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.

Non-convulsive status epilepticus in the setting of cannabidiol adjunctive therapy

Anti-seizure medications (ASMs) can cause non-convulsive status epilepticus (NCSE), but account for less than 5% of all NCSE cases. We present a 63-year-old, right-handed male with a history of intractable focal epilepsy since age seven years old, whose bouts of NCSE were triggered by cannabidiol (CBD) adjunctive therapy. His most common seizure types included focal myoclonic or tonic seizures with vocalization, usually with awakening, which occurred on a monthly basis despite the combination of tiagabine, perampanel, levetiracetam, lacosamide and clonazepam. After CBD was initiated, he began to exhibit episodes of prolonged confusion, at times with myoclonic or tonic seizures. Increasing CBD doses led to more frequent and prolonged episodes. The confusional episodes occurred predominantly in the morning, with spontaneous resolution by the afternoon. During one of these episodes, he was hospitalized, and NCSE was confirmed by video-EEG monitoring. CBD was withdrawn and the patient had no further episodes of NCSE. While CBD can cause NCSE, the medication interaction between CBD and tiagabine also needs to be considered.

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.

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).

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.

Effects of ketamine on EEG in baboons with genetic generalized epilepsy.

Ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, used as an anesthetic has been reported to induce seizures both in humans and baboons predisposed to epilepsy. In this study, we aimed to characterize the acute effects of ketamine on scalp (sc-EEG) and intracranial EEG (ic-EEG) in the baboon, which offers a natural model of genetic generalized epilepsy (GGE). We evaluated the electroclinical response to ketamine in three epileptic baboons. The raw EEG data were analyzed within 10 min of intramuscular ketamine (5-6 mg/kg) administration. Earliest EEG changes occurred after 30 s in sc-EEG and after 15 s in ic-EEG of ketamine administration. These initial changes involved increased paroxysmal fast activity (PFA) followed by slowing, the latter emerging first occipitally, and then spreading more anteriorly. Generalized spike-and-wave discharges (GSWDs) were evident on both sc-EEG and ic-EEG within two minutes, but focal occipital discharges were already increased on ic-EEG after 15 s. Occipital slowing emerged on ic-EEG after 30 s, before spreading fronto-centrally and orbito-frontally. By 60-120 seconds post-injection, ic-EEG demonstrated a parieto-occipital burst suppression (BS), which was not noted on sc-EEG. Ketamine waves and seizures, especially if the latter were subclinical, also appeared earlier on ic-EEG. This study highlights the anesthetic and proconvulsant effects of ketamine originate in the occipital lobes before fronto-central regions. We speculate that NMDAR concentration difference in cortical regions, such as the occipital and frontal cortices, are mainly involved in the expression of ketamine's EEG effects, both physiological and epileptic.

Adult-onset Rasmussen's Syndrome with associated cortical dysplasia.

We describe a 23-year-old woman with previous right temporal lobe surgeries for underlying cortical dysplasia, presenting with drug-resistant right hemispheric seizures and epilepsia partialis continua (EPC). After anti-seizure medication adjustments, she developed focal status epilepticus with progressive EEG and neuroimaging changes. Cerebrospinal fluid and serum autoimmune panels were negative except for an elevated serum acetylcholine-receptor antibody titer, but she underwent immunosuppressive therapy. Stereotactic-EEG evaluation demonstrated multifocal independent ictal patterns in the right hemisphere. Rasmussen's Syndrome was confirmed by brain biopsy, and a hemispherectomy was performed. This patient demonstrates the rare association of adult-onset EPC with cortical dysplasia, precipitously evolving into Rasmussen's Syndrome.

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.

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.

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.

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.

Cerebrospinal Fluid Levels of Monoamine Metabolites in the Epileptic Baboon.

The baboon represents a natural model for genetic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). In this retrospective study, cerebrospinal fluid (CSF) monoamine metabolites and scalp electroencephalography (EEG) were evaluated in 263 baboons of a pedigreed colony. CSF monoamine abnormalities have been linked to reduced seizure thresholds, behavioral abnormalities and SUDEP in various animal models of epilepsy. The levels of 3-hydroxy-4-methoxyphenylglycol, 5-hydroxyindolacetic acid and homovanillic acid in CSF samples drawn from the cisterna magna were analyzed using high-performance liquid chromatography. These levels were compared between baboons with seizures (SZ), craniofacial trauma (CFT) and asymptomatic, control (CTL) baboons, between baboons with abnormal and normal EEG studies. We hypothesized that the CSF levels of major monoaminergic metabolites (i.e., dopamine, serotonin and norepinephrine) associate with the baboons' electroclinical status and thus can be used as clinical biomarkers applicable to seizures/epilepsy. However, despite apparent differences in metabolite levels between the groups, usually lower in SZ and CFT baboons and in baboons with abnormal EEG studies, we did not find any statistically significant differences using a logistic regression analysis. Significant correlations between the metabolite levels, especially between 5-HIAA and HVA, were preserved in all electroclinical groups. While we were not able to demonstrate significant differences in monoamine metabolites in relation to seizures or EEG markers of epilepsy, we cannot exclude the monoaminergic system as a potential source of pathogenesis in epilepsy and SUDEP. A prospective study evaluating serial CSF monoamine levels in baboons with recently witnessed seizures, and evaluation of abnormal expression and function of monoaminergic receptors and transporters within epilepsy-related brain regions, may impact the electroclinical status.

Craniofacial trauma as a clinical marker of seizures in a baboon colony.

Baboons provide a natural model of epilepsy. However, spontaneous seizures are usually sporadic, brief, and may not be observed. We hypothesized that various types of craniofacial trauma (CFT) may serve as reliable markers for epilepsy. We evaluated the type, demographics, and clinical significance of CFT in a large baboon colony. CFT was categorized according to somatotopic location, propensity to recur, and association with witnessed seizures or abnormal EEG findings. We divided the baboons with CFT into 2 groups: those with known histories of seizures (CFT+Sz, n = 176) and those without seizure histories (CFTonly; n = 515). In CFT+Sz baboons, the 568 injuries identified included periorbital (57%), scalp (27%), muzzle (12%), and facial (4%) injuries; multiple somatotopic locations or body parts were affected in 21 baboons. The most common CFT injuries associated with seizures were periorbital and scalp lesions (43% for each region). Compared with those in CFTonly animals, EEG abnormalities, including interictal epileptic discharges (IED) and photosensitivity were more prevalent in the CFT+Sz group, particularly among baboons with periorbital or scalp injuries. Compared with CFT+Sz animals, CFTonly baboons tended to have later onset and less frequent recurrence of CFT but higher prevalence of muzzle and tooth injuries. IED and photosensitivity were less prevalent in the CFTonly than the CFT+Sz group, with periorbital injuries carrying the highest and muzzle injuries the lowest association with IED or photosensitivity in both groups. Therefore, CFT in general and periorbital injuries in particular may be markers for seizures in baboons.

Epileptic baboons have lower numbers of neurons in specific areas of cortex.

Epilepsy is characterized by recurrent seizure activity that can induce pathological reorganization and alter normal function in neocortical networks. In the present study, we determined the numbers of cells and neurons across the complete extent of the cortex for two epileptic baboons with naturally occurring seizures and two baboons without epilepsy. Overall, the two epileptic baboons had a 37% average reduction in the number of cortical neurons compared with the two nonepileptic baboons. The loss of neurons was variable across cortical areas, with the most pronounced loss in the primary motor cortex, especially in lateral primary motor cortex, representing the hand and face. Less-pronounced reductions of neurons were found in other parts of the frontal cortex and in somatosensory cortex, but no reduction was apparent in the primary visual cortex and little in other visual areas. The results provide clear evidence that epilepsy in the baboon is associated with considerable reduction in the numbers of cortical neurons, especially in frontal areas of the cortex related to motor functions. Whether or not the reduction of neurons is a cause or an effect of seizures needs further investigation.

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.

Electroclinical phenotypes in a pedigreed baboon colony.

This is the first large-scale epidemiological study evaluating the prevalence of interictal epileptic discharges (IEDs) and photosensitivity (PS) recorded by scalp EEG in a natural nonhuman-primate model of photosensitive, generalized epilepsy. Scalp EEG was used to characterize electroclinical phenotypes in a large baboon pedigree housed at the Southwest National Primate Research Center at the Texas Biomedical Research Institute (Texas Biomed) based upon IEDs and photosensitivity. Scalp EEG studies including intermittent light stimulation (ILS) were performed in 671 baboons. Clinical histories were available for 531 (79%) of the animals. The EEG studies lasted 53 (±11) min, during which the baboons were lightly sedated with intramuscular ketamine doses of 5.6 (±0.8) mg. The animals were further classified according to electroclinical phenotypes recorded by scalp EEG: presence or absence of IEDs, seizures and photoparoxysmal or photoconvulsive responses. Effects of age, gender, and species on EEG phenotypes were compared using (Chi-square, two-sided, α<0.05). Sensitivity and specificity of IEDs and photosensitivity to detect a history of seizures was calculated. Generalized IEDs and photosensitivity were identified in 324 (49%) and 156 (23%) pedigreed baboons, respectively. Only photosensitivity was associated with gender, significantly increased in males. Otherwise, while IEDs were marginally more prevalent among males, there were no other significant associations of IEDs or photosensitivity with age or subspecies. Photosensitivity was significantly associated with IEDs, with demonstrating a possible association with gender and subspecies. Of 531 baboons with histories of clinical events, 91 (17%) had witnessed seizures and 269 (51%) were asymptomatic. IEDs demonstrated sensitivity and specificity of 62% and 57%, and photosensitivity of 40% and 83%, for prediction of seizures, respectively. While these EEG findings mirror the high prevalence of seizures in the colony, the sensitivity and specificity of scalp EEG may have been affected by ketamine's ability to lower the threshold for IEDs and seizures, particularly in animals predisposed to epilepsy. Photosensitivity provides a specific biological marker for epilepsy in future epidemiological, genetic, behavioral and histopathological studies.

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.

Epidemiology and characterization of seizures in a pedigreed baboon colony.

This study evaluated the incidence, prevalence, and clinical features of seizures in a pedigreed captive colony of baboons. The association of seizures with subspecies, age, sex, and various clinical features was assessed. Records for 1527 captive, pedigreed baboons were reviewed, and 3389 events were identified in 1098 baboons. Of these events, 1537 (45%) represented witnessed seizures, whereas the remaining 1852 presented with craniofacial trauma or episodic changes in behavior that were suggestive, but not diagnostic, of seizure activity. Seizures were generalized myoclonic or tonic-clonic, with two thirds of the events witnessed in the morning. Seizure onset occurred in adolescence (age, 5 y), with an average of 3 seizures in a lifetime. The incidence and prevalence of seizures were 2.5% and 26%, respectively, whereas the prevalence of recurrent seizures (that is, epilepsy) was 15%. Seizures were more prevalent in male baboons, which tended to present with earlier onset and more seizures over a lifetime than did female baboons. Seizures were equally distributed between the subspecies; age of onset and seizure recurrences did not differ significantly between subspecies. Clinical features including age of onset, characteristics, and diurnal presentation of seizures in baboons suggested similarities to juvenile myoclonic epilepsy in humans. Facial trauma may be useful marker for epilepsy in baboons, but its specificity should be characterized.

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.