Kymberly D. Young

Real-time FMRI neurofeedback training of amygdala activity in patients with major depressive disorder.

Background Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD), and normalize with remission. Real-time functional MRI neurofeedback (rtfMRI-nf) offers a non-invasive method to modulate this regional activity. We examined whether depressed participants can use rtfMRI-nf to enhance amygdala responses to positive autobiographical memories, and whether this ability alters symptom severity. Methods Unmedicated MDD subjects were assigned to receive rtfMRI-nf from either left amygdala (LA; experimental group, n = 14) or the horizontal segment of the intraparietal sulcus (HIPS; control group, n = 7) and instructed to contemplate happy autobiographical memories (AMs) to raise the level of a bar representing the hemodynamic signal from the target region to a target level. This 40s Happy condition alternated with 40s blocks of rest and counting backwards. A final Transfer run without neurofeedback information was included. Results Participants in the experimental group upregulated their amygdala responses during positive AM recall. Significant pre-post scan decreases in anxiety ratings and increases in happiness ratings were evident in the experimental versus control group. A whole brain analysis showed that during the transfer run, participants in the experimental group had increased activity compared to the control group in left superior temporal gyrus and temporal polar cortex, and right thalamus. Conclusions Using rtfMRI-nf from the left amygdala during recall of positive AMs, depressed subjects were able to self-regulate their amygdala response, resulting in improved mood. Results from this proof-of-concept study suggest that rtfMRI-nf training with positive AM recall holds potential as a novel therapeutic approach in the treatment of depression.

Functional anatomy of autobiographical memory recall deficits in depression.

Background Major depressive disorder (MDD) is associated with deficits in recalling specific autobiographical memories (AMs). Extensive research has examined the functional anatomical correlates of AM in healthy humans, but no studies have examined the neurophysiological underpinnings of AM deficits in MDD. The goal of the present study was to examine the differences in the hemodynamic response between patients with MDD and controls while they engage in AM recall. Method Participants (12 unmedicated MDD patients; 14 controls) underwent functional magnetic resonance imaging (fMRI) scanning while recalling AMs in response to positive, negative and neutral cue words. The hemodynamic response during memory recall versus performing subtraction problems was compared between MDD patients and controls. Additionally, a parametric linear analysis examined which regions correlated with increasing arousal ratings. Results Behavioral results showed that relative to controls, the patients with MDD had fewer specific (p=0.013), positive (p=0.030), highly arousing (p=0.036) and recent (p=0.020) AMs, and more categorical (p<0.001) AMs. The blood oxygen level-dependent (BOLD) response in the parahippocampus and hippocampus was higher for memory recall versus subtraction in controls and lower in those with MDD. Activity in the anterior insula was lower for specific AM recall versus subtraction, with the magnitude of the decrement greater in MDD patients. Activity in the anterior cingulate cortex was positively correlated with arousal ratings in controls but not in patients with MDD. Conclusions We replicated previous findings of fewer specific and more categorical AMs in patients with MDD versus controls. We found differential activity in medial temporal and prefrontal lobe structures involved in AM retrieval between MDD patients and controls as they engaged in AM recall. These neurophysiological deficits may underlie AM recall impairments seen in MDD.

Prefrontal control of the amygdala during real-time fMRI neurofeedback training of emotion regulation.

We observed in a previous study (PLoS ONE 6:e24522) that the self-regulation of amygdala activity via real-time fMRI neurofeedback (rtfMRI-nf) with positive emotion induction was associated, in healthy participants, with an enhancement in the functional connectivity between the left amygdala (LA) and six regions of the prefrontal cortex. These regions included the left rostral anterior cingulate cortex (rACC), bilateral dorsomedial prefrontal cortex (DMPFC), bilateral superior frontal gyrus (SFG), and right medial frontopolar cortex (MFPC). Together with the LA, these six prefrontal regions thus formed the functional neuroanatomical network engaged during the rtfMRI-nf procedure. Here we perform a structural vector autoregression (SVAR) analysis of the effective connectivity for this network. The SVAR analysis demonstrates that the left rACC plays an important role during the rtfMRI-nf training, modulating the LA and the other network regions. According to the analysis, the rtfMRI-nf training leads to a significant enhancement in the time-lagged effect of the left rACC on the LA, potentially consistent with the ipsilateral distribution of the monosynaptic projections between these regions. The training is also accompanied by significant increases in the instantaneous (contemporaneous) effects of the left rACC on four other regions – the bilateral DMPFC, the right MFPC, and the left SFG. The instantaneous effects of the LA on the bilateral DMPFC are also significantly enhanced. Our results are consistent with a broad literature supporting the role of the rACC in emotion processing and regulation. Our exploratory analysis provides, for the first time, insights into the causal relationships within the network of regions engaged during the rtfMRI-nf procedure targeting the amygdala. It suggests that the rACC may constitute a promising target for rtfMRI-nf training along with the amygdala in patients with affective disorders, particularly posttraumatic stress disorder (PTSD).

Behavioral and neurophysiological correlates of autobiographical memory deficits in patients with depression and individuals at high risk for depression.

IMPORTANCE Individuals with major depressive disorder (MDD) compared with healthy control subjects (HCs) consistently recall fewer specific and more categorical autobiographical memories (AMs). This effect is most pronounced for positive AMs and persists into remission. OBJECTIVES To determine whether individuals at high familial risk for developing MDD (HR group) also show an AM overgenerality bias and to use functional magnetic resonance imaging to assess differences in functional correlates of AM recall across HR, currently depressed MDD, and HC groups. DESIGN While recalling AMs in response to emotionally valenced cue words, study participants underwent functional magnetic resonance imaging. Control tasks involved generating examples from a given category and counting the number of risers in a letter string. SETTING Testing was conducted at the Laureate Institute for Brain Research, Tulsa, Oklahoma. PARTICIPANTS Participants included 16 unmedicated patients with MDD, 16 HR participants, and 16 HCs. MAIN OUTCOMES AND MEASURES Percentage of specific and categorical AMs recalled and brain regions in which hemodynamic activity changed during specific and positive AM recall compared with example generation. RESULTS Both the MDD and HR groups generated fewer specific, more categorical, and fewer positive AMs than the HC group (P ≤ .02 for all). During specific AM recall compared with example generation, neuroimaging results showed between-group differences in the left cuneus (Talairach space coordinates x, y, z = -7, -71, 18; F = 7.55), right medial frontal cortex (x, y, z = 7, 59, 12; F = 8.53), right frontal operculum (x, y, z = 23, 23, 12; F = 8.25), and right and left pregenual anterior cingulate cortex (x, y, z = 9, 37, 10 and x, y, z = -3, 43, 6; F = 6.84 and F = 7.13, respectively). CONCLUSIONS AND RELEVANCE Autobiographic memory deficits exist in HR individuals, suggesting that these impairments constitute traitlike abnormalities in MDD. We also found distinct patterns of hemodynamic activity for each group as they recalled specific AMs. Specifically, the HR and MDD groups showed differential hemodynamic activity from HCs in medial prefrontal and occipital regions, suggesting that these groups may use different self-referential focus during successful retrieval of specific memories.

Resting-State Functional Connectivity Modulation and Sustained Changes After Real-Time Functional Magnetic Resonance Imaging Neurofeedback Training in Depression

Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD) and normalize with remission. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) training with the goal of upregulating amygdala activity during recall of happy autobiographical memories (AMs) has been suggested, and recently explored, as a novel therapeutic approach that resulted in improvement in self-reported mood in depressed subjects. In this study, we assessed the possibility of sustained brain changes as well as the neuromodulatory effects of rtfMRI-nf training of the amygdala during recall of positive AMs in MDD and matched healthy subjects. MDD and healthy subjects went through one visit of rtfMRI-nf training. Subjects were assigned to receive active neurofeedback from the left amygdale (LA) or from a control region putatively not modulated by AM recall or emotion regulation, that is, the left horizontal segment of the intraparietal sulcus. To assess lasting effects of neurofeedback in MDD, the resting-state functional connectivity before and after rtfMRI-nf in 27 depressed subjects, as well as in 27 matched healthy subjects before rtfMRI-nf was measured. Results show that abnormal hypo-connectivity with LA in MDD is reversed after rtfMRI-nf training by recalling positive AMs. Although such neuromodulatory changes are observed in both MDD groups receiving feedback from respective active and control brain regions, only in the active group are larger decreases of depression severity associated with larger increases of amygdala connectivity and a significant, positive correlation is found between the connectivity changes and the days after neurofeedback. In addition, active neurofeedback training of the amygdala enhances connectivity with temporal cortical regions, including the hippocampus. These results demonstrate lasting brain changes induced by amygdala rtfMRI-nf training and suggest the importance of reinforcement learning in rehabilitating emotion regulation in depression.

Functional neuroimaging of sex differences in autobiographical memory recall.

Autobiographical memory (AM) is episodic memory for personally experienced events. The brain areas underlying AM retrieval are known to include several prefrontal cortical and medial temporal lobe regions. Sex differences in AM recall have been reported in several behavioral studies, but the functional anatomical correlates underlying such differences remain unclear. This study used fMRI to compare the neural correlates of AM recall between healthy male and female participants (n = 20 per group). AM recall in response to positive, negative, and neutral cue words was compared to a semantic memory task involving the generation of examples from a category using emotionally valenced cues. Behaviorally, females recalled more negative and fewer positive AMs compared with males, while ratings of arousal, vividness, and memory age did not differ significantly between sexes. Males and females also did not differ significantly in their performance on control tasks. Neurophysiologically, females showed increased hemodynamic activity compared to males in the dorsolateral prefrontal cortex (DLPFC), dorsal anterior insula, and precuneus while recalling specific AMs (all valences combined); increased activity in the DLPFC, transverse temporal gyrus, and precuneus while recalling positive AMs; and increased activity in the anterior cingulate cortex, precuneus, amygdala, and temporopolar cortex when recalling negative AMs. When comparing positive to negative AMs directly, males and females differed in their BOLD responses in the hippocampus and DLPFC. We propose that the differential hemodynamic changes may reflect sex‐specific cognitive strategies during recall of AMs irrespective of the phenomenological properties of those memories. Hum Brain Mapp 34:3320–3332, 2013.

Randomized Clinical Trial of Real-Time fMRI Amygdala Neurofeedback for Major Depressive Disorder: Effects on Symptoms and Autobiographical Memory Recall

OBJECTIVE Patients with depression show blunted amygdala hemodynamic activity to positive stimuli, including autobiographical memories. The authors examined the therapeutic efficacy of real-time functional MRI neurofeedback (rtfMRI-nf) training aimed at increasing the amygdalas hemodynamic response to positive memories in patients with depression. METHOD In a double-blind, placebo-controlled, randomized clinical trial, unmedicated adults with depression (N=36) were randomly assigned to receive two sessions of rtfMRI-nf either from the amygdala (N=19) or from a parietal control region not involved in emotional processing (N=17). Clinical scores and autobiographical memory performance were assessed at baseline and 1 week after the final rtfMRI-nf session. The primary outcome measure was change in score on the Montgomery-Åsberg Depression Rating Scale (MADRS), and the main analytic approach consisted of a linear mixed-model analysis. RESULTS In participants in the experimental group, the hemodynamic response in the amygdala increased relative to their own baseline and to the control group. Twelve participants in the amygdala rtfMRI-nf group, compared with only two in the control group, had a >50% decrease in MADRS score. Six participants in the experimental group, compared with one in the control group, met conventional criteria for remission at study end, resulting in a number needed to treat of 4. In participants receiving amygdala rtfMRI-nf, the percent of positive specific memories recalled increased relative to baseline and to the control group. CONCLUSIONS rtfMRI-nf training to increase the amygdala hemodynamic response to positive memories significantly decreased depressive symptoms and increased the percent of specific memories recalled on an autobiographical memory test. These data support a role of the amygdala in recovery from depression.

Amygdala Activity During Autobiographical Memory Recall in Depressed and Vulnerable Individuals: Association With Symptom Severity and Autobiographical Overgenerality

OBJECTIVE In healthy individuals, autobiographical memory recall is biased toward positive and away from negative events, while the opposite is found in depressed individuals. This study examined amygdala activity during autobiographical memory recall as a putative mechanism underlying biased memory recall and depressive symptoms in currently depressed adults and two vulnerable populations: individuals remitted from depression and otherwise healthy individuals at high familial risk of developing depression. Identification of such vulnerability factors could enable interception strategies that prevent depression onset. METHOD Sixty healthy control subjects, 45 unmedicated currently depressed individuals, 25 unmedicated remitted depressed individuals, and 30 individuals at high familial risk of developing depression underwent functional MRI while recalling autobiographical memories in response to emotionally valenced cue words. Amygdala reactivity and connectivity with anatomically defined amygdala regions were examined. RESULTS During positive recall, depressed participants exhibited significantly decreased left amygdala activity and decreased connectivity with regions of the salience network compared with the other groups. During negative recall, control subjects had significantly decreased left amygdala activity compared with the other groups, while depressed participants exhibited increased amygdala connectivity with the salience network. In depressed participants, left amygdala activity during positive recall correlated significantly with depression severity (r values >-0.38) and percent of positive specific memories recalled (r values >0.59). CONCLUSIONS The results suggest that left amygdala hyperactivity during negative autobiographical recall is a trait-like marker of depression, as both vulnerable groups showed activity similar to the depressed group, while amygdala hypoactivity during positive autobiographical recall is a state marker of depression manifesting in active disease. Treatments targeting amygdala hypoactivity and blunted salience during positive autobiographical recall could exert antidepressant effects.

Neurophysiological correlates of autobiographical memory deficits in currently and formerly depressed subjects.

BACKGROUND Individuals with major depressive disorder (MDD) tested in either the depressed (dMDD) or remitted phase (rMDD) recall fewer specific and more categorical autobiographical memories (AMs) compared to healthy controls (HCs). The current study aimed to replicate findings of AM overgenerality in dMDD or rMDD, and to elucidate differences in neurophysiological correlates of AM recall between these MDD samples and HCs. METHOD Unmedicated participants who met criteria for the dMDD, rMDD or HC groups (n = 16/group) underwent functional magnetic resonance imaging (fMRI) while recalling AMs in response to emotionally valenced cue words. Control tasks involved generating examples from an assigned semantic category and counting the number of risers in a letter string. RESULTS The results showed fewer specific and more categorical AMs in both MDD samples versus HCs; dMDDs and rMDDs performed similarly on these measures. The neuroimaging results showed differences between groups in the dorsomedial prefrontal cortex (DMPFC), lateral orbitofrontal cortex (OFC), anterior insula, inferior temporal gyrus and parahippocampus/hippocampus during specific AM recall versus example generation. During specific AM recall cued by positively valenced words, group differences were evident in the DMPFC, middle temporal gyrus, parahippocampus/hippocampus and occipital gyrus, whereas differences during specific AM recall cued by negatively valenced words were evident in the DMPFC, superior temporal gyrus and hippocampus. CONCLUSIONS AM deficits exist in rMDDs, suggesting that these impairments constitute trait-like abnormalities in MDD. We also found distinct patterns of hemodynamic activity for each group as they recalled specific AMs, raising the possibility that each group used a partly unique strategy for self-referential focus during successful retrieval of specific memories.

Dose-Dependent Effects of Hydrocortisone Infusion on Autobiographical Memory Recall

The glucocorticoid hormone cortisol has been shown to impair episodic memory performance. The present study examined the effect of two doses of hydrocortisone (synthetic cortisol) administration on autobiographical memory retrieval. Healthy volunteers (n = 66) were studied on two separate visits, during which they received placebo and either moderate-dose (0.15 mg/kg IV; n = 33) or high-dose (0.45 mg/kg IV; n = 33) hydrocortisone infusion. From 75 to 150 min post-infusion subjects performed an Autobiographical Memory Test and the California Verbal Learning Test (CVLT). The high-dose hydrocortisone administration reduced the percent of specific memories recalled (p = .04), increased the percent of categorical (nonspecific) memories recalled (p < .001), and slowed response times for categorical memories (p < .001), compared with placebo performance. Under moderate-dose hydrocortisone the autobiographical memory performance did not change significantly with respect to percent of specific or categorical memories recalled or reaction times. Performance on the CVLT was not affected by hydrocortisone. These findings suggest that cortisol affects accessibility of autobiographical memories in a dose-dependent manner. Specifically, administration of hydrocortisone at doses analogous to those achieved under severe psychosocial stress impaired the specificity and speed of retrieval of autobiographical memories.