Activity In Subcortical Structures Research Articles

Experimental study of the influence of phenozanic acid and its combination with valproic acid on the development of the epileptic system

To study the effect of phenosanic acid (PA) and its combination with valproic acid (VA) on the development of the Epi system. A model of focal chronic epilepsy in rats was created by applying metallic cobalt to the surface of the sensorimotor area of the cortex. Long-term electrodes were implanted in the sensorimotor cortex of the left and right hemispheres, the hippocampus, and the hypothalamus. The effect of PA (80 mg/kg) and its combination with VA (200 mg/kg) on discharge activity was carried out on the 2nd day and at the stage of generalization of the Epi system - on the 6th day. The stability of the Epi system on day 10 was assessed by provoking the development of epileptic status (Epi status) in response to the administration of thiolactone homocysteine (HMC) at a dose of 5.5 mmol/kg. In rats treated with PA, low discharge activity is observed, which is confirmed by the absence of EEG and motor manifestations of status epilepticus caused by HMC. PA does not suppress paroxysmal activity at the stages of development of the Epi system. VA significantly suppresses paroxysmal activity, but does not affect the formation of new foci of Epi activity in subcortical structures and the contralateral cortex. The epi system of rats treated with VA is characterized by high discharge activity by the 10th day of the experiment and lability to provocation of epi status. The combination of drugs is more pronounced than PA, but less than VA, reduces the numerical characteristics of paroxysmal activity in the brain structures of rats. PA when administered alone, in combination with VA, causes a slowdown in the generalization of convulsive foci of Epi activity and prevents the formation of a stable Epi system. VA, having a pronounced anticonvulsant effect, does not weaken the development of the Epi system in the model of focal cobalt-induced epilepsy.

A unified hypothesis of SUDEP: Seizure-induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray.

Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in people with epilepsy (PWE). Postictal apnea leading to cardiac arrest is the most common sequence of terminal events in witnessed cases of SUDEP, and postconvulsive central apnea has been proposed as a potential biomarker of SUDEP susceptibility. Research in SUDEP animal models has led to the serotonin and adenosine hypotheses of SUDEP. These neurotransmitters influence respiration, seizures, and lethality in animal models of SUDEP, and are implicated in human SUDEP cases. Adenosine released during seizures is proposed to be an important seizure termination mechanism. However, adenosine also depresses respiration, and this effect is mediated, in part, by inhibition of neuronal activity in subcortical structures that modulate respiration, including the periaqueductal gray (PAG). Drugs that enhance the action of adenosine increase postictal death in SUDEP models. Serotonin is also released during seizures, but enhances respiration in response to an elevated carbon dioxide level, which often occurs postictally. This effect of serotonin can potentially compensate, in part, for the adenosine-mediated respiratory depression, acting to facilitate autoresuscitation and other restorative respiratory response mechanisms. A number of drugs that enhance the action of serotonin prevent postictal death in several SUDEP models and reduce postictal respiratory depression in PWE. This effect of serotonergic drugs may be mediated, in part, by actions on brainstem sites that modulate respiration, including the PAG. Enhanced activity in the PAG increases respiration in response to hypoxia and other exigent conditions and can be activated by electrical stimulation. Thus, we propose the unifying hypothesis that seizure-induced adenosine release leads to respiratory depression. This can be reversed by serotonergic action on autoresuscitation and other restorative respiratory responses acting, in part, via the PAG. Therefore, we hypothesize that serotonergic or direct activation of this brainstem site may be a useful approach for SUDEP prevention.

The dynamics of EEG correlates of activity of subcortical structures of the bird brain in conditions of chronic stress

In birds, acute stress (a three-day 12-hour inversion of the photomode) is associated with the dominant activity of the sympathetic hypothalamus and hippocampus, which suppress the tone of the parasympathetic section and the reticular formation of the midbrain. The effect of hyperglycemia on the background of a negative chronotropic effect indicates a mismatch of the functions of the autonomic sections of the hypothalamus on the 30th day. Chronic stress in birds (30-days crowding) causes persistent pathological stress of the functions of the anterior hypothalamus and reticular formation of the middle brain with the suppression of parasympathetic tone of the posterior hypothalamus and high functional activity of the hippocampus, determining the switching of the ventricles of the heart to a more economical mode of functioning by the 30th day. Using central cholinoblockers or tranquilizers, having a cholinoblocking component in the mechanism of its influence during neurogenic stress and in the post-stress period is excluded, but it is possible to use stressprotektors.

A dynamical model for the basal ganglia-thalamo-cortical oscillatory activity and its implications in Parkinson\u2019s disease

We propose to investigate brain electrophysiological alterations associated with Parkinson’s disease through a novel adaptive dynamical model of the network of the basal ganglia, the cortex and the thalamus. The model uniquely unifies the influence of dopamine in the regulation of the activity of all basal ganglia nuclei, the self-organised neuronal interdependent activity of basal ganglia-thalamo-cortical circuits and the generation of subcortical background oscillations. Variations in the amount of dopamine produced in the neurons of the substantia nigra pars compacta are key both in the onset of Parkinson’s disease and in the basal ganglia action selection. We model these dopamine-induced relationships, and Parkinsonian states are interpreted as spontaneous emergent behaviours associated with different rhythms of oscillatory activity patterns of the basal ganglia-thalamo-cortical network. These results are significant because: (1) the neural populations are built upon single-neuron models that have been robustly designed to have eletrophysiologically-realistic responses, and (2) our model distinctively links changes in the oscillatory activity in subcortical structures, dopamine levels in the basal ganglia and pathological synchronisation neuronal patterns compatible with Parkinsonian states, this still remains an open problem and is crucial to better understand the progression of the disease.

Affect in the Aging Brain: A Neuroimaging Meta-Analysis of Older Vs. Younger Adult Affective Experience and Perception.

We report the first functional neuroimaging meta-analysis on age-related differences in adult neural activity during affect. We identified and coded experimental contrasts from 27 studies (published 1997-2018) with 490 older adults (55-87years, M age = 69years) and 470 younger adults (18-39years, M age = 24years). Using multilevel kernel density analysis, we assessed functional brain activation contrasts for older vs. younger adult affect across in-scanner tasks (i.e., affect induction and perception). Relative to older adults, younger adults showed more reliable activation in subcortical structures (e.g., amygdala, thalamus, caudate) and in relatively more posterior aspects of specific brain structures (e.g., posterior insula, mid- and posterior cingulate). In contrast, older adults exhibited more reliable activation in the prefrontal cortex and more anterior aspects of specific brain structures (e.g., anterior insula, anterior cingulate). Meta-analytic coactivation network analyses further revealed that in younger adults, the amygdala and mid-cingulate were more central, locally efficient network nodes, whereas in older adults, regions in the superior and medial prefrontal cortex were more central, locally efficient network nodes. Collectively, these findings help characterize age differences in the brain basis of affect and provide insights for future investigations into the neural mechanisms underlying affective aging.

In vivo imaging of deep neural activity from the cortical surface during hippocampal epileptiform events in the rat brain using electrical impedance tomography

Electrical impedance tomography (EIT) is a medical imaging technique which reconstructs images of the internal impedance changes within an object using non-penetrating surface electrodes. To date, EIT has been used to image fast neural impedance changes during somatosensory evoked potentials and epileptiform discharges through the rat cerebral cortex with a resolution of 2 ​ms and <300 ​μm. However, imaging of neural activity in subcortical structures has never been achieved with this technique. Here, we evaluated the feasibility of using EIT to image epileptiform activity in the rat hippocampus using non-penetrating electrodes implanted on the cortical surface. Hippocampal epileptiform events, comprising repetitive 30–50 ​Hz ictal spikes, were induced by electrically stimulating the perforant path of rats anaesthetised with fentanyl-isoflurane. For each of ≥30 seizures, impedance measurements were obtained by applying 100 ​μA current at 1.4 ​kHz through an independent pair of electrodes on a 54-electrode planar epicortical array and recording boundary voltages on all remaining electrodes. EIT images of averaged ictal spikes were reconstructed using impedance recordings from all seizures in each animal. These revealed a focus of neural activity localised to the dentate gyrus which was spatially and temporally aligned to local field potential (LFP) recordings and could be reconstructed reproducibly in all animals with a localisation accuracy of ≤400 ​μm (p ​< ​0.03125, N ​= ​5). These findings represent the first experimental evidence of the ability of EIT to image neural activity in subcortical structures from the surface of the cortex with high spatiotemporal resolution and suggest that this method may be used for improving understanding of functional connectivity between cortico-hippocampal networks in both physiological and pathophysiological states.

The neural and genetic correlates of satisfying sexual activity in heterosexual pair-bonds.

IntroductionIn humans, satisfying sexual activity within a pair‐bond plays a significant role in relationship quality and maintenance, beyond reproduction. However, the neural and genetic correlates for this basic species‐supporting function, in response to a pair‐bonded partner, are unknown.MethodsWe examined the neural correlates of oxytocin‐ (Oxtr rs53576) and vasopressin‐ (Avpr1a rs3) receptor genotypes with sexual satisfaction and frequency, among a group of individuals in pair‐bonds (M relationship length = 4.1 years). Participants were scanned twice (with functional MRI), about 1‐year apart, while viewing face images of their spouse and a familiar, neutral acquaintance.ResultsSex satisfaction scores showed significant interactions with Oxtr and Avpr variants associated with social behaviors in a broad network of regions involved in reward and motivation (ventral tegmental area, substantia nigra [SN], and caudate), social bonding (ventral pallidum), emotion and memory (amygdala/hippocampus), hormone control (hypothalamus); and somatosensory and self‐other processing (SII, frontal, and temporal lobe). Sexual frequency interactions also showed activations in the SN and paraventricular hypothalamus for Avpr, and the prefrontal cortex for Oxtr.ConclusionsSatisfying sexual activity in pair‐bonds is associated with activation of subcortical structures that support basic motivational and physiological processes; as well as cortical regions that mediate complex thinking, empathy, and self‐other processes highlighting the multifaceted role of sex in pair‐bonds. Oxtr and Avpr gene variants may further amplify both basic and complex neural processes for pair‐bond conservation and well‐being.

Abnormal subcortical activity in congenital mirror movement disorder with RAD51 mutation

Congenital mirror movement disorder (CMMD) is characterized by unintended, nonsuppressible, homologous mirroring activity contralateral to the movement on the intended side of the body. In healthy controls, unilateral movements are accompanied with predominantly contralateral cortical activity, whereas in CMMD, in line with the abnormal behavior, bilateral cortical activity is observed for unilateral motor tasks. However, task-related activities in subcortical structures, which are known to play critical roles in motor actions, have not been investigated in CMMD previously. We investigated the functional activation patterns of the motor components in CMMD patients. By using linkage analysis and exome sequencing, common mutations were revealed in seven affected individuals from the same family. Next, using functional magnetic resonance imaging (fMRI) we investigated cortical and subcortical activity during manual motor actions in two right-handed affected brothers and sex, age, education, and socioeconomically matched healthy individuals. Genetic analyses revealed heterozygous RAD51 c.401C>T mutation which cosegregated with the phenotype in two affected members of the family. Consistent with previous literature, our fMRI results on these two affected individuals showed that mirror movements were closely related to abnormal cortical activity in M1 and SMA during unimanual movements. Furthermore, we have found previously unknown abnormal task-related activity in subcortical structures. Specifically, we have found increased and bilateral activity during unimanual movements in thalamus, striatum, and globus pallidus in CMMD patients. These findings reveal further neural correlates of CMMD, and may guide our understanding of the critical roles of subcortical structures for unimanual movements in healthy individuals.

Sparsity enables estimation of both subcortical and cortical activity from MEG and EEG

Subcortical structures play a critical role in brain function. However, options for assessing electrophysiological activity in these structures are limited. Electromagnetic fields generated by neuronal activity in subcortical structures can be recorded noninvasively, using magnetoencephalography (MEG) and electroencephalography (EEG). However, these subcortical signals are much weaker than those generated by cortical activity. In addition, we show here that it is difficult to resolve subcortical sources because distributed cortical activity can explain the MEG and EEG patterns generated by deep sources. We then demonstrate that if the cortical activity is spatially sparse, both cortical and subcortical sources can be resolved with M/EEG. Building on this insight, we develop a hierarchical sparse inverse solution for M/EEG. We assess the performance of this algorithm on realistic simulations and auditory evoked response data, and show that thalamic and brainstem sources can be correctly estimated in the presence of cortical activity. Our work provides alternative perspectives and tools for characterizing electrophysiological activity in subcortical structures in the human brain.

Neural Correlates of Contrast and Humor: Processing Common Features of Verbal Irony.

Irony is a kind of figurative language used by a speaker to say something that contrasts with the context and, to some extent, lends humor to a situation. However, little is known about the brain regions that specifically support the processing of these two common features of irony. The present study had two main aims: (i) investigate the neural basis of irony processing, by delivering short ironic spoken sentences (and their literal counterparts) to participants undergoing fMRI; and (ii) assess the neural effect of two irony parameters, obtained from normative studies: degree of contrast and humor appreciation. Results revealed activation of the bilateral inferior frontal gyrus (IFG), posterior part of the left superior temporal gyrus, medial frontal cortex, and left caudate during irony processing, suggesting the involvement of both semantic and theory-of-mind networks. Parametric models showed that contrast was specifically associated with the activation of bilateral frontal and subcortical areas, and that these regions were also sensitive to humor, as shown by a conjunction analysis. Activation of the bilateral IFG is consistent with the literature on humor processing, and reflects incongruity detection/resolution processes. Moreover, the activation of subcortical structures can be related to the reward processing of social events.

New evidence of corticospinal network modulation induced by motor imagery.

Motor imagery (MI) is the mental simulation of movement, without the corresponding muscle contraction. Whereas the activation of cortical motor areas during MI is established, the involvement of spinal structures is still under debate. We used original and complementary techniques to probe the influence of MI on spinal structures. Amplitude of motor-evoked potentials (MEPs), cervico-medullary-evoked potentials (CMEPs), and Hoffmann (H)-reflexes of the flexor carpi radialis (FCR) muscle and of the triceps surae muscles was measured in young, healthy subjects at rest and during MI. Participants were asked to imagine maximal voluntary contraction of the wrist and ankle, while the targeted limb was fixed (static condition). We confirmed previous studies with an increase of FCR MEPs during MI compared with rest. Interestingly, CMEPs, but not H-reflexes, also increased during MI, revealing a possible activation of subcortical structures. Then, to investigate the effect of MI on the spinal network, we used two techniques: 1) passive lengthening of the targeted muscle via an isokinetic dynamometer and 2) conditioning of H-reflexes with stimulation of the antagonistic nerve. Both techniques activate spinal inhibitory presynaptic circuitry, reducing the H-reflex amplitude at rest. In contrast, no reduction of H-reflex amplitude was observed during MI. These findings suggest that MI has modulatory effects on the spinal neuronal network. Specifically, the activation of low-threshold spinal structures during specific conditions (lengthening and H-reflex conditioning) highlights the possible generation of subliminal cortical output during MI.

A broadband acoustic stimulus is more likely than a pure tone to elicit a startle reflex and prepared movements.

A loud acoustic stimulus that elicits a startle reflex has long been used to study the neurophysiology of cortical and subcortical neural circuits. More recent investigations have shown that startle can act as an early trigger for prepared actions, suggesting a brainstem role in the preparation and initiation of actions. However, in order to attribute any startle-triggered voluntary responses to activation in subcortical structures it is necessary to measure a startle-related activity in these structures. The current study investigated the most effective stimulus for eliciting a detectible startle reflex. While more intense stimuli are more likely to elicit a startle reflex, the current study examined whether broadband noise is more likely than a pure tone to produce a startle at various intensities above 100 dB. Participants performed a button release reaction time task in response to either a 1 kHz tone or a broadband noise pulse with intensities ranging from 82 to 124 dB. Reaction time and EMG from the wrist extensors and the sternocleidomastoid (SCM) were measured. Results showed that startle-related SCM EMG was elicited more frequently by broadband noise compared to pure tones. The higher proportion of startle reflexes observed in SCM was associated with a higher incidence of the voluntary task being triggered early. A higher incidence of startle following broadband noise is attributed to the activation of a larger proportion of the basilar membrane; thus, a lower intensity broadband noise stimulus may be used to elicit startle reflex at a similar rate as a higher intensity pure tone.

Childhood trauma and neural responses to personalized stress, favorite-food and neutral-relaxing cues in adolescents.

Previous studies have found childhood trauma to be associated with functional and structural abnormalities in corticostriatal-limbic brain regions, which may explain the associations between trauma and negative mental and physical health outcomes. However, functional neuroimaging of maltreatment-related trauma has been limited by largely using generic and predominantly aversive stimuli. Personalized stress, favorite-food, and neutral/relaxing cues during functional magnetic resonance imaging were used to probe the neural correlates of emotional/motivational states in adolescents with varying exposure to maltreatment-related trauma. Sixty-four adolescents were stratified into high- or low-trauma-exposed groups. Cue-related measures of subjective anxiety and craving were collected. Relative to the low-trauma-exposed group, high-trauma-exposed adolescents displayed an increased activation of insula, anterior cingulate, and prefrontal cortex in response to stress cues. Activation in subcortical structures, including the hippocampus, was inversely correlated with subjective anxiety in the high- but not the low-trauma-exposed group. The high-trauma-exposed group displayed hypoactivity of cerebellar regions in response to neutral/relaxing cues. No group differences were observed in response to favorite-food cues. The relationship between trauma exposure and altered cortico-limbic circuitry may in part explain the association between childhood trauma and heightened vulnerability to emotional disturbances and risky behaviour. This may be particularly pertinent during adolescence when such difficulties often emerge. Further work is needed to elucidate the mechanism linking trauma to obesity.

Using fMRI non-local means denoising to uncover activation in sub-cortical structures at 1.5 T for guided HARDI tractography.

In recent years, there has been ever-increasing interest in combining functional magnetic resonance imaging (fMRI) and diffusion magnetic resonance imaging (dMRI) for better understanding the link between cortical activity and connectivity, respectively. However, it is challenging to detect and validate fMRI activity in key sub-cortical areas such as the thalamus, given that they are prone to susceptibility artifacts due to the partial volume effects (PVE) of surrounding tissues (GM/WM interface). This is especially true on relatively low-field clinical MR systems (e.g., 1.5 T). We propose to overcome this limitation by using a spatial denoising technique used in structural MRI and more recently in diffusion MRI called non-local means (NLM) denoising, which uses a patch-based approach to suppress the noise locally. To test this, we measured fMRI in 20 healthy subjects performing three block-based tasks : eyes-open closed (EOC) and left/right finger tapping (FTL, FTR). Overall, we found that NLM yielded more thalamic activity compared to traditional denoising methods. In order to validate our pipeline, we also investigated known structural connectivity going through the thalamus using HARDI tractography: the optic radiations, related to the EOC task, and the cortico-spinal tract (CST) for FTL and FTR. To do so, we reconstructed the tracts using functionally based thalamic and cortical ROIs to initiates seeds of tractography in a two-level coarse-to-fine fashion. We applied this method at the single subject level, which allowed us to see the structural connections underlying fMRI thalamic activity. In summary, we propose a new fMRI processing pipeline which uses a recent spatial denoising technique (NLM) to successfully detect sub-cortical activity which was validated using an advanced dMRI seeding strategy in single subjects at 1.5 T.

Structural-Functional Characteristics of Brain Functioning on Performance and Imagination of Motor Tasks in Healthy People (EEG and fMRI studies)

Bioelectrical (EEG) and hemodynamic (fMRI responses) reactions of the brain to motor tasks for the right and left hands and imaginary performance of those tasks were studied in 15 healthy right-handed subjects (21‐39 years old). In real movements, the main fMRI response was recorded in the central gyri of the contralateral (to the working hand) hemisphere. Activation zones were also seen in the supplementary motor area and the ipsilateral hemisphere of the cerebellum. The corresponding EEG showed increases in the coherence of the high-frequency alpha and beta frequencies in the activated hemisphere. Imagination of movements produced fMRI reactions which were highly variable in terms of extent and topography; weakening of responses was seen in the motor zone and cerebellum, with increased activation of subcortical structures in the parietal associative zones. Changes in the EEG in this situation were very variable; there were increases in the coherence of high-frequency alpha and beta oscillations, in the right hemisphere. Changes in spectral power were similar in real and imaginary movements and consisted of increases in the power and mean frequency of beta oscillations not confined to the activated hemisphere but also appearing in the left hemisphere. These reflected the nonspecific component of the responses.

Lesions of the nucleus accumbens disrupt reinforcement omission effects in rats

The reinforcement omission effects (ROEs) have been attributed to both motivational and attentional consequences of the surprising reinforcement omission. Some studies have been showed amygdala is part of a circuit involved in the ROEs modulation. The view that amygdala lesions interfere with the ROEs is supported by evidence involving amygdala in responses correlated with motivational processes. These processes depend on the operation of separate amygdala areas and their connections with other brain systems. It has been suggested the interaction between the amygdala and the nucleus accumbens (NAC) is important to the modulation of motivational processes. Recent neuroimaging studies in human revealed reward delivery enhances activity of subcortical structures (NAC and amygdala), whereas reward omission reduces the activity in these same structures. The present study aimed to clarify whether the mechanisms related to ROEs depend on NAC. Prior to acquisition training, rats received bilateral excitotoxic lesions of NAC (NAC group) or sham lesions (Sham group). Following postoperative recovery, the rats were trained on a fixed-interval with limited hold signaled schedule of reinforcement. After acquisition of stable performance, the training was changed from 100% to 50% schedule of reinforcement. Both NAC and Sham groups presented the ROEs. However, after nonreinforcement, the response rates of the NAC group were lower than those registered in the Sham group. The performance of the NAC group decreased in the period following nonreinforcement when compared to the period preceding reinforcement omission. These findings suggest the NAC is part of the neural substrate involved in the ROEs modulation.

Bifrontal tDCS prevents implicit learning acquisition in antidepressant-free patients with major depressive disorder

The findings for implicit (procedural) learning impairment in major depression are mixed. We investigated this issue using transcranial direct current stimulation (tDCS), a method that non-invasively increases/decreases cortical activity. Twenty-eight age- and gender-matched, antidepressant-free depressed subjects received a single-session of active/sham tDCS. We used a bifrontal setup - anode and cathode over the left and the right dorsolateral prefrontal cortex (DLPFC), respectively. The probabilistic classification-learning (PCL) task was administered before and during tDCS. The percentage of correct responses improved during sham; although not during active tDCS. Procedural or implicit learning acquisition between tasks also occurred only for sham. We discuss whether DLPFC activation decreased activity in subcortical structures due to the depressive state. The deactivation of the right DLPFC by cathodal tDCS can also account for our results. To conclude, active bifrontal tDCS prevented implicit learning in depressive patients. Further studies with different tDCS montages and in other samples are necessary.

Levodopa changes brain motor network function during ankle movements in Parkinson’s disease

Bradykinesia-the cardinal symptom in Parkinson's disease (PD)-affects both upper and lower limbs. While several functional imaging studies investigated the impact of levodopa on movement-related neural activity in Parkinson's disease during upper limb movements, analogue studies on lower limb movements are rare. We studied 20 patients with PD (mean age 66.8±7.2years) after at least 12h drug withdrawal (OFF-state) and a second time approximately 40min after oral administration of 200mg levodopa (ON-state) behaviourally and by functional magnetic resonance imaging (fMRI) at 3T during externally cued active ankle movements of the more affected foot at fixed rate. Results were compared with that obtained in ten healthy controls (HC) to separate pure pharmacological from disease-related levodopa-induced effects and to allow for interaction analyses. Behaviourally, all patients improved by at least 20% regarding the motor score of the Unified Parkinson's disease rating scale after levodopa-challenge (mean scores OFF-state: 38.4±10.1; ON-state: 25.5±8.1). On fMRI, levodopa application elicited increased activity in subcortical structures (contralateral putamen and thalamus) in the patients. In contrast, no significant levodopa-induced activation changes were found in HC. The interaction between "PD/HC group factor" and "levodopa OFF/ON" did not show significant results. Given the levodopa-induced activation increases in the putamen and thalamus with unilateral ankle movements in patients with PD but not in HC, we speculate that these regions show the most prominent response to levodopa within the cortico-subcortical motor-circuit in the context of nigrostriatal dysfunction.

Emotion in the brain: of low roads, high roads and roads less travelled

2 . With regard to previous anatomical studies that did not report this pathway, we should remind ourselves that absence of evidence about a phenomenon is not equivalent to evidence that the phenomenon is absent. Multiple visual pathways There are indeed multiple extrageniculostri- ate anatomical pathways that potentially relay visual information to the amygdala and to other cortical targets, besides the superior colliculus-pulvinar route. Some of these have been linked to specific visual functions, such as motion perception, but not to non- conscious emotion perception. Moreover, there is no evidence that activity in extrastri- ate cortical areas during non-conscious emotion perception precedes and/or arises independently from modulatory activity in subcortical structures. Therefore, the notion that is defended in the Perspective 1 , that

Are Generalized Tonic–Clonic Seizures Really “Generalized”?

Cortical and Subcortical Networks in Human Secondarily Generalized Tonic–Clonic Seizures. Blumenfeld H, Varghese GI, Purcaro MJ, Motelow JE, Enev M, McNally KA, Levin AR, Hirsch LJ, Tikofsky R, Zubal IG, Paige AL, Spencer SS. Brain 2009;132(Pt 4):999–1012. Generalized tonic–clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single-photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analyzed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: 1) during the partial seizure phase prior to generalization; 2) during the generalization period; and 3) postictally. We found that in the pregeneralization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus, and basal ganglia. Postictally, there was a marked progressive CBF increase in the cerebellum that spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus, and cingulate gyrus during and following seizures, similar to the “default mode” regions reported previously to show decreased activity in seizures and in normal behavioral tasks. Analysis of patient behavior during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic–clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem, and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic–clonic seizures. Understanding the networks involved in generalized tonic–clonic seizures can provide insights into mechanisms of behavioral changes, and may elucidate targets for improved therapies.