Reward-Based Decision-Making Engages Distinct Modes of Cross-Frequency Coupling.

Prefrontal cortex exerts control over sensory and motor systems via cross-frequency coupling. However, it is unknown whether these signals play a role in reward-based decision-making and whether such dynamic network configuration is altered in a major depressive episode. We recruited men and women with and without depression to perform a streamlined version of the Expenditure of Effort for Reward Task during recording of electroencephalography. Goal-directed behavior was quantified as willingness to exert physical effort to obtain reward, and reward-evaluation was the degree to which the decision to exert effort was modulated by incentive level. We found that the amplitude of frontal-midline theta oscillations was greatest in participants with the greatest reward-evaluation. Furthermore, coupling between frontal theta phase and parieto-occipital gamma amplitude was positively correlated with reward-evaluation. In addition, goal-directed behavior was positively correlated with coupling between frontal delta phase to motor beta amplitude. Finally, we performed a factor analysis to derive 2 symptom dimensions and found that mood symptoms positively tracked with reward-evaluation and motivation symptoms negatively tracked with goal-directed behavior. Altogether, these results provide evidence that 2 aspects of reward-based decision-making are instantiated by different modes of prefrontal top-down control and are modulated in different symptom dimensions of depression.

Targeting reduced neural oscillations in patients with schizophrenia by transcranial alternating current stimulation.

Transcranial alternating current stimulation (tACS) modulates endogenous neural oscillations in healthy human participants by the application of a low-amplitude electrical current with a periodic stimulation waveform. Yet, it is unclear if tACS can modulate and restore neural oscillations that are reduced in patients with psychiatric illnesses such as schizophrenia. Here, we asked if tACS modulates network oscillations in schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast tACS with transcranial direct current stimulation (tDCS) and sham stimulation in 22 schizophrenia patients with auditory hallucinations. We used high-density electroencephalography to investigate if a five-day, twice-daily 10Hz-tACS protocol enhances alpha oscillations and modulates network dynamics that are reduced in schizophrenia. We found that 10Hz-tACS enhanced alpha oscillations and modulated functional connectivity in the alpha frequency band. In addition, 10Hz-tACS enhanced the 40Hz auditory steady-state response (ASSR), which is reduced in patients with schizophrenia. Importantly, clinical improvement of auditory hallucinations correlated with enhancement of alpha oscillations and the 40Hz-ASSR. Together, our findings suggest that tACS has potential as a network-level approach to modulate reduced neural oscillations related to clinical symptoms in patients with schizophrenia.

Reduction in Left Frontal Alpha Oscillations by Transcranial Alternating Current Stimulation in Major Depressive Disorder Is Context Dependent in a Randomized Clinical Trial.

BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for noninvasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind, placebo-controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Eighty-four participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally salient images before and after stimulation to investigate whether the modulation of alpha oscillation by tACS exhibited specificity with regard to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared with placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSIONS: Together, these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.

Stimulus-specific regulation of visual oddball differentiation in posterior parietal cortex.

The frequency at which a stimulus is presented determines how it is interpreted. For example, a repeated image may be of less interest than an image that violates the prior sequence. This process involves integration of sensory information and internal representations of stimulus history, functions carried out in higher-order sensory areas such as the posterior parietal cortex (PPC). Thus far, there are few detailed reports investigating the single-neuron mechanisms for processing of stimulus presentation frequency in PPC. To address this gap in knowledge, we recorded PPC activity using 2-photon calcium imaging and electrophysiology during a visual oddball paradigm. Calcium imaging results reveal differentiation at the level of single neurons for frequent versus rare conditions which varied depending on whether the stimulus was preferred or non-preferred by the recorded neural population. Such differentiation of oddball conditions was mediated primarily by stimulus-independent adaptation in the frequent condition.

Identifying and Engaging Neuronal Oscillations by Transcranial Alternating Current Stimulation in Patients With Chronic Low Back Pain: A Randomized, Crossover, Double-Blind, Sham-Controlled Pilot Study.

Chronic pain is associated with maladaptive reorganization of the central nervous system. Recent studies have suggested that disorganization of large-scale electrical brain activity patterns, such as neuronal network oscillations in the thalamocortical system, plays a key role in the pathophysiology of chronic pain. Yet, little is known about whether and how such network pathologies can be targeted with noninvasive brain stimulation as a nonpharmacological treatment option. We hypothesized that alpha oscillations, a prominent thalamocortical activity pattern in the human brain, are impaired in chronic pain and can be modulated with transcranial alternating current stimulation (tACS). We performed a randomized, crossover, double-blind, sham-controlled study in patients with chronic low back pain (CLBP) to investigate how alpha oscillations relate to pain symptoms for target identification and whether tACS can engage this target and thereby induce pain relief. We used high-density electroencephalography to measure alpha oscillations and found that the oscillation strength in the somatosensory region at baseline before stimulation was negatively correlated with pain symptoms. Stimulation with alpha-tACS compared to sham (placebo) stimulation significantly enhanced alpha oscillations in the somatosensory region. The stimulation-induced increase of alpha oscillations in the somatosensory region was correlated with pain relief. Given these findings of successful target identification and engagement, we propose that modulating alpha oscillations with tACS may represent a target-specific, nonpharmacological treatment approach for CLBP. This trial has been registered in ClinicalTrials.gov (NCT03243084). PERSPECTIVE: This study suggests that a rational design of transcranial alternating current stimulation, which is target identification, engagement, and validation, could be a nonpharmacological treatment approach for patients with CLBP.

Targeting the Autonomic Nervous System Balance in Patients with Chronic Low Back Pain Using Transcranial Alternating Current Stimulation: A Randomized, Crossover, Double-Blind, Placebo-Controlled Pilot Study.

BACKGROUND: Chronic low back pain (CLBP) is characterized by an alteration in pain processing by the central nervous system that may affect autonomic nervous system (ANS) balance. Heart rate variability (HRV) reflects the balance of parasympathetic and sympathetic ANS activation. In particular, respiratory sinus arrhythmia (RSA) solely reflects parasympathetic input and is reduced in CLBP patients. Yet, it remains unknown if non-invasive brain stimulation can alter ANS balance in CLBP patients. OBJECTIVE: To evaluate if non-invasive brain stimulation modulates the ANS, we analyzed HRV metrics collected in a previously published study of transcranial alternating current stimulation (tACS) for the modulation of CLBP through enhancing alpha oscillations. We hypothesized that tACS would increase RSA. METHODS: A randomized, crossover, double-blind, sham-controlled pilot study was conducted to investigate the effects of 10Hz-tACS on metrics of ANS balance calculated from electrocardiogram (ECG). ECG data were collected for 2 mins before and after 40 mins of 10Hz-tACS or sham stimulation. RESULTS: There were no significant changes in RSA or other frequency-domain HRV components from 10Hz-tACS. However, exploratory time-domain HRV analyses revealed a significant increase in the standard deviation of normal intervals between R-peaks (SDNN), a measure of ANS balance, for 10Hz-tACS relative to sham. CONCLUSION: Although tACS did not significantly increase RSA, we found in an exploratory analysis that tACS modulated an integrated HRV measure of both ANS branches. These findings support the further study of how the ANS and alpha oscillations interact and are modulated by tACS. CLINICALTRIALSGOV: Transcranial Alternating Current Stimulation in Back Pain - Pilot Study, NCT03243084.

Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD).

Major depressive disorder (MDD) is one of the most common psychiatric disorders, but pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Here we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) at 10 Hz, which we hypothesized would improve clinical symptoms by renormalizing alpha oscillations in the left dorsolateral prefrontal cortex (dlPFC). To this end, 32 participants with MDD were randomized to 1 of 3 arms and received daily 40 min sessions of either 10 Hz-tACS, 40 Hz-tACS, or active sham stimulation for 5 consecutive days. Symptom improvement was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary outcome. High-density electroencephalograms (hdEEGs) were recorded to measure changes in alpha oscillations as the secondary outcome. For the primary outcome, we did not observe a significant interaction between treatment condition (10 Hz-tACS, 40 Hz-tACS, sham) and session (baseline to 4 weeks after completion of treatment); however, exploratory analyses show that 2 weeks after completion of the intervention, the 10 Hz-tACS group had more responders (MADRS and HDRS) compared with 40 Hz-tACS and sham groups (n = 30, p = 0.026). Concurrently, we found a significant reduction in alpha power over the left frontal regions in EEG after completion of the intervention for the group that received per-protocol 10 Hz-tACS (n = 26, p < 0.05). Our data suggest that targeting oscillations with tACS has potential as a therapeutic intervention for treatment of MDD.

Randomized trial of transcranial alternating current stimulation for treatment of auditory hallucinations in schizophrenia.

BACKGROUND: Approximately 30% of patients with schizophrenia experience auditory hallucinations that are refractory to antipsychotic medications. Here, we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) that we hypothesized would improve auditory hallucination symptoms by enhancing synchronization between the frontal and temporo-parietal areas of the left hemisphere. METHOD: 22 participants were randomized to one of three arms and received twice daily, 20 min sessions of sham, 10 Hz 2 mA peak-to-peak tACS, or 2 mA tDCS over the course of 5 consecutive days. Symptom improvement was assessed using the Auditory Hallucination Rating Scale (AHRS) as the primary outcome measure. The Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia (BACS) were secondary outcomes. RESULTS: Primary and secondary behavioral outcomes were not significantly different between the three arms. However, effect size analyses show that tACS had the greatest effect based on the auditory hallucinations scale for the week of stimulation (1.31 for tACS; 1.06 and 0.17, for sham and tDCS, respectively). Effect size analysis for the secondary outcomes revealed heterogeneous results across measures and stimulation conditions. CONCLUSIONS: To our knowledge, this is the first clinical trial of tACS for the treatment of symptoms of a psychiatric condition. Further studies with larger sample sizes are needed to better understand the effect of tACS on auditory hallucinations.