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Deep brain stimulation (DBS) is an emerging treatment for an increasing number of neurological and psychiatric brain disorders. High frequency electric stimulation delivered at grey matter such as thalamic nuclei prevents neural activity locally mimicking a focal lesion. Thereby, DBS provides an opportunity for investigating brain structure-function relationship online in humans engaged in cognitive tasks. With this approach we have provided causal evidence for the role of thalamic nuclei in human affective and cognitive functions.

The DBS target for treatment of refractory epilepsy is anterior nucleus of thalamus (ANT), a key node in the limbic circuitry. We alternated stimulation periods on and off in patients treated with ANT-DBS due to refractory epilepsy while they were engaged in a visual attention task with intervening threat-related emotional distractors and their EEG was recorded. We found increased emotional interference of performance speed (RT) and increased amplitude of event related potentials (ERP, N2-P3) linked with attention in context of emotional distractors. We concluded ANT-DBS to increase attention allocation to threat, which may reflect potential vulnerability to depression symptoms previously reported in patients treated with ANT-DBS. As part of the limbic circuitry ANT has been linked with emotion-related functions. However, according to our knowledge our work provides the first direct evidence for ANT’s role in emotion-attention interaction in humans.  

Adjacent to ANT is mediodorsal nucleus of thalamus (MD), a key node in the fronto-thalamic circuits involved in working memory. While MD has been associated with working memory in previous animal and human studies, causal evidence for its role in humans has been lacking. We found that high frequency electric stimulation at MD impaired working memory performance in humans in comparison to when ANT was stimulated or when no stimulation was delivered, providing causal evidence for the role of MD in human working memory.  In contrast to working memory impairment due to DBS at MD, vagus nerve stimulation (VNS) was shown to improve working memory performance in humans. While high frequency electric stimulation at MD disrupted working memory performance it is possible that other type of neuromodulation of MD might enhance working memory performance, with vast potential implications for restoring or enhancing cognition.

In order to adjust neuromodulation treatments towards optimally restored brain activity supporting healthy or improved affective and cognitive functions, biomarkers for the impact of neuromodulation on affective and cognitive brain circuits are needed. A potential biomarker for the immediate effects of neuromodulation on affective circuits is frontal alpha asymmetry. In line with previous work indicating potential vulnerability to depression symptoms we found ANT-DBS to increase rightward frontal alpha activity during a cognitive task with intervening emotional stimuli.  Task-related frontal alpha asymmetry along with measure of emotional interference of behavior could be used as a potential biomarker to objectively asses and gear the affective effects of neuromodulation treatments. While clinical relevance of such an index requires further research, it provides an objective measure for a wide range of scientific experiments aimed at better understanding the dynamics of affective circuits, their dysfunction, or the impact of neuromodulation on them.

In summary, DBS opens a unique window into human brain structure-function relationship and furthermore provides an opportunity for investigating the effects of DBS on brain circuits and functions, with aims of restoring disrupted brain activity in brain disorders towards optimal brain health.