Functional Magnetic Resonance Imaging of the Amygdala and Subregions at 3 Tesla: A Scoping Review.

The amygdalae are a pair of small brain structures, each of which is composed of three main subregions and whose function is implicated in neuropsychiatric conditions. Functional Magnetic Resonance Imaging (fMRI) has been utilized extensively in investigation of amygdala activation and functional connectivity (FC) with most clinical research sites now utilizing 3 Tesla (3T) MR systems. However, accurate imaging and analysis remains challenging not just due to the small size of the amygdala, but also its location deep in the temporal lobe. Selection of imaging parameters can significantly impact data quality with implications for the accuracy of study results and validity of conclusions. Wide variation exists in acquisition protocols with spatial resolution of some protocols suboptimal for accurate assessment of the amygdala as a whole, and for measuring activation and FC of the three main subregions, each of which contains multiple nuclei with specialized roles. The primary objective of this scoping review is to provide a broad overview of 3T fMRI protocols in use to image the activation and FC of the amygdala with particular reference to spatial resolution. The secondary objective is to provide context for a discussion culminating in recommendations for a standardized protocol for imaging activation of the amygdala and its subregions. As the advantages of big data and protocol harmonization in imaging become more apparent so, too, do the disadvantages of data heterogeneity. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Functional connectivity of amygdala subnuclei in PTSD: a narrative review.

While the amygdala is often implicated in the neurobiology of posttraumatic stress disorder (PTSD), the pattern of results remains mixed. One reason for this may be the heterogeneity of amygdala subnuclei and their functional connections. This review used PRISMA guidelines to synthesize research exploring the functional connectivity of three primary amygdala subnuclei, basolateral (BLA), centromedial (CMA), and superficial nuclei (SFA), in PTSD (N = 331) relative to trauma-exposed (N = 155) and non-trauma-exposed controls (N = 210). Although studies were limited (N = 11), preliminary evidence suggests that in PTSD compared to trauma-exposed controls, the BLA shows greater connectivity with the dorsal anterior cingulate, an area involved in salience detection. In PTSD compared to non-trauma-exposed controls, the BLA shows greater connectivity with the middle frontal gyrus, an area involved in attention. No other connections were replicated across studies. A secondary aim of this review was to outline the limitations of this field to better shape future research. Importantly, the results from this review indicate the need to consider potential mediators of amygdala subnuclei connectivity, such as trauma type and sex, when conducting such studies. They also highlight the need to be aware of the limited inferences we can make with such small samples that investigate small subcortical structures on low field strength magnetic resonance imaging scanners. Collectively, this review demonstrates the importance of exploring the differential connectivity of amygdala subnuclei to understand the pathophysiology of PTSD and stresses the need for future research to harness the strength of ultra-high field imaging to gain a more sensitive picture of the neural connectivity underlying PTSD.

A comparison of the functional connectome in mild traumatic brain injury and post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) often co-occur in the context of threat to one's life. These conditions also have an overlapping symptomatology and include symptoms of anxiety, poor concentration and memory problems. A major challenge has been articulating the underlying neurobiology of these overlapping conditions. The primary aim of this study was to compare intrinsic functional connectivity between mTBI (without PTSD) and PTSD (without mTBI). The study included functional MRI data from 176 participants: 42 participants with mTBI, 67 with PTSD and a comparison group of 66 age and sex-matched healthy controls. We used network-based statistical analyses for connectome-wide comparisons of intrinsic functional connectivity between mTBI relative to PTSD and controls. Our results showed no connectivity differences between mTBI and PTSD groups. However, we did find that mTBI had significantly reduced connectivity relative to healthy controls within an extensive network of regions including default mode, executive control, visual and auditory networks. The mTBI group also displayed hyperconnectivity between dorsal and ventral attention networks and perceptual regions. The PTSD group also demonstrated abnormal connectivity within these networks relative to controls. Connectivity alterations were not associated with severity of PTSD or post-concussive symptoms in either clinical group. Taken together, the similar profiles of intrinsic connectivity alterations in these two conditions provide neural evidence that can explain, in part, the overlapping symptomatology between mTBI and PTSD.

Negative association between anterior insula activation and resilience during sustained attention: an fMRI twin study.

BACKGROUND: While previous studies have suggested that higher levels of cognitive performance may be related to greater wellbeing and resilience, little is known about the associations between neural circuits engaged by cognitive tasks and wellbeing and resilience, and whether genetics or environment contribute to these associations. METHODS: The current study consisted of 253 monozygotic and dizygotic adult twins, including a subsample of 187 early-life trauma-exposed twins, with functional Magnetic Resonance Imaging data from the TWIN-E study. Wellbeing was measured using the COMPAS-W Wellbeing Scale while resilience was defined as a higher level of positive adaptation (higher levels of wellbeing) in the presence of trauma exposure. We probed both sustained attention and working memory processes using a Continuous Performance Task in the scanner. RESULTS: We found significant negative associations between resilience and activation in the bilateral anterior insula engaged during sustained attention. Multivariate twin modelling showed that the association between resilience and the left and right insula activation was mostly driven by common genetic factors, accounting for 71% and 87% of the total phenotypic correlation between these variables, respectively. There were no significant associations between wellbeing/resilience and neural activity engaged during working memory updating. CONCLUSIONS: The findings suggest that greater resilience to trauma is associated with less activation of the anterior insula during a condition requiring sustained attention but not working memory updating. This possibly suggests a pattern of 'neural efficiency' (i.e. more efficient and/or attenuated activity) in people who may be more resilient to trauma.

Rostral Anterior Cingulate Cortex Oscillatory Power Indexes Treatment-Resistance to Multiple Therapies in Major Depressive Disorder.

INTRODUCTION: High rostral anterior cingulate cortex (rACC) activity is proposed as a nonspecific prognostic marker for treatment response in major depressive disorder, independent of treatment modality. However, other studies report a negative association between baseline high rACC activation and treatment response. Interestingly, these contradictory findings were also found when focusing on oscillatory markers, specifically rACC-theta power. An explanation could be that rACC-theta activity dynamically changes according to number of previous treatment attempts and thus is mediated by level of treatment-resistance. METHODS: Primarily, we analyzed differences in rACC- and frontal-theta activity in large national cross-sectional samples representing various levels of treatment-resistance and resistance to multimodal treatments in depressed patients (psychotherapy [n = 175], antidepressant medication [AD; n = 106], repetitive transcranial magnetic stimulation [rTMS; n = 196], and electroconvulsive therapy [ECT; n = 41]), and the respective difference between remitters and non-remitters. For exploratory purposes, we also investigated other frequency bands (delta, alpha, beta, gamma). RESULTS: rACC-theta activity was higher (p < 0.001) in the more resistant rTMS and ECT patients relative to the less resistant psychotherapy and AD patients (psychotherapy-rTMS: d = 0.315; AD-rTMS: d = 0.320; psychotherapy-ECT: d = 1.031; AD-ECT: d = 1.034), with no difference between psychotherapy and AD patients. This association was even more pronounced after controlling for frontal-theta. Post hoc analyses also yielded effects for delta, beta, and gamma bands. CONCLUSION: Our findings suggest that by factoring in degree of treatment-resistance during interpretation of the rACC-theta biomarker, its usefulness in treatment selection and prognosis could potentially be improved substantially in future real-world practice. Future research should however also investigate specificity of the theta band.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Inhibition-related modulation of salience and frontoparietal networks predicts cognitive control ability and inattention symptoms in children with ADHD.

Attention-deficit hyperactivity disorder (ADHD) is associated with pervasive impairments in attention and cognitive control. Although brain circuits underlying these impairments have been extensively investigated with resting-state fMRI, little is known about task-evoked functional brain circuits and their relation to cognitive control deficits and inattention symptoms in children with ADHD. Children with ADHD and age, gender and head motion matched typically developing (TD) children completed a Go/NoGo fMRI task. We used multivariate and dimensional analyses to investigate impairments in two core cognitive control systems: (i) cingulo-opercular "salience" network (SN) anchored in the right anterior insula, dorsal anterior cingulate cortex (rdACC), and ventrolateral prefrontal cortex (rVLPFC) and (ii) dorsal frontoparietal "central executive" (FPN) network anchored in right dorsolateral prefrontal cortex (rDLPFC) and posterior parietal cortex (rPPC). We found that multivariate patterns of task-evoked effective connectivity between brain regions in SN and FPN distinguished the ADHD and TD groups, with rDLPFC-rPPC connectivity emerging as the most distinguishing link. Task-evoked rdACC-rVLPFC connectivity was positively correlated with NoGo accuracy, and negatively correlated with severity of inattention symptoms. Brain-behavior relationships were robust against potential age, gender, and head motion confounds. Our findings highlight aberrancies in task-evoked modulation of SN and FPN connectivity in children with ADHD. Crucially, cingulo-frontal connectivity was a common locus of deficits in cognitive control and clinical measures of inattention symptoms. Our study provides insights into a parsimonious systems neuroscience model of cognitive control deficits in ADHD, and suggests specific circuit biomarkers for predicting treatment outcomes in childhood ADHD.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Common and differential neural mechanisms underlying mood disorders.

BACKGROUND: Despite homogenous clinical presentations between bipolar and unipolar disorders, there are distinct neurobiological differences. Chronicity of illness may be a factor impacting and sustaining certain neural features. The goal of this study was to investigate common and shared neural mechanisms underlying mood disorders, and possible sustained neural changes relating to illness chronicity by investigating a cohort of euthymic patients with bipolar disorder (BD), unipolar depression who had responded to treatment (treatment-sensitive depression, TSD), and a chronically treatment-resistant depressed (TRD) group. METHODS: One hundred and seventy-two participants (40 BD, 39 TSD, 40 TRD, and 53 age-gender-matched healthy controls) underwent resting-state fMRI scans. Seed-based and independent component analyses were performed to investigate group differences in resting-state connectivity between the four groups. RESULTS: All three clinical groups had significantly lower connectivity within the frontoparietal network (FPN) relative to controls. TRD and BD were significantly different from TSD (TRD, BD > TSD) but were not significantly different from each other. TRDs were also significantly different from both BD and TSD for salience network connectivity with the posterior cingulate (DMN) and the FPN with frontal pole (DMN). Additionally, the BD group exhibited greater DMN-FPN (sgACC-RDLPFC) connectivity relative to TRD, TSD, and controls, which was correlated with a previous number of depressive episodes, in the BD group only. CONCLUSIONS: BD demonstrated shared and differential connectivity features relative to symptomatic TRD and euthymic TSD groups. The increased sgACC-RDLPFC connectivity in BD and its correlation with a number of depressive episodes could be a neural feature associated with illness chronicity.

Neural processes during response inhibition in complex posttraumatic stress disorder.

BACKGROUND: A common feature of complex posttraumatic stress disorder (CPTSD) is impulsivity. Despite the importance of this characteristic in functional difficulties in CPTSD, little is known about its mechanisms. The aim of this study was to identify the distinctive neural profile of CPTSD during attempted inhibition. METHODS: The present study examined functional alterations in neural networks involved in inhibitory control across functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) paradigms in CPTSD (n = 30), PTSD (n = 40), and healthy control (n = 40) participants who completed a Go/NoGo response inhibition task during separate fMRI and EEG sessions. Brain activations were calculated during the NoGo trials relative to the baseline to evaluate response inhibition functioning. RESULTS: There was reduced bilateral thalamic activation in participants with CPTSD relative to PTSD and controls during inhibition trials, but no activation differences between PTSD and controls for this brain region. There were no differences in functional connectivity between the thalamus and other regions involved in cognitive control between groups. No differences were observed between groups on EEG responses. CONCLUSIONS: These findings provide initial evidence of aberrant functioning in the neurocircuitry of inhibitory control, involving the thalamus, in CPTSD. This evidence suggests that CPTSD is distinguished from PTSD by impaired neural processes implicated in response inhibition.

Distinct neural mechanisms of emotional processing in prolonged grief disorder.

BACKGROUND: Prolonged grief disorder (PGD) has recently been recognized as a separate psychiatric diagnosis, despite controversy over the extent to which it is distinctive from posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). METHODS: This study investigated distinctive neural processes underpinning emotion processing in participants with PGD, PTSD, and MDD with functional magnetic resonance study of 117 participants that included PGD (n = 21), PTSD (n = 45), MDD (n = 26), and bereaved controls (BC) (n = 25). Neural responses were measured across the brain while sad, happy, or neutral faces were presented at both supraliminal and subliminal levels. RESULTS: PGD had greater activation in the pregenual anterior cingulate cortex (pgACC), bilateral insula, bilateral dorsolateral prefrontal cortices and right caudate and also greater pgACC-right pallidum connectivity relative to BC during subliminal processing of happy faces. PGD was distinct relative to both PTSD and MDD groups with greater recruitment of the medial orbitofrontal cortex during supraliminal processing of sad faces. PGD were also distinct relative to MDD (but not PTSD) with greater activation in the left amygdala, caudate, and putamen during subliminal presentation of sad faces. There was no distinction between PGD, PTSD, and MDD during processing of happy faces. CONCLUSIONS: These results provide initial evidence of distinct neural profiles of PGD relative to related psychopathological conditions, and highlight activation of neural regions implicated in reward networks. This pattern of findings validates current models of PGD that emphasize the roles of yearning and appetitive processes in PGD.

The distinctive neural circuitry of complex posttraumatic stress disorder during threat processing.

BACKGROUND: There is controversy over the extent to which the new International Classification of Diseases (ICD-11) diagnosis of complex posttraumatic stress disorder (CPTSD) is distinct from posttraumatic stress disorder (PTSD). This study aimed to conduct the first investigation of distinctive neural processes during threat processing in CPTSD relative to PTSD. METHOD: This cross-sectional functional magnetic resonance study included 99 participants who met criteria for PTSD (PTSD = 32, CPTSD = 28) and 39 trauma-exposed controls. PTSD was assessed with the Clinician-Administered PTSD Scale (CAPS). CPTSD was assessed with an adapted version of the International Trauma Questionnaire. Neural responses were measured across the brain while threat or neutral faces were presented at both supraliminal and subliminal levels. RESULTS: During supraliminal presentations of threat stimuli, there was greater bilateral insula and right amygdala activation in CPTSD participants relative to PTSD. Reduced supraliminal right dorsolateral prefrontal cortex activation and increased subliminal amygdala and insula activation were observed as common dysfunction for both CPTSD and PTSD groups relative to trauma controls. There were no significant differences in terms of subliminal presentations and no differences in functional connectivity. Dissociative responses were positively associated with right insula activation (r = 0.347, p < 0.01). CONCLUSIONS: These results provide the first evidence of distinct neural profiles of CPTSD and PTSD during threat processing. The observation of increased insula and right amygdala activation in CPTSD accords with the proposal that CPTSD is distinguished from PTSD by disturbances in emotion regulation and self-concept.

Reappraisal-related neural predictors of treatment response to cognitive behavior therapy for post-traumatic stress disorder.

BACKGROUND: Although trauma-focused cognitive behavior therapy (TF-CBT) is the frontline treatment for post-traumatic stress disorder (PTSD), one-third of patients are treatment non-responders. To identify neural markers of treatment response to TF-CBT when participants are reappraising aversive material. METHODS: This study assessed PTSD patients (n = 37) prior to TF-CBT during functional magnetic brain resonance imaging (fMRI) when they reappraised or watched traumatic images. Patients then underwent nine sessions of TF-CBT, and were then assessed for symptom severity on the Clinician-Administered PTSD Scale. FMRI responses for cognitive reappraisal and emotional reactivity contrasts of traumatic images were correlated with the reduction of PTSD severity from pretreatment to post-treatment. RESULTS: Symptom improvement was associated with decreased activation of the left amygdala during reappraisal, but increased activation of bilateral amygdala and hippocampus during emotional reactivity prior to treatment. Lower connectivity of the left amygdala to the subgenual anterior cingulate cortex, pregenual anterior cingulate cortex, and right insula, and that between the left hippocampus and right amygdala were also associated with symptom improvement. CONCLUSIONS: These findings provide evidence that optimal treatment response to TF-CBT involves the capacity to engage emotional networks during emotional processing, and also to reduce the engagement of these networks when down-regulating emotions.

Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder.

Although major depressive disorder (MDD) is associated with altered functional coupling between disparate neural networks, the degree to which such measures are ameliorated by antidepressant treatment is unclear. It is also unclear whether functional connectivity can be used as a predictive biomarker of treatment response. Here, we used whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response. 163 MDD and 62 healthy individuals underwent functional MRI during pre-treatment baseline and 8-week follow-up sessions. Patients were randomized to escitalopram, sertraline or venlafaxine-XR antidepressants and assessed at follow-up for remission. Baseline measures of intrinsic functional connectivity between each pair of 333 regions were analyzed to identify pre-treatment connectomic features that distinguish remitters from non-remitters. We then interrogated these connectomic differences to determine if they changed post-treatment, distinguished patients from controls, and were modulated by medication type. Irrespective of medication type, remitters were distinguished from non-remitters by greater connectivity within the default mode network (DMN); specifically, between the DMN, fronto-parietal and somatomotor networks, the DMN and visual, limbic, auditory and ventral attention networks, and between the fronto-parietal and somatomotor networks with cingulo-opercular and dorsal attention networks. This baseline hypo-connectivity for non-remitters also distinguished them from controls and increased following treatment. In contrast, connectivity for remitters was higher than controls at baseline and also following remission, suggesting a trait-like connectomic characteristic. Increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression.

Investigating neural circuits of emotion regulation to distinguish euthymic patients with bipolar disorder and major depressive disorder.

BACKGROUND: Up to 40% of patients with bipolar disorder (BD) are initially diagnosed as having major depressive disorder (MDD), and emotional lability is a key aspect of both sets of mood disorders. However, it remains unknown whether differences in the regulation of emotions through cognitive reappraisal may serve to distinguish BD and MDD. Therefore, we examined this question in euthymic BD and MDD patients. METHODS: Thirty-eight euthymic BD, 33 euthymic MDD and 37 healthy control (HC) participants, matched for age, gender and depression severity, engaged in an emotion regulation (ER) cognitive reappraisal task during an fMRI scan were examined. Participants either reappraised (Think condition) or passively watched negative (Watch condition) or neutral (Neutral condition) pictures and rated their affect. Activation and connectivity analyses were used to examine group differences in reappraisal (Think vs Watch) and reactivity (Watch vs Neutral) conditions in ER-specific neural circuits. RESULTS: Irrespective of group, participants rated most negatively the images during the Watch condition relative to Think and Neutral conditions, and more negatively to Think relative to Neutral. Notably, BD participants exhibited reduced subgenual anterior cingulate activation (sgACC) relative to MDD during reappraisal, but exhibited greater sgACC activation relative to MDD during reactivity, whereas MDD participants elicited greater activation in right amygdala relative to BD during reactivity. We found no group differences in task-related connectivity. CONCLUSIONS: Euthymic BD and MDD patients engage differential brain regions to process and regulate emotional information. These differences could serve to distinguish the clinical groups and provide novel insights into the underlying pathophysiology of BD.

Investigating the neural basis of cognitive control dysfunction in mood disorders.

OBJECTIVES: Dysfunction of cognitive control is a feature of both bipolar disorder (BP) and major depression (MDD) and persists through to remission. However, it is unknown whether these disorders are characterized by common or distinct disruptions of cognitive control function and its neural basis. We investigated this gap in knowledge in asymptomatic BP and MDD participants, interpreted within a framework of normative function. METHODS: Participants underwent fMRI scans engaging cognitive control through a working memory task and completed a cognitive battery evaluating performance across multiple subdomains of cognitive control, including attention, impulsivity, processing speed, executive function, and memory. Analysis was performed in two stages: (i) cognitive control-related brain activation and deactivation were correlated with cognitive control performance in 115 healthy controls (HCs), then, (ii) significantly correlated regions from (i) were compared between 25 asymptomatic BP, 25 remitted MDD, and with 25 different HCs, matched for age and gender. RESULTS: Impulsivity and executive function performance were significantly worse in BP compared to both MDD and HCs. Both BP and MDD had significantly poorer memory performance compared to HCs. Greater deactivation of the medial prefrontal cortex (MPFC) during the fMRI task was associated with better executive function in healthy controls. Significantly less deactivation in this region was present in both BP and MDD compared to HCs. CONCLUSIONS: Failure to deactivate the MPFC, a key region of the default mode network, during working memory processing is a shared neural feature present in both bipolar and major depression and could be a source of common cognitive dysfunction.

Differential neural predictors of treatment response for fear and dysphoric features of posttraumatic stress disorder.

BACKGROUND: Although trauma-focused cognitive behavioral therapy (TF-CBT) is the frontline treatment for posttraumatic stress disorder (PTSD), at least one-third of patients are treatment nonresponders. This study aimed to identify neural markers of treatment response, specifically the prediction of remission of specific PTSD symptoms. METHODS: This study assessed PTSD treatment-seeking patients (n = 40) before TF-CBT during functional magnetic brain resonance imaging (fMRI) when they processed fearful, sad, happy, and neutral faces. Patients underwent nine sessions of TF-CBT and were independently assessed on the Clinician-Administered PTSD Scale (CAPS) following treatment. Treatment responders and nonresponders were compared with healthy controls (n = 40). The severity of PTSD was assessed with the CAPS. fMRI responses were calculated for each emotion face compared to neutral contrast, which were correlated with reduction in PTSD severity from pretreatment to posttreatment. Treatment response was categorized by at least 50% reduction in the severity of PTSD. RESULTS: The activation of left insula during the processing of both sad and fearful faces was associated with a greater reduction of fear but not with dysphoric symptoms after treatment. Connectivity of the left insula to the pregenual anterior cingulate cortex was associated with poorer response to treatment. Responders and controllers had similar levels of activation and connectivity and were different from nonresponders. CONCLUSIONS: Positive response to TF-CBT is predicted during emotion processing by normal levels of recruitment of neural networks implicated in emotional information. These findings suggest that distinct neural networks are predictive of PTSD fear and dysphoric symptom reduction following TF-CBT.

The role of progressive oral implant rehabilitation in mastication, cognition and oral health-related quality of life outcomes-A pilot to define the protocol.

BACKGROUND: The implications of oral rehabilitation after tooth loss require further investigation. OBJECTIVES: To conduct a pilot study to investigate: (a) changes in masticatory performance with progressive oral implant rehabilitation (POR); (b) association between POR and neurocognitive function using functional magnetic resonance imaging (fMRI); and (c) oral health-related quality of life (OHQoL) outcomes. METHODS: Four completely edentulous patients (mean age: 73 ± 1.4 years) participated. Each received new complete removable dental prostheses (RDPs) transitioned to mandibular two implant-retained RDPs (IR-RDP). Assessments were performed at 4 time points for neurocognitive skills, fMRI with functional tasks (jaw clenching, working memory and sustained attention, inhibition), masticatory performance with colour-changing gum and OHQoL. Assessments were performed with new complete RDPs (T0 as baseline data) and IR-RDPs at 1 week (T1), 6 weeks (T2) and 12 months (T3) post-insertion. Data analyses were based on intra-patient and inter-patient results. RESULTS: Masticatory performance and QoL improved with an IR-RDP at each time point. FMRI jaw clenching sensory and motor cortical activity decreased at T1, with motor cortical activity increasing to T0 levels at T2. For cognitive fMRI activation tasks, cortical activity decreased from T0 to T1 across all regions of interests (ROI) and increased at T2 throughout the cognitive brain regions. Neurocognitive skills declined at T1, followed by improvement to or beyond T0 levels at T2. CONCLUSION: Improvements in masticatory performance and OHQoL occurred from complete RDPs to IR-RDP. Prosthetic adaptation was associated with neurocognitive changes to pre-insertion activity levels or greater after 6 weeks. These pilot data suggest both behavioural and neural associations between POR and cognition; however, larger study numbers are required.

Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants.

Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.