Deep Brain Stimulation of the Thalamus as a Treatment for Epilepsy

What's the science?

Patients with epilepsy demonstrate abnormally elevated neuron firing and synchronization which contributes to seizures. Developing treatments that can reduce this neuron excitability and synchrony is a promising area of research. Many patients do not respond to anti-epileptic drugs or are not good candidates for surgery (for removal of seizure-generating brain tissue). In particular, deep brain stimulation of the anterior nucleus of the thalamus has shown promising results, however, the mechanism through which it improves symptoms remains unclear. This week in Brain, Yu and colleagues investigate the mechanism by which deep brain stimulation of the thalamus alters activity in brain regions of seizure onset.

How did they do it?

Nine patients with drug-resistant epilepsy underwent surgery for deep brain stimulation where electrodes are implanted deep in the brain. Intermittent high frequency stimulation of the anterior thalamus (130 Hz) was applied 5 days after surgery on the same side of the brain as the seizure onset region and local field potentials (neuronal activity) were recorded simultaneously from the seizure onset site using stereoelectroencephalography (SEEG) to better understand the resulting changes in neuronal activity and synchrony. Stimulation was  applied in a range of frequencies (5 Hz-130 Hz) to assess the effect of frequency on brain activity at the seizure onset site. The seizure onset site varied among patients, but was located either in the hippocampus (6 patients), frontal lobe (2 patients) or temporal lobe (1 patient). Activity was recorded for 7 to 10 days in the seizure onset zones to ensure that at least 3 seizures were captured. They also tested ‘cortico-cortical evoked potentials’ by stimulating the thalamus and measuring the response in the hippocampus and vice versa to understand how these two brain regions interact in response to an electrical stimulus.

What did they find?

For patients with seizure onset in the hippocampus, high frequency stimulation of the anterior nucleus of the thalamus resulted in immediate desynchronization and reduction of neuronal activity in the hippocampus. This effect lasted while stimulation was turned on, and neuronal activity returned to baseline levels once stimulation was turned off. This effect was specific to the anterior nucleus of the thalamus (i.e. there was no similar effect for stimulation on other regions of the thalamus). This effect was also specific to patients with seizures originating in the hippocampus, as no activity changes were seen for patients with other seizure onset zones (i.e. frontal cortex or temporal lobe). Seizure-associated spiking activity of neurons in the hippocampus (also known as interictal spikes) and high frequency oscillations were reduced during high frequency stimulation of the anterior nucleus of the thalamus, but not during stimulation of other thalamic regions or for other seizure onset zones. This indicates that seizure-related activity was reduced in the seizure onset zone. Low frequency stimulation of the thalamus resulted in increased synchrony of neuronal activity in the hippocampus, while frequencies higher than 45 Hz resulted in desynchronization. They then examined cortico-cortical evoked potentials between the thalamus and the hippocampus and demonstrated that these regions are directly and reciprocally connected, which helps to explain why thalamic stimulation reduced seizure activity in the hippocampus.

Brain, Servier Medical Art, image by BrainPost, CC BY-SA 3.0

What's the impact?

This is the first study to demonstrate the mechanism underlying the effects of deep brain stimulation of the anterior nucleus of the thalamus on seizure activity in epilepsy. Deep brain stimulation of the anterior nucleus of the thalamus results in desynchronization and reduction of activity in the hippocampus which are reciprocally connected. These findings improve our understanding of epilepsy originating in the hippocampus and suggest that deep brain stimulation of the anterior nucleus of the thalamus may be a promising treatment for epilepsy patients.

Word of caution: As the number of patients was low and there were few patients with neocortical seizure onset areas, the specific seizure type and seizure areas that respond to deep brain stimulation need to be clarified in a larger patient group.

Yu et al., High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans. Brain (2018). Access the original scientific publication here.

Aggressive Intent is Reduced by Stimulation of the Dorsolateral Prefrontal Cortex

What's the science?

Injury or impairment of the prefrontal cortex is known to be a risk factor for aggressive and antisocial behaviour, including aggressive sexual behaviour. In particular, the dorsolateral prefrontal cortex (DLPFC) is known to play a role in aggressive behaviour, however, the neuroimaging evidence for this is correlational rather than causal. The causal role of the DLPFC on aggressive behaviour is not known. This week in the Journal of Neuroscience, Choy and colleagues used transcranial direct current stimulation (tDCS) to stimulate the DLPFC and assess intent to commit aggressive behaviour.

How did they do it?

The authors designed a double-blind randomized trial in which anodal, active tDCS and sham tDCS (as a placebo) were administered bilaterally to the DLPFC. Eighty-one healthy adults were included in the final sample. A standard 20-minute tDCS protocol was applied to half of the participants, while the other half received sham tDCS, in which the stimulation was turned off after the first 30 seconds. Participants then completed questionnaires in which they a) read scenarios describing physical or sexual aggression and described how likely they would be to commit them and b) rated how morally wrong it would be to act in an aggressive scenario. Participants were also given a ‘voodoo doll’ and asked how much ‘negative energy’ they would like to release by inserting pins into the doll, which represents a family member or close friend. Finally, they assess whether moral wrongfulness mediated the group differences (active tDCS versus sham tDCS) in intent to commit an aggressive act. Participants also self-reported previous criminal activity and baseline aggression levels.

What did they find?

Participants in the active tDCS group were less likely to report intent to engage in aggressive acts, physical assault, and sexual assault compared to participants in the sham tDCS group after controlling for baseline criminal activity and aggression levels. No differences between groups on the voodoo doll aggression task were found. The active tDCS group perceived aggressive acts as more morally wrong, and moral wrongfulness partly mediated the relationship between group and intent to commit aggressive acts. Moral wrongfulness also mediated the relationship between group and intent to commit sexual but not physical assault.

What's the impact?

This is the first study to assess the effects of tDCS of the DLPFC on aggressive intent. Further, the perception of these acts as immoral mediated the relationship between tDCS stimulation and aggression. Damage to the prefrontal cortex is a known risk factor for aggressive behaviour, so understanding the causal role of the DLPFC in inhibiting aggression is critical for addressing aggression as a public health issue and for disorders such as antisocial and borderline personality disorders.

Choy et al., Stimulation of the Prefrontal Cortex Reduces Intentions to Commit Aggression: A Randomized, Double-Blind, Placebo-Controlled, Stratified, Parallel-Group Trial. Journal of Neuroscience (2018). Access the original scientific publication here.

New Hippocampal Neurons are Involved in Stress Resilience

What’s the science?

The hippocampus plays an important role in memory and cognition, but also in stress and anxiety. In many brain regions there is no neurogenesis (new neurons generated) in adulthood, however, neurogenesis does occur in the ventral dentate gyrus of the hippocampus. These adult-born neurons are known to play a role in mood regulation, but their role in protecting against stress-induced anxiety behaviours is not known. This week in Nature, Anacker and colleagues inhibited adult-born neurons in the ventral dentate gyrus to assess their role in resilience to chronic stress.

How did they do it?

The authors developed a new model to silence adult-born neurons (granule cells) of the ventral dentate gyrus in mice by expressing a ‘designer receptor exclusively activated by designer drugs’ (DREADD). Specifically, they crossed a tamoxifen-induced CreERT2 recombinase transgenic mouse line with mice expressing loxP-STOP-mCherry-loxP-hM4Di. Then, they could administer an agonist for the DREADD (clozapine-N-oxide) to decrease activity of adult-born neurons. Mice with DREADDs (Cre+ mice) underwent a short social-defeat paradigm (5 days) in which they fought and were defeated by an aggressive mouse. Then, the authors tested whether mice would change their social behaviour or exploration patterns (less exploring an open area indicates anxiety) after the social-defeat paradigm. In control mice, this social-defeat paradigm had been shown to be short enough not to change the mouse’s subsequent response to social interactions. To examine any effects of adult-born neuron silencing on neural activity of mature neurons of the ventral dentate gyrus, the authors examined Fos gene expression and performed electrophysiological recordings during perforant path stimulation (the main glutamatergic input into the ventral dentate gyrus) in vivo. To test whether neurogenesis could promote resilience to stress, they deleted the Bax gene (‘iBax mice’) to promote increased neurogenesis. Control mice and iBax mice were subjected to a 10 day chronic social-defeat paradigm, which usually increases anxiety and reduces social behaviours in control mice. They also assessed whether the activity of mature neurons (indicated by c-Fos+ neurons) increased in iBax mice. Finally, they performed cell selectivity analyses using calcium imaging to assess whether certain cells were selective for different neuronal events in control mice and iBax mice during the chronic social-defeat task.

What did they find?

After mice with activated DREADDs underwent the social-defeat paradigm, they explored an open area and approached novel mice less in a social interaction test. This indicates that the inhibition of young neurons increases stress responses/anxiety. Fos gene expression was increased in mature neurons following social-defeat in Cre+ mice (versus control mice), and increased mature neuronal activity was found following performant path stimulation. This indicates that mature neurons may be more activated by stress after silencing young neurons. In iBax mice (who had increased neurogenesis) compared with control mice, the authors found normal levels of social interaction following a chronic social defeat paradigm, suggesting that increased neurogenesis in iBax mice made them resilient to stress. After X-ray irradiation of the ventral dentate gyrus in iBax mice, these effects were no longer seen, providing further evidence that adult-born neurons are responsible for resilience to stress.

When the authors assessed activity of mature neurons (c-Fos+ levels) they found that iBax mice had less c-Fos+ cells after stress, indicating that new neurons can decrease the activity of the dentate gyrus. During attack periods, using cell selectivity analysis, they found 17% of ventral dentate gyrus cells to be selective for the attack periods during the chronic social defeat task. This population of attack-selective cells increased to over 30% after chronic stress. Interestingly, these cells were less active (lower calcium transient rates) during attacks in iBax mice. This indicates that neurogenesis could result in lower activity of attack-selective cells (i.e. inhibition). The authors then mimicked the effect of neurogenesis on inhibiting the dentate gyrus by directly expressing inhibitory DREADD receptors in mature granule cells. By doing this, they found that directly inhibiting the ventral dentate gyrus is sufficient to confer stress resilience.

What’s the impact?

This is the first study to demonstrate the role of new neurons in the ventral dentate gyrus of the hippocampus in response to stress and anxiety in mice. Neurogenesis in the ventral dentate gyrus appears to reduce the response to stress, and silencing new neurons in this region appears to increase the response to stress. Understanding the role of new neurons in this region is critical to understand vulnerability to stress and could be applicable in psychiatric disorders. The study also suggests that novel strategies aimed at inhibiting the ventral dentate gyrus could be used to treat or prevent stress-induced psychiatric disorders.

Anacker et al., Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature (2018). Access the original scientific publication here.