Amygdala real-time fMRI neurofeedback upregulation in treatment resistant depression: Proof of concept and dose determination.

Previous work has shown that adults suffering from major depressive disorder (MDD) can increase their amygdala reactivity while recalling positive memories via real-time neurofeedback (rt-fMRI-nf) training, which is associated with reduction in depressive symptoms. This study investigated if this intervention could also be considered for patients suffering from MDD who do not respond to standard psychological and pharmacological interventions, i.e., treatment resistant (TR-MDD). 15 participants received 5 neurofeedback sessions. Outcome measures were depressive symptoms assessed by BDI scores up to 12 weeks following acute intervention, and amygdala activity changes from initial baseline to final transfer run during neurofeedback sessions (neurofeedback success). Participants succeeded in increasing their amygdala activity. A main effect of visit on BDI scores indicated a significant reduction in depressive symptomatology. Percent signal change in the amygdala showed a learning curve during the first session only. Neurofeedback success computed by session was significantly positive only during the second session. When examining the baseline amygdala response, baseline activity stabilized/asymptoted by session 3. This proof-of-concept study suggests that only two neurofeedback sessions are necessary to enable those patients to upregulate their amygdala activity, warranting a future RCT. Over the course of the rtfMRI-nf intervention, participants also reported reduced depressive symptomatology. Clinical trial registration number: NCT03428828 on ClinicalTrials.gov.

Recall of Autobiographical Memories Following Odor vs Verbal Cues Among Adults With Major Depressive Disorder.

Importance: Major depressive disorder (MDD) is associated with deficits in autobiographical memory (AM) recall, which is thought to stem from disruptions in effortful recall. Understanding whether these deficits are mitigated when recall is stimulated more directly, such as by odor cues, could inform therapeutic interventions for MDD. Objective: To evaluate whether deficits in specific AM recall in MDD are mitigated when odor cues vs word cues are used to prompt memory. Design, Setting, and Participants: This cross-sectional study assessed recall of specific AMs in response to both odor cues and word cues (in a randomized, counterbalanced order) in a repeated measures design. Data were collected between September 2021 and November 2022. The study took place at the University of Pittsburgh School of Medicine in Pennsylvania and included adults with a primary diagnosis of MDD, according to the Mini International Neuropsychiatric Interview. Data were analyzed from January to June 2023. Main Outcomes and Measures: The primary outcome measure was the percentage of specific AMs recalled in response to odor-cued memories vs word-cued memories. Additional outcome measures included ratings of arousal, vividness, repetition, and recall response time for odor-cued memories vs word-cued memories. Results: Thirty-two adults (mean [SD] age, 30.0 [10.1] years; 26 [81.3%] female; 6 [18.8%] male) with a primary diagnosis of MDD completed the study. Participants recalled more specific AMs for odor cues than word cues (mean [SD], 68.4% [20.4%] vs 52.1% [23.3%]; Cohen d, 0.78; P < .001). Additionally, odor-cued recall was rated more arousing (mean [SD], 3.0 [0.8] vs 2.6 [0.7]; Cohen d, 1.28; P < .001) and vivid (mean [SD], 3.3 [0.7] vs 3.0 [0.7]; Cohen d, 0.67; P < .001), and was slower than word-cued recall (mean [SD], 14.5 [3.6] vs 8.9 [3.4] seconds; Cohen d, 1.18; P < .001). When compared with the population mean for word cues in healthy controls (80%), participants recalled fewer specific memories in response to words (Cohen d, 1.18; P < .001), supporting the presence of overgenerality. Notably, the percentage of specific memories recalled in response to odor cues did not differ from the healthy control population mean (Cohen d, 0.26; P = .15). Conclusions and Relevance: In this cross-sectional study, adults with MDD recalled more specific AMs in response to odor cues compared with word cues. This study suggests that AM deficits may only be observed when verbal cues are used and provides a potential new method for increasing specific AM recall in patients with MDD.

Enhanced efficacy of CBT following augmentation with amygdala rtfMRI neurofeedback in depression.

BACKGROUND: Despite cognitive behavioral therapy (CBT) being a standard treatment in major depressive disorder (MDD), nearly half of patients do not respond. As one of the predictors of CBT's efficacy is amygdala reactivity to positive information, which is often decreased in MDD, we explored whether real-time fMRI neurofeedback (rtfMRI-nf) training to increase amygdala responses during positive memory recall prior CBT would enhance its efficacy. METHODS: In a double-blind, placebo controlled, randomized clinical trial, 35 adults with MDD received two sessions of rtfMRI-nf training to increase their amygdala (experimental group, n = 16) or parietal (control group, n = 19) responses during positive memory neurofeedback prior to receiving 10 CBT sessions. Depressive symptomatology was monitored between the rtfMRI sessions, the first three, 9th and 10th sessions of CBT and at 6 months and 1 year follow-up. RESULTS: Participants in the experimental group showed decreased depressive symptomatology and higher remission rates at 6 months and 1 year follow-up than the control group. Analysis of CBT content highlighted that participants in the experimental group focused more on positive thinking and behaviors than the control group. LIMITATIONS: The study was relatively small and not sufficiently powered to detect small effects. CONCLUSIONS: CBT, when combined with amygdala neurofeedback, results in sustained clinical changes and leads to long-lasting clinical improvement, potentially by increasing focus on positive memories and cognitions.

Real-time functional magnetic resonance imaging neurofeedback training of amygdala upregulation increases affective flexibility in depression.

BACKGROUND: Decreased affective flexibility is associated with depression symptoms, and it has been suggested that common interventions may target this mechanism. To explore this hypothesis, we evaluated whether real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training to increase the amygdala responses during positive memory recall resulted in both symptom improvements, as has been observed previously, and flexibility to decrease amygdala reactivity in response to a cognitive task among patients with major depressive disorder (MDD). METHODS: In a double-blind, placebo-controlled, randomized clinical trial, adults with MDD received 2 sessions of rtfMRI-nf training to increase their amygdala (experimental group) or parietal (control group) responses during positive autobiographical memory recall. We evaluated signal changes in the amygdala during both the positive memory neurofeedback and a subsequent counting condition. RESULTS: We included 38 adults with MDD, including 16 in the experimental group and 22 in the control group. In the experimental group, amygdala activity increased (t > 2.01, df < 27, p < 0.05, d > 0.5) and depressive symptoms decreased (-8.57, 95 % confidence interval [CI] -15.12 to -2.59; t 13 = -3.06, p = 0.009, d = 1). Amygdala activity during the count condition decreased after rtfMRI-nf (-0.16, 95 % CI -0.23 to -0.09; t 396 = 4.73, p < 0.001, d = 0.48) and was correlated with decreased depression scores (r = 0.46, p = 0.01). We replicated previous results and extended them to show decreased amygdala reactivity to a cognitive task during which no neurofeedback was provided. LIMITATIONS: The count condition was reported by participants as negative, but emotionality or accuracy during this condition was not assessed. CONCLUSION: These results suggest that nominally targeting unidimensional change in neural mechanisms could have implications for bidirectional control, increasing the likely reach and explanatory framework for how common depression interventions work.Trial registration: ClinicalTrials.gov NCT02709161.