly investigate this inconsistency, we sought to determine whether neocortical surface orientation was a critical determinant of regional activation. METHODS: MR images were used to construct cortical and scalp surfaces for 18 subjects. The angle (θ) between the cortical surface normal and its nearest scalp normal for ~50,000 cortical points per subject was used to quantify cortical location (i.e., gyral vs. sulcal). TMS-induced activations of primary motor cortex (M1) were compared to brain activations recorded during a finger-tapping task using concurrent positron emission tomographic (PET) imaging. RESULTS: Brain activations were primarily sulcal for both the TMS and task activations (P < 0.001 for both) compared to the overall cortical surface orientation. Also, the location of maximal blood flow in response to either TMS or finger-tapping correlated well using the cortical surface orientation angle or distance to scalp (P < 0.001 for both) as criteria for comparison between different neocortical activation modalities. CONCLUSION: This study provides further evidence that a major factor in cortical activation using TMS is the orientation of the cortical surface with respect to the induced electric field. The results show that, despite the gyral crown of the cortex being subjected to a larger magnetic field magnitude, the sulcal bank of M1 had larger cerebral blood flow (CBF) responses during TMS.

Baboon model of generalized epilepsy: continuous intracranial video-EEG monitoring with subdural electrodes.

The baboon provides a natural non-human primate model for photosensitive, generalized epilepsy. This study describes an implantation procedure for the placement of subdural grid and strip electrodes for continuous video-EEG monitoring in the epileptic baboon to evaluate the generation and propagation of ictal and interictal epileptic discharges. Subdural grid, strip and depth electrodes were implanted in six baboons, targeting brain regions that were activated in functional neuroimaging studies during photoparoxysmal responses. The baboons were monitored with continuous video-EEG monitoring for 2-21 (mean 9) days. Although the animals were tethered, the EEG signal was transmitted wirelessly to optimize their mobility. Spontaneous seizures, interictal epileptic discharges (IEDs), and responses to intermittent light stimulation (ILS) were assessed. Due to cortical injuries related to the electrode implantation and their displacement, the procedure was modified. Habitual myoclonic and generalized tonic-clonic seizures were recorded in three baboons, all associated with a generalized ictal discharge, but were triggered multiregionally, in the frontal, parietal and occipital cortices. IEDs were similarly expressed multiregionally, and responsible for triggering most generalized spike-and-wave discharges. Generalized photoparoxysmal responses were activated only in one baboon, while driving responses recorded in all three photosensitive baboons were 2.5 times the stimulus rate. In contrast to previous intracranial investigations in this model, generalized ictal and interictal epileptic discharges were triggered by parietal and occipital, in addition to the frontocentral cortices. Furthermore, targeted visual areas responded differently to ILS in photosensitive than nonphotosensitive baboons, but further studies are required before mechanisms can be implicated for ILS-induced activation of the epileptic networks.

Functional PET Evaluation of the Photosensitive Baboon.

The baboon provides a unique, natural model of epilepsy in nonhuman primates. Additionally, photosensitivity of the epileptic baboon provides an important window into the mechanism of human idiopathic generalized epilepsies. In order to better understand the networks underlying this model, our group utilized functional positron emission tomography (PET) to compare cerebral blood flow (CBF) changes occurring during intermittent light stimulation (ILS) and rest between baboons photosensitive, epileptic (PS) and asymptomatic, control (CTL) animals. Our studies utilized subtraction and covariance analyses to evaluate CBF changes occurring during ILS across activation and resting states, but also evaluated CBF correlations with ketamine doses and interictal epileptic discharge (IED) rate during the resting state. Furthermore, our group also assessed the CBF responses related to variation of ILS in PS and CTL animals. CBF changes in the subtraction and covariance analyses reveal the physiological response and visual connectivity in CTL animals and pathophysiological networks underlying responses associated with the activation of ictal and interictal epileptic discharges in PS animals. The correlation with ketamine dose is essential to understanding differences in CBF responses between both groups, and correlations with IED rate provides an insight into an epileptic network independent of visual activation. Finally, the ILS frequency dependent changes can help develop a framework to study not only spatial connectivity but also the temporal sequence of regional activations and deactivations related to ILS. The maps generated by the CBF analyses will be used to target specific nodes in the epileptic network for electrophysiological evaluation using intracranial electrodes.