Unexpected study results complicate the use of brain stimulation for anxiety

A new study suggests that a promising noninvasive brain stimulation technique may not function exactly as psychiatrists had hoped for patients with combined depression and anxiety. Researchers found that while electrical stimulation of the brain’s frontal cortex improved mental focus and reaction times, it also unexpectedly heightened sensitivity to potential threats.

These findings indicate that the treatment might wake up the brain’s alertness systems rather than simply calming down fear responses. The results were published in the journal Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

Major depressive disorder is one of the world’s most persistent public health burdens. It becomes even harder to treat when accompanied by anxiety. This combination is common. Patients with both conditions often experience more severe symptoms and are less likely to respond to standard antidepressants or talk therapy. This resistance to treatment has led scientists to look for biological causes within the brain’s circuitry.

Neuroscientists have identified specific patterns of brain activity in people with anxious depression. Typically, the prefrontal cortex shows lower than average activity. This area sits just behind the forehead. It is responsible for planning, decision-making, and regulating emotions. At the same time, the amygdala often shows hyperactivity. The amygdala is a deep brain structure that acts as the body’s alarm system for danger. In a healthy brain, the prefrontal cortex helps quiet the amygdala when a threat is not real. In anxious depression, this regulatory system often fails.

Researchers have been exploring transcranial direct current stimulation as a way to correct this imbalance. This technique involves placing electrodes on the scalp to deliver a weak electrical current. The goal is to encourage neurons in the prefrontal cortex to fire more readily. Theoretically, boosting the “thinking” part of the brain should help it exert better control over the “feeling” alarm system.

A team led by Tate Poplin and senior author Maria Ironside at the Laureate Institute for Brain Research in Tulsa, Oklahoma, sought to test this theory in a large clinical sample. They recruited 101 adults who were currently experiencing a major depressive episode and high levels of anxiety. The researchers wanted to see if a single session of stimulation could alter the way these patients processed threats.

The study was designed as a double-blind, randomized trial. This is the gold standard for clinical research. The participants were divided into two groups. One group received thirty minutes of active stimulation to the dorsolateral prefrontal cortex. The other group received a sham, or placebo, stimulation. The sham version mimicked the physical sensations of the device but did not deliver the therapeutic current. This ensured that neither the patients nor the staff knew who was receiving the real treatment.

The researchers administered the stimulation while the participants lay inside a magnetic resonance imaging scanner. This allowed the team to observe changes in blood flow within the brain in real time. During the scan, the participants completed a cognitive task. They viewed pictures of faces with fearful or neutral expressions. Letters were superimposed over the faces. The participants had to identify the letters.

This task was designed to measure “attentional load.” Some rounds were easy and required little mental effort. Other rounds were difficult and demanded intense focus. This design allowed the researchers to see how the brain prioritized information. They wanted to know if the stimulation would help the brain ignore the fearful faces and focus on the letters.

After the brain scans, the participants underwent a physical test of their anxiety levels. This involved measuring the startle reflex. The researchers placed sensors on the participants’ faces to detect eye blinks. The participants then listened to bursts of white noise. Sometimes the noise signaled a predictable electric shock. Other times, the shock was unpredictable.

This distinction is important in psychology. Reacting to a known danger is considered fear. Reacting to an unknown or unpredictable threat is considered anxiety. By measuring how hard the participants blinked in anticipation of the shock, the researchers could physically quantify their threat sensitivity.

The findings painted a complex picture of how the stimulation affected the brain. On one hand, the treatment appeared to improve cognitive performance. The group that received active stimulation was more accurate at identifying the letters than the placebo group. They also reacted faster.

The brain scans supported this behavioral improvement. When the task was difficult, the active group showed increased activity in the inferior frontal gyrus and the parietal cortex. These regions are heavily involved in attention and executive control. This suggests the stimulation successfully engaged the brain’s command centers.

However, the results regarding emotional regulation contradicted the team’s original predictions. The researchers hypothesized that the stimulation would reduce the amygdala’s reaction to the fearful faces. Instead, the opposite occurred during the easy version of the task. The amygdala showed greater activation in the active group compared to the placebo group.

The startle test revealed a similar pattern. The researchers found that active stimulation did not calm the participants’ physical reflexes. In fact, it made them jumpier. The active group showed a stronger startle response during the unpredictable threat condition. They also reported feeling higher levels of anxiety during these moments of uncertainty.

Ironside noted the dual nature of these results. “Compared to the sham stimulation, frontal tDCS increased the activation of the bilateral inferior frontal gyrus… when the task was more cognitively demanding and, unexpectedly, increased amygdala… response when the task was less cognitively demanding,” she said.

Ironside also highlighted the physical findings. “We also observed that tDCS increased eyeblink startle response under conditions of unpredictable threat.”

These results suggest that transcranial direct current stimulation does not act as a simple tranquilizer for the brain. Instead, it may function as a general amplifier of arousal and engagement. By boosting the excitability of the frontal cortex, the treatment might make the brain more alert to everything. This includes both the task at hand and potential threats in the environment.

The increase in startle response might reflect a state of heightened vigilance. When the brain is more engaged, it may process all incoming signals more intensely. This interpretation aligns with the improved reaction times on the cognitive task. The participants were “sharper,” but this sharpness came with a cost of increased sensitivity to anxiety-provoking stimuli.

There are several important caveats to consider regarding this study. First, the participants only received a single session of stimulation. Clinical treatments for depression typically involve daily sessions over several weeks. It is possible that the cumulative effect of repeated stimulation is different from the acute effect of a single dose. Long-term changes in brain plasticity might take time to develop.

Second, the environment may have influenced the results. Undergoing a brain scan can be stressful. The MRI machine is loud and confining. For people who already suffer from high anxiety, this environment might have heightened their baseline stress levels. Receiving electrical stimulation in such a high-stress context could have interacted with their anxiety in unique ways.

The researchers also noted that the demographics of the study leaned heavily toward women. While this reflects the higher prevalence of depression and anxiety in women, it means the results might not fully generalize to men.

Despite the unexpected increase in threat sensitivity, the authors believe the findings offer a path forward. The clear improvement in task engagement and frontal brain activity is a positive signal. It suggests that the stimulation is effectively reaching the target brain regions and altering their function.

The failure to reduce anxiety might be due to the passive nature of the treatment. In this study, participants received stimulation while resting or doing a simple task. The researchers suggest that future trials should explore “context-dependent” stimulation.

This approach would involve pairing the brain stimulation with active therapy. For example, if a patient is undergoing exposure therapy to face their fears, the stimulation might help them engage more fully with the therapeutic exercises. If the stimulation boosts the brain’s ability to focus and learn, it could act as a catalyst for psychological interventions.

The study, “Frontal Cortex Stimulation Modulates Attentional Circuits and Increases Anxiety-Potentiated Startle in Anxious Depression,” was authored by Tate Poplin, Rayus Kuplicki, Ebony A. Walker, Kyle Goldman, Cheldyn Ramsey, Nicholas Balderston, Robin L. Aupperle, Martin P. Paulus, and Maria Ironside.