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.

Importance of test-retest reliability for promoting fMRI based screening and interventions in major depressive disorder.

Proponents of personalized medicine have promoted neuroimaging in three areas of clinical application for major depression: clinical prediction, outcome evaluation, and treatment, via neurofeedback. Whereas psychometric considerations such as test-retest reliability are basic precursors to clinical adoption for most clinical instruments, we show, in this article, that basic psychometrics have not been regularly attended to in fMRI of depression. For instance, no fMRI neurofeedback study has included measures of test-retest reliability, despite the implicit assumption that brain signals are stable enough to train. We consider several factors that could be useful to aid clinical translation, including (1) attending to how the BOLD response is parameterized, (2) identifying and promoting regions or voxels with stronger psychometric properties, (3) accounting for within-individual changes (e.g., in symptomatology) across time, and (4) focusing on tasks and clinical populations that are relevant for the intended clinical application. We apply these principles to published prognostic and neurofeedback data sets. The broad implication of this work is that attention to psychometrics is important for clinical adoption of mechanistic assessment, is feasible, and may improve the underlying science.

Gender identity better than sex explains individual differences in episodic and semantic components of autobiographical memory: An fMRI study.

Advances in the literature of sex-related differences in autobiographical memory increasingly tend to highlight the importance of psychosocial factors such as gender identity, which may explain these differences better than sex as a biological factor. To date, however, none of these behavioral studies have investigated this hypothesis using neuroimaging. The purpose of this fMRI study is to examine for the first time sex and gender identity-related differences in episodic and semantic autobiographical memory in healthy participants (M=19, W=18). No sex-related differences were found; however, sex-related effects of masculine and feminine gender identity were identified in men and women independently. These results confirm the hypothesis that differences in episodic and semantic autobiographical memory are best explained by gender but are an interaction between biological sex and gender identity and extend these findings to the field of neuroimaging. We discuss the importance of hormonal factors to be taken into consideration in the future.

Gender identity better than sex explains individual differences in episodic and semantic components of autobiographical memory and future thinking.

A recently tested hypothesis suggests that inter-individual differences in episodic autobiographical memory (EAM) are better explained by individual identification of typical features of a gender identity than by sex. This study aimed to test this hypothesis by investigating sex and gender related differences not only in EAM but also during retrieval of more abstract self-knowledge (i.e., semantic autobiographical memory, SAM, and conceptual self, CS), and considering past and future perspectives. No sex-related differences were identified, but regardless of the sex, feminine gender identity was associated with clear differences in emotional aspects that were expressed in both episodic and more abstract forms of AM, and in the past and future perspectives, while masculine gender identity was associated with limited effects. In conclusion, our results support the hypothesis that inter-individual differences in AM are better explained by gender identity than by sex, extending this assumption to both episodic and semantic forms of AM and future thinking.

Sex Differences in the Neural Correlates of Specific and General Autobiographical Memory.

Autobiographical memory (AM) underlies the formation and temporal continuity over time of personal identity. The few studies on sex-related differences in AM suggest that men and women adopt different cognitive or emotional strategies when retrieving AMs. However, none of the previous works has taken into account the distinction between episodic autobiographical memory (EAM), consisting in the retrieval of specific events by means of mental time travel, and semantic autobiographical memory (SAM), which stores general personal events. Thus, it remains unclear whether differences in these strategies depend on the nature of the memory content to be retrieved. In the present study we employed functional MRI to examine brain activity underlying potential sex differences in EAM and SAM retrieval focusing on the differences in strategies related to the emotional aspects of memories while controlling for basic cognitive strategies. On the behavioral level, there was no significant sex difference in memory performances or subjective feature ratings of either type of AM. Activations common to men and women during AM retrieval were observed in a typical bilateral network comprising medial and lateral temporal regions, precuneus, occipital cortex as well as prefrontal cortex. Contrast analyses revealed that there was no difference between men and women in the EAM condition. In the SAM condition, women showed an increased activity, compared to men, in the dorsal anterior cingulate cortex, inferior parietal and precentral gyrus. Overall, these findings suggest that differential neural activations reflect sex-specific strategies related to emotional aspects of AMs, particularly regarding SAM. We propose that this pattern of activation during SAM retrieval reflects the cognitive cost linked to emotion regulation strategies recruited by women compared to men. These sex-related differences have interesting implications for understanding psychiatric disorders with differential sex prevalence and in which one of key features is overgenerality in AM.

Self-reference recollection effect and its relation to theory of mind: An investigation in healthy controls and schizophrenia.

This study explores the links between the Self-Reference Effect (SRE) and Theory of Mind (ToM) in typical adults and patients with schizophrenia. Participants were assessed with a self-referential memory paradigm investigating the mnemonic effect of both semantic and episodic self-reference with a recognition task associated with the Remember/Know/Guess paradigm. They also completed a self-descriptive scale and shortened versions of the attribution of intention task and the reading the mind in the eyes test as measures of cognitive and affective ToM respectively. Unlike typical adults, the patients showed no semantic SRRE (correct recognition associated with remembering), and there was no episodic SRRE and no SRE (on the number of correct recognitions) in either group. Semantic SRRE was correlated with the affective ToM in patients and with the positivity of the self-concept in the healthy group. We discuss that patients and typical adults use different strategies during self and other-reflection.

[Does the brain have a gender? A literature review in younger and older adults]. / Le cerveau a-t-il un genre? Revue de la littérature chez les adultes jeunes et âgés.

There are no longer doubts about the existence of gender's differences in cognition, only their origin is still controversial. The literature provides evidence of differences in cognitive performance and brain activation patterns and links these differences in men and women with biological, social and psychological measures. To date, the favored hypothesis explaining these differences is the cognitive style hypothesis according to which women and men would favor different strategies while resolving some tasks. Some of these tasks are autobiographical memory tasks, which are also the most sensitive to the effects of age but very few studies had explored the impact of aging on the differences in cognition between men and women. We discuss the importance of such studies about the gender's differences in aging. A better understanding of gender differences in cognition in pathological aging as in health would provide the opportunity to offer a more personalized care.