Human single-neuron activity is modulated by intracranial theta burst stimulation of the basolateral amygdala
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eLife Assessment
This important study provides a description of how single-neuron firing rates in the human medial temporal lobe and frontal cortex are modulated by theta-burst stimulation of the basolateral amydala. The results are supported by solid evidence obtained from a rigorous task design and analysis of an incredibly rare dataset. The results may help guide future studies incorporating amygdala stimulation to improve patient health. Additional analyses could have been performed, and additional experimental details included, to address open questions related to mechanistic effects of the stimulation protocol on single unit properties and memory-related behavior.
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Abstract
Direct electrical stimulation of the human brain has been used for numerous clinical and scientific applications. Previously, we demonstrated that intracranial theta burst stimulation (TBS) of the basolateral amygdala (BLA) can enhance declarative memory, likely by modulating hippocampal-dependent memory consolidation. At present, however, little is known about how intracranial stimulation affects activity at the microscale. In this study, we recorded intracranial EEG data from a cohort of patients with medically refractory epilepsy as they completed a visual recognition memory task. During the memory task, brief trains of TBS were delivered to the BLA. Using simultaneous microelectrode recordings, we isolated neurons in the hippocampus, amygdala, orbitofrontal cortex, and anterior cingulate cortex and tested whether stimulation enhanced or suppressed firing rates. Additionally, we characterized the properties of modulated neurons, patterns of firing rate coactivity, and the extent to which modulation affected memory task performance. We observed a subset of neurons (∼30%) whose firing rate was modulated by TBS, exhibiting highly heterogeneous responses with respect to onset latency, duration, and direction of effect. Notably, location and baseline activity predicted which neurons were most susceptible to modulation, although the impact of this neuronal modulation on memory remains unclear. These findings advance our limited understanding of how focal electrical fields influence neuronal firing at the single-cell level and motivate future neuromodulatory therapies that aim to recapitulate specific patterns of activity implicated in cognition and memory.
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eLife Assessment
This important study provides a description of how single-neuron firing rates in the human medial temporal lobe and frontal cortex are modulated by theta-burst stimulation of the basolateral amydala. The results are supported by solid evidence obtained from a rigorous task design and analysis of an incredibly rare dataset. The results may help guide future studies incorporating amygdala stimulation to improve patient health. Additional analyses could have been performed, and additional experimental details included, to address open questions related to mechanistic effects of the stimulation protocol on single unit properties and memory-related behavior.
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Reviewer #1 (Public review):
Summary:
In this manuscript, Campbell et al. assess how intracranial theta-burst stimulation (TBS) applied to the basolateral amygdala in 23 epilepsy patients affects neuronal spiking in the medial temporal lobe and prefrontal cortex during a visual recognition memory task.
Strengths:
This is an incredibly rare dataset; collecting single-unit spiking data from behaving humans during active intracranial stimulation is a Herculaean task, with immense potential for translational studies of how stimulation may be applied to modulate biological mechanisms of memory. The authors utilize careful, high-quality methodology throughout (e.g. task design, spike recording and sorting, statistical analysis), providing high confidence in the validity of their findings.
Weaknesses:
(1) This is an exploratory study that …
Reviewer #1 (Public review):
Summary:
In this manuscript, Campbell et al. assess how intracranial theta-burst stimulation (TBS) applied to the basolateral amygdala in 23 epilepsy patients affects neuronal spiking in the medial temporal lobe and prefrontal cortex during a visual recognition memory task.
Strengths:
This is an incredibly rare dataset; collecting single-unit spiking data from behaving humans during active intracranial stimulation is a Herculaean task, with immense potential for translational studies of how stimulation may be applied to modulate biological mechanisms of memory. The authors utilize careful, high-quality methodology throughout (e.g. task design, spike recording and sorting, statistical analysis), providing high confidence in the validity of their findings.
Weaknesses:
(1) This is an exploratory study that doesn't explore quite enough. Critically, the authors make a point of mentioning that neuronal firing properties vary across cell types, but only use baseline firing rate as a proxy metric for cell type. This leaves several important explorations on the table, not limited to the following:
a) Do waveform shape features, which can also be informative of cell type, predict the effect of stimulation?
b) Is the autocorrelation of spike timing, which can be informative about temporal dynamics, altered by stimulation? This is especially interesting if theta-burst stimulation either entrains theta-rhythmic spiking or is more modulatory of endogenously theta-modulated units.
c) The authors reference the relevance of spike-field synchrony (30-55 Hz) in animal work, but ignore it here. Does spike-field synchrony (comparing the image presentation to post-stimulation) change in this frequency range? This does not seem beyond the scope of investigation here.
d) How does multi-unit activity respond to stimulation? At this somewhat low count of neurons (total n=156 included) it would be valuable to provide input on multi-unit responses to stimulation as well.
e) Several intracranial studies have implicated proximity to white matter in determining the effects of stimulation on LFPs; do the authors see an effect of white matter proximity here?(2) It is a little confusing to interpret stimulation-induced modulation of neuronal spiking in the absence of stimulation-induced change in behavior. How do the authors findings tell us anything about the neural mechanisms of stimulation-modulated memory if memory isn't altered? In line with point #1, I would suggest a deeper dive into behavior (e.g. reaction time? Or focus on individual sessions that do change in Figure 4A?) to make a stronger statement connecting the neural results to behavioral relevance.
(3) It is not clear to me why the assessment of firing rates after image onset and after stim offset is limited to one second - this choice should be more theoretically justified, particularly for regions that spike as sparsely as these.
(4) This work coincides with another example of human intracranial stimulation investigating the effect on firing rates (doi: https://doi.org/10.1101/2024.11.28.625915). Given how incredibly rare this type of work is, I think the authors should discuss how their work converges with this work (or doesn't).
(5) What information does the pseudo-population analysis add? It's not totally clear to me.
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Reviewer #2 (Public review):
Summary:
This study presents a valuable characterization of the effects of intracranial theta-burst stimulation of the basolateral amygdala on single units spiking activity in several areas in the human brain, associated with memory processing. It is written clearly and concisely, allowing readers to fully understand the analysis used.
The authors used a visual recognition memory task previously employed by their group to characterize the effects of basolateral amygdala stimulation upon memory consolidation (Inman et al, 2018). This current report is an interesting analysis to complement the results reported in the 2018 paper.
Strengths:
Rare combination of human neurophysiology and behavior -
The type of experiment performed in the manuscript, which contains both neurophysiological data, behavior, and a …Reviewer #2 (Public review):
Summary:
This study presents a valuable characterization of the effects of intracranial theta-burst stimulation of the basolateral amygdala on single units spiking activity in several areas in the human brain, associated with memory processing. It is written clearly and concisely, allowing readers to fully understand the analysis used.
The authors used a visual recognition memory task previously employed by their group to characterize the effects of basolateral amygdala stimulation upon memory consolidation (Inman et al, 2018). This current report is an interesting analysis to complement the results reported in the 2018 paper.
Strengths:
Rare combination of human neurophysiology and behavior -
The type of experiment performed in the manuscript, which contains both neurophysiological data, behavior, and a deep brain stimulation intervention (DBS), is incredibly rare, takes many years to accomplish with tight collaboration between clinical and research teams. Our understanding of spiking dynamics of human neurons is very limited, and this report is an important piece in the puzzle that allows DBS to be used in future interventions that will benefit patients' health.Multiple brain areas included -
It's important to note that the report analyzes brain areas with which the Amygdala has extensive connections (Fig. 1A) - Hippocampus, OFC, Amygdala, ACC. It seems that neurons in all these areas were modulated by the stimulation, except the ACC, in which firing rates were so low, that only a handful of neurons were included in the analysis. This is an important demonstration that low amplitude stimulation (even when reduced to 0.5mA) can travel far and wide across the human brain.The experiment is cleverly designed to tease apart responses due to visual stimuli (image presentation) and electrical stimulation. Authors suggest that the units modulated by stimulation are largely distinct from those responsive to image offset during trials without stimulation. The subpopulation that responds strongly also tends to have a higher baseline of firing rate. It's important to add that the chosen modulation index is more likely to be significant in neurons with higher firing rates.
Weaknesses:
Readers can benefit from understanding with more details the locations chosen for stimulation - in light of previous studies that found differences between effects based on proximity to white matter (For example - PMID 32446925, Mohan et al, Brain Stimul. 2020 and PMID 33279717 Mankin et al Brain Stimul. 2021).
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