The Effects of Amygdalar Size Normalization on Group Analysis in Late-Life Depression

Structural MRI has been utilized in numerous ways to measure morphologic characteristics of subcortical brain regions. Volumetric analysis is frequently used to quantify the size of brain structures to ultimately compare size differences between individuals. In order to make such comparisons, inter-subject variability in brain and/or head size must be taken into consideration. A heterogeneous set of methods are commonly used to normalize regional volume by brain and/or head size yielding inconsistent findings making it diffcult to interpret and compare results from published volumetric studies. This study investigated the effect that various volume normalization methodologies might have on group analysis. Specifically, the amygdalae were the regions of interest in elderly, healthy and depressed individuals. Normalization methods investigated included spatial transformations, brain and head volume, and tissue volume techniques. Group analyses were conducted with independent t-tests by dividing amygdalar volumes by various volume measures, as well as with univariate analysis of covariance (ANCOVA) analyses by using amygdalar volumes as dependent variables and various volume measures as covariates. Repeated measures ANOVA was performed to assess the effect of each normalization procedure. Results indicate that volumetric differences between groups varied based on the normalization method utilized, which may explain, in part, the discrepancy found in amygdalar volumetric studies. We believe the findings of this study are extensible to other brain regions and demographics, and thus, investigators should carefully consider the normalization methods utilized in volumetric studies to properly interpret the results and conclusions

Data-Driven Subgroups in Depression Derived from Directed Functional Connectivity Paths at Rest

Depressed patients show abnormalities in brain connectivity at rest, including hyperconnectivity within the default mode network (DMN). However, there is well-known heterogeneity in the clinical presentation of depression that is overlooked when averaging connectivity data. We used data-driven parsing of neural connectivity to reveal subgroups among 80 depressed patients completing resting state fMRI. Directed functional connectivity paths (eg, region A influences region B) within a depression-relevant network were characterized using Group Iterative Multiple Model Estimation, a method shown to accurately recover the direction and presence of connectivity paths in individual participants. Individuals were clustered using community detection on neural connectivity estimates. Subgroups were compared on network features and on clinical and biological/demographic characteristics that influence depression prognosis. Two subgroups emerged. Subgroup A, containing 71% of the patients, showed a typical pattern of connectivity across DMN nodes, as previously reported in depressed patients on average. Subgroup B exhibited an atypical connectivity profile lacking DMN connectivity, with increased dorsal anterior cingulate-driven connectivity paths. Subgroup B members had an over-representation of females (87% of Subgroup B vs 65% of Subgroup A; χ2=3.89, p=0.049), comorbid anxiety diagnoses (42.9% of Subgroup B vs 17.5% of Subgroup A; χ2=5.34, p=.02), and highly recurrent depression (63.2% of Subgroup B vs 31.8% of Subgroup A; χ2=5.38, p=.02). Neural connectivity-based categorization revealed an atypical pattern of connectivity in a depressed patient subset that would be overlooked in group comparisons of depressed and healthy participants, and tracks with clinically relevant phenotypes including anxious depression and episodic recurrence. Data-driven parsing suggests heterogeneous substrates of depression; ideally, future work building on these findings will inform personalized treatment

ORIGINAL ARTICLES Can’t Shake that Feeling: Event-Related fMRI Assessment of Sustained Amygdala Activity in Response to Emotional Information in Depressed Individuals

individuals engage in prolonged elaborative processing of emotional information. A computational neural network model of emotional information processing suggests this process involves sustained amygdala activity in response to processing negative features of information. This study examined whether brain activity in response to emotional stimuli was sustained in depressed individuals, even following subsequent distracting stimuli. Methods: Seven depressed and 10 never-depressed individuals were studied using event-related functional magnetic resonance imaging during alternating 15-sec emotional processing (valence identification) and nonemotional processing (Sternberg memory) trials. Amygdala regions were traced on high-resolution structural scans and coregistered to the functional data. The time course of activity in these areas during emotional and nonemotional processing trials was examined. Results: During emotional processing trials, never-depressed individuals displayed amygdalar responses to all stimuli, which decayed within 10 sec. In contrast, depressed individuals displayed sustained amygdala responses to negative words that lasted throughout the following nonemotional processing trials (25 sec later). The difference in sustained amygdala activity to negative and positive words was moderately related to self-reported rumination. Conclusions: Results suggest that depression is associated with sustained activity in brain areas responsible for coding emotional features. Biol Psychiatry 2002;51

Low Cost MR Compatible Haptic Stimulation with Application to fMRI Neurofeedback

The most common feedback displays in the fMRI environment are visual, e.g., in which participants try to increase or decrease the level of a thermometer. However, haptic feedback is increasingly valued in computer interaction tasks, particularly for real-time fMRI feedback. fMRI-neurofeedback is a clinical intervention that has not yet taken advantage of this trend. Here we describe a low-cost, user-friendly, MR-compatible system that can provide graded haptic vibrotactile stimulation in an initial application to fMRI neurofeedback. We also present a feasibility demonstration showing that we could successfully set up the system and obtain data in the context of a neurofeedback paradigm. We conclude that vibrotactile stimulation using this low-cost system is a viable method of feedback presentation, and encourage neurofeedback researchers to incorporate this type of feedback into their studies

Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood

There is well-known heterogeneity in affective mechanisms in depression that may extend to positive affect. We used data-driven parsing of neural connectivity to reveal subgroups present across depressed and healthy individuals during positive processing, informing targets for mechanistic intervention

Altered Gamma-Band Activity in Recovered Depression

Background: The neurophysiological mechanisms of cognitive reactivity, the primary vulnerability factor of major depressive disorder (MDD) recurrence, remain unclear in individuals with recovered MDD (rMDD). Because gamma-band responses (GBRs) can be used to measure cognitive processing, they may also be useful for elucidating the mechanisms underlying cognitive reactivity. Identifying these mechanisms may permit the development of an index for predicting and preempting MDD recurrence. Here, to identify the neurophysiological mechanisms of cognitive reactivity, we examined the characteristics of the GBRs evoked/induced by emotional words in participants with and without rMDD after inducing a negative mood. Methods: Thirty-three healthy control participants and 18 participants with rMDD completed a lexical emotion identification task during electroencephalography along with assessments of cognitive reactivity after negative mood induction. Results: No between-group differences were identified for the task reaction times; however, the rMDD group had significantly higher cognitive reactivity scores than did the control group. Furthermore, the power of late GBRs to positive words was significantly greater in the rMDD group, with the greater power of late GBRs being related to higher cognitive reactivity. Limitations: Considering the population studied, our findings cannot be completely generalized to populations other than adolescents, people with rMDD, and those without a history of co-morbid disorders and early life stress. Conclusions: Our findings indicate that the dysfunction of neural circuits related to higher-order processes like memory and attention might underlie cognitive reactivity. Altered late GBRs to positive information may be persistent biomarkers of the depression recurrence risk

Pediatric functional magnetic resonance neuroimaging: tactics for encouraging task compliance

<p>Abstract</p> <p>Background</p> <p>Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population.</p> <p>Method</p> <p>In this preliminary investigation, we describe the development and application of an approach for increasing the number of fMRI tasks children complete during neuroimaging. Twenty-eight healthy children ages 9-13 years participated. Generalization of the approach was examined in additional fMRI and event-related potential investigations with children at risk for depression, children with anxiety and children with depression (N = 120). Essential features of the approach include a preference assessment for identifying multiple individualized rewards, increasing reinforcement rates during imaging by pairing tasks with chosen rewards and presenting a visual 'road map' listing tasks, rewards and current progress.</p> <p>Results</p> <p>Our results showing a higher percentage of fMRI task completion by healthy children provides proof of concept data for the recommended tactics. Additional support was provided by results showing our approach generalized to several additional fMRI and event-related potential investigations and clinical populations.</p> <p>Discussion</p> <p>We proposed that some forms of task noncompliance may emerge from less than optimal reward protocols. While our findings may not directly support the effectiveness of the multiple reward compliance protocol, increased attention to how rewards are selected and delivered may aid cooperation with completing fMRI tasks</p> <p>Conclusion</p> <p>The proposed approach contributes to the pediatric neuroimaging literature by providing a useful way to conceptualize and measure task noncompliance and by providing simple cost effective tactics for improving the effectiveness of common reward-based protocols.</p

Increased amygdala reactivity following early life stress : a potential resilience enhancer role

Background: Amygdala hyper-reactivity is sometimes assumed to be a vulnerability factor that predates depression; however, in healthy people, who experience early life stress but do not become depressed, it may represent a resilience mechanism. We aimed to test these hypothesis examining whether increased amygdala activity in association with a history of early life stress (ELS) was negatively or positively associated with depressive symptoms and impact of negative life event stress in never-depressed adults. Methods: Twenty-four healthy participants completed an individually tailored negative mood induction task during functional magnetic resonance imaging (fMRI) assessment along with evaluation of ELS. Results: Mood change and amygdala reactivity were increased in never-depressed participants who reported ELS compared to participants who reported no ELS. Yet, increased amygdala reactivity lowered effects of ELS on depressive symptoms and negative life events stress. Amygdala reactivity also had positive functional connectivity with the bilateral DLPFC, motor cortex and striatum in people with ELS during sad memory recall. Conclusions: Increased amygdala activity in those with ELS was associated with decreased symptoms and increased neural features, consistent with emotion regulation, suggesting that preservation of robust amygdala reactions may reflect a stress buffering or resilience enhancing factor against depression and negative stressful events