Abstract
Feng L, Motelow JE, Ma C, Biche W, McCafferty C, Smith N, Liu M, Zhan Q, Jia R, Xiao B, Duque A, Blumenfeld H. J Neurosci 2017;37:11441–11454.
The thalamus plays diverse roles in cortical-subcortical brain activity patterns. Recent work suggests that focal temporal lobe seizures depress subcortical arousal systems and convert cortical activity into a pattern resembling slow-wave sleep. The potential simultaneous and paradoxical role of the thalamus in both limbic seizure propagation, and in sleep-like cortical rhythms has not been investigated. We recorded neuronal activity from the central lateral (CL), anterior (ANT), and ventral posteromedial (VPM) nuclei of the thalamus in an established female rat model of focal limbic seizures. We found that population firing of neurons in CL decreased during seizures while the cortex exhibited slow waves. In contrast, ANT showed a trend toward increased neuronal firing compatible with polyspike seizure discharges seen in the hippocampus. Meanwhile, VPM exhibited a remarkable increase in sleep spindles during focal seizures. Single-unit juxtacellular recordings from CL demonstrated reduced overall firing rates, but a switch in firing pattern from single spikes to burst firing during seizures. These findings suggest that different thalamic nuclei play very different roles in focal limbic seizures. While limbic nuclei, such as ANT, appear to participate directly in seizure propagation, arousal nuclei, such as CL, may contribute to depressed cortical function, whereas sleep spindles in relay nuclei, such as VPM, may interrupt thalamocortical information flow. These combined effects could be critical for controlling both seizure severity and impairment of consciousness. Further understanding of differential effects of seizures on different thalamocortical networks may lead to improved treatments directly targeting these modes of impaired function.
Commentary
Temporal lobe epilepsy is a common adulthood form of refractory epilepsy characterized by seizures with focal onset and impaired awareness rising from the limbic areas. Yet the role of the thalamus during focal limbic seizures is not well established despite the fact that thalamic nuclei receive significant inputs from the limbic system. Traditionally, thalamus and thalamo-cortical rhythms have been implicated in non-motor generalized seizures with impaired awareness (i.e., absence seizures). However, these rhythms are ascribed to the reticular thalamic nucleus and thalamo-cortical neurons such as those found in the ventrolateral thalamic nucleus (1). Sleep spindles are also generated in the thalamic reticular nucleus and for widespread presence in the areas of cortex they require significant cortical feedbacks (2). Thus, there is a strong thalamic interconnection between arousal and generalized seizures. Yet, the functional connection between focal, temporal lobe seizures and thalamic circuits responsible for arousal (consciousness) and sleep is still terra incognita.
Investigators in this study took an unusual, yet well-justified and important, step to determine the influence of ongoing temporal lobe seizures on the arousal function of the thalamic nuclei. Feng et al. focused their attention on three very different thalamic nuclei. First, they investigated the central lateral nucleus (CL), which is a part of the intralaminar thalamic group. Neurons in this nucleus have significant depolarizing output to the striatal medium spiny interneurons (3). Activity of neurons in CL reflects attention effort (Schiff et al 2013) and is essential for performance (but not acquisition) in stimulus-induced learning and also for behavioral flexibility (5). The authors’ own study in limbic seizures found decreased Blood-Oxygen-Level-Dependent (BOLD) signal in the intralaminar thalamic nuclei, indicating their significant involvement (6). Next, the anterior thalamic nucleus (ANT) was selected, because clinical data show that ANT is an effective deep brain stimulation target in patients with intractable epilepsy (7). A study in patients with implanted ANT electrodes for deep brain stimulation also suggested an important role of ANT in memory recognition and modality-dependent memory encoding, possibly because of reciprocal connections of ANT with the hippocampus (8). Finally, a relay ventral posteromedial nucleus (VPM) was probed. This nucleus mediates somatosensory information from the face (trigeminal) to the primary somatosensory cortex. Interestingly, a study in rats found significant neuronal degeneration in this nucleus after status epilepticus originating in the hippocampus (9). All of these studies indicate that heterogeneous thalamic nuclei have functional connections with the limbic system and may be an important part of arousal, attention, and memory circuits.
For their model of focal seizures the authors used stimulation of the dorsal hippocampus of lightly anesthetized female rats. Only those stimulus-induced seizures longer than 30 seconds not generalizing to the frontal cortex were included in the analysis. Interestingly, female rats are less susceptible to develop secondary generalization compared with male rats. Multiunit activity was recorded with a monopolar tungsten microelectrode stereotaxically inserted to one of the studied thalamic nuclei. Juxtacellular single-unit recordings were additionally obtained from the CL. All activity was studied during baseline (prior to hippocampal stimulation), during focal hippocampal seizures, immediately postictally, and during the recovery period. The authors found that an ongoing hippocampal seizure suppresses firing of CL neurons, which recovers almost immediately with seizure cessation. At the same time, neuronal firing in the ANT increases insignificantly and after short postictal suppression quickly normalizes. And finally, VPM neuronal firing also increases during the seizure, persists postically, and only slowly normalizes during the recovery period. Yet this is not the main issue in the VPM. As a thalamic nucleus containing thalamocortical cells (1), VPM participates in spindle generation and power of the spindles goes up and stays up postictally and normalizes only during recovery period. At the same time, electrographic activity in the frontal cortex increases its delta wave power about four times, which remains increased through postictal period and only during recovery period power of delta waves returns to the baseline.
These findings provide a mechanistic substrate for observational findings during focal temporal lobe seizures. First, CL, which is a major nucleus of the thalamic arousal system (with inputs from the brainstem and limbic cortex, reciprocal connections with the cingulate cortex, and outputs to the caudate-putamen, somatosensory and visual cortex as well as to diencephalic regions; [10]), decreases its activity during a limbic seizure, which indicates that the arousal drive of this nucleus is substantially diminished. ANT shows only insignificant increases in activity if averaged for the entire cohort, though in some subjects these increases may become substantial. ANT has direct reciprocal connections with the hippocampal formation and, thus, may play a role in seizure propagation. This finding rationalizes ANT utilization in the deep brain stimulation for refractory epilepsy. ANT also plays a role in the propagation of theta rhythms, which are important for hippocampal synaptic plasticity, spatial navigation, and cortical plasticity, including visual memory (11). The current study reinforces ANT use for deep brain stimulation in intractable epilepsy; however, the role of ANT during focal temporal lobe seizures is likely limited, possibly to interference of these seizures with learning and plasticity processes that were not investigated here. Finally, VPM neurons, by changing their firing, give rise to frequent spindle waves (1–3 seconds long, 7–14 Hz crescendo-decrescendo oscillations) usually associated with sleep (1). During these periods of spindle VPM activity, local field potentials in the lateral orbitofrontal cortex displayed increased delta wave power, again consistent with sleep findings. These spindles may be additionally modulated by decreased subcortical cholinergic activity during the hippocampal seizure (6), further contributing to decrease of arousal.
In conclusion, the authors clearly show that the thalamus has a significant role in arousal control during focal hippocampal seizures. During these seizures, activity in the thalamic arousal centers decreases, while the activity in the sleep centers increases. Both findings may synergistically contribute to limbic seizure-induced impaired consciousness. The authors also point to some limitations of the study. The recordings were performed in lightly anesthetized animals. The level of anesthesia, while tightly maintained, might have contributed to inconsistencies found in the ANT recordings. Thus, transferring the model to freely moving animals (and also males) would be extremely beneficial. Second, if females were used, what is the relationship of the outcome to their estrous cycle (again a possible confounder for ANT recordings)? In women, there is a relationship between ovarian cycle phase and occurrence of intractable focal temporal lobe seizures with impaired awareness (catamenial epilepsy) (12). Third, for functional investigation of thalamic structures, the authors suggest adopting optogenetic silencing. This is a great idea, especially if they intend to investigate a single defined neuronal population within these targets. For crude silencing of the entire nuclei, many simple techniques are available (induction of spreading depolarization; GABAA receptor agonist microinfusions; focal electrical stimulation or combination of the previous) that will provide results quickly and reliably. Some of these techniques can be quite well controlled. Finally studies of secondarily generalized seizures would represent great expansion and addition of current experiments.