Major Depressive Disorder (MDD) and Obsessive-Compulsive Disorder (OCD) are common and potentially incapacitating conditions. Even when recognized and adequately treated, in over a third of patients ...with these conditions the response to first-line pharmacological and psychotherapeutic measures is not satisfactory. After more assertive measures including pharmacological augmentation (and in the case of depression, transcranial magnetic stimulation, electroconvulsive therapy, or treatment with ketamine or esketamine), a significant number of individuals remain severely symptomatic. In these persons, different ablation and deep-brain stimulation (DBS) psychosurgical techniques have been employed. However, apart from the cost and potential morbidity associated with surgery, on average only about half of patients show adequate response, which limits the widespread application of these potentially life-saving interventions. Possible reasons are considered for the wide variation in outcomes across different series of patients with MDD or OCD exposed to ablative or DBS psychosurgery, including interindividual anatomical and etiological variability. Low-intensity focused ultrasound (LIFU) is an emerging technique that holds promise in its ability to achieve anatomically circumscribed, noninvasive, and reversible neuromodulation of deep brain structures. A possible role for LIFU in the personalized presurgical definition of neuromodulation targets in the individual patient is discussed, including a proposed roadmap for clinical trials addressed at testing whether this technique can help to improve psychosurgical outcomes.
Repetitive negative thinking (RNT) is a frequent symptom of major depressive disorder (MDD) that is associated with poor outcomes and treatment resistance. While most studies on RNT have focused on ...structural and functional characteristics of gray matter, this study aimed to examine the association between white matter (WM) tracts and interindividual variability in RNT.
A probabilistic tractography approach was used to characterize differences in the size and anatomical trajectory of WM fibers traversing psychosurgery targets historically useful in the treatment of MDD (anterior capsulotomy, anterior cingulotomy, and subcaudate tractotomy) in patients with MDD and low (n = 53) or high (n = 52) RNT, and healthy control subjects (n = 54). MDD samples were propensity matched on depression and anxiety severity and demographics.
WM tracts traversing left hemisphere targets and reaching the ventral anterior body of the corpus callosum (thus extending to contralateral regions) were larger in the high-RNT MDD group compared with low-RNT (effect size D = 0.27, p = .042) and healthy control (D = 0.23, p = .02) groups. MDD was associated with greater size of tracts that converge onto the right medial orbitofrontal cortex regardless of RNT intensity. Other RNT-nonspecific findings in MDD involved tracts reaching the left primary motor and right primary somatosensory cortices.
This study provides the first evidence to our knowledge that WM connectivity patterns, which could become targets of intervention, differ between high- and low-RNT participants with MDD. These WM differences extend to circuits that are not specific to RNT, possibly subserving reward mechanisms and psychomotor activity.
Resting-state functional connectivity (RSFC) has been proposed as a potential indicator of repetitive negative thinking (RNT) in depression. However, identifying the specific functional process ...associated with RSFC alterations is challenging, and it remains unclear whether alterations in RSFC for depressed individuals are directly related to the RNT process or to individual characteristics distinct from the negative thinking process per se. To investigate the relationship between RSFC alterations and the RNT process in individuals with major depressive disorder (MDD), we compared RSFC with functional connectivity during an induced negative-thinking state (NTFC) in terms of their predictability of RNT traits and associated whole-brain connectivity patterns using connectome-based predictive modeling (CPM) and connectome-wide association (CWA) analyses. Thirty-six MDD participants and twenty-six healthy control participants underwent both resting state and induced negative thinking state fMRI scans. Both RSFC and NTFC distinguished between healthy and depressed individuals with CPM. However, trait RNT in depressed individuals, as measured by the Ruminative Responses Scale-Brooding subscale, was only predictable from NTFC, not from RSFC. CWA analysis revealed that negative thinking in depression was associated with higher functional connectivity between the default mode and executive control regions, which was not observed in RSFC. These findings suggest that RNT in depression involves an active mental process encompassing multiple brain regions across functional networks, which is not represented in the resting state. Although RSFC indicates brain functional alterations in MDD, they may not directly reflect the negative thinking process.
•Resting-state functional connectivity (RSFC) did not predict rumination in MDD.•Negative-thinking-state functional connectivity (NTFC) predicted rumination in MDD.•Both RSFC and NTFC distinguished between healthy and depressed individuals.•Rumination in depression involves active mental process across functional networks.•NTFC associated with higher FC between default mode and executive control regions.
Repetitive negative thinking (RNT), often referred to as rumination in the mood disorders literature, is a symptom dimension associated with poor prognosis and suicide in major depressive disorder ...(MDD). Given the transdiagnostic nature of RNT, this study aimed to evaluate the hypothesis that neurobiological substrates of RNT in MDD may share the brain mechanisms underlying obsessions, particularly those involving cortico-striatal-thalamic-cortical (CSTC) circuits.
Thirty-nine individuals with MDD underwent RNT induction during fMRI. Trait-RNT was measured by the Ruminative Response Scale (RRS) and state-RNT was measured by a visual analogue scale. We employed a connectome-wide association analysis examining the association between RNT intensity with striatal and thalamic connectivity.
A greater RRS score was associated with hyperconnectivity of the right mediodorsal thalamus with prefrontal cortex, including lateral orbitofrontal cortex, along with Wernicke's area and posterior default mode network nodes (t = 4.66-6.70). A greater state-RNT score was associated with hyperconnectivity of the right laterodorsal thalamus with bilateral primary sensory and motor cortices, supplementary motor area, and Broca's area (t = 4.51-6.57). Unexpectedly, there were no significant findings related to the striatum.
The present results suggest RNT in MDD is subserved by abnormal connectivity between right thalamic nuclei and cortical regions involved in both visceral and higher order cognitive processing. Emerging deep-brain neuromodulation methods may be useful to establish causal relationships between dysfunction of right thalamic-cortical circuits and RNT in MDD.
OBJECTIVESemantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether ...SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology SNAP) or persons who are diagnosed with other brain disorders affecting cognition.
METHODSEighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy−), or other neurological/psychiatric diagnosis (Amy−). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning).
RESULTSSIs on measures of PSI and frPSI distinguished between Amy+ AD and SNAP and other non-AD cases. PSI and frPSI intrusions evidenced moderately high associations with reduced volumes in the entorhinal cortex, superior temporal regions, and supramarginal gyrus. No such associations were observed in cases with SNAP.
CONCLUSIONSSIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy− participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.
•MDD-High exhibited lower striatal reward anticipation than MDD-Low.•MDD-High had higher sICAM-1 and IL-6 concentrations than MDD-Low and HC.•Within MDD-High, higher sICAM-1 levels were associated ...with lower striatal reward anticipation.•MDD exhibited lower precuneus response to large wins than HC.•MDD had higher IL-1ra, MDC and MIP-1α concentrations than HC.
Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and up to 40% of individuals with MDD do not respond to current treatments. Studies suggest that peripheral inflammation plays an important role in the striatal mesolimbic dopamine pathway and corticostriatal reward circuitry in MDD. Although MDD patients show blunted striatal responses to reward, the link between degree of inflammation and attenuation of reward processing is unclear. We investigated whether MDD patients with elevated peripheral inflammation exhibit attenuated reward responses to enhance our understanding of MDD pathophysiology and develop more effective treatments for current non-responders.
MDD subjects varying on serum C-reactive protein (CRP) concentrations (MDD-High CRP, >3 mg/L, n = 44; MDD-Low CRP, <3 mg/L, n = 44) and healthy comparisons (HC, n = 44) completed a monetary incentive delay (MID) task and provided blood samples to measure inflammation-related markers. MDD-High and MDD-Low were propensity score-matched on age, sex, body mass index (BMI), smoking status, exercise and MID task head motion. Percent change in blood oxygen level-dependent (BOLD) signal during anticipation of wins and losses was extracted from bilateral nucleus accumbens, dorsal caudate and dorsolateral putamen regions of interest (ROIs). A linear mixed-effects model was used to test group (MDD-High, MDD-Low and HC), condition (large-win, small-win and no win), and their interaction for these ROIs as well as whole-brain voxelwise data. Analyses also tested group differences in inflammatory mediators. Correlations were used to explore the relationship between inflammatory mediators and brain regions showing differences between MDD-High and MDD-Low.
MDD-High exhibited: (a) lower BOLD signal change in dorsal caudate, thalamus, left insula and left precuneus during anticipation of small wins than MDD-Low; and (b) higher serum soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 6 (IL-6) concentrations than MDD-Low and HC. MDD as a whole, regardless of CRP-based inflammation, exhibited: (a) lower precuneus BOLD signal change to large wins than HC; and (b) higher Interleukin 1 receptor antagonist (IL-1ra), macrophage-derived chemokine (MDC) and macrophage inflammatory protein-1 alpha (MIP-1α) concentrations than HC. Higher serum sICAM-1 concentrations were associated with lower caudate BOLD signal change to small wins only within the MDD-High group.
Within MDD patients, high inflammation (CRP, sICAM-1) was linked to reduced striatal activation recruited to discriminate intermediate reward magnitudes. These findings support an association between levels of peripheral inflammation and the degree of reward-related activation in individuals with MDD.
The ClinicalTrials.gov identifier for the clinical protocol associated with data published in this current paper is NCT02450240, “Latent Structure of Multi-level Assessments and Predictors of Outcomes in Psychiatric Disorders.”
Repetitive negative thinking (RNT) is a symptom that can negatively impact the treatment and course of common psychiatric disorders such as depression and anxiety. We aimed to characterize behavioral ...and genetic correlates of RNT to infer potential contributors to its genesis and maintenance.
We applied a machine learning (ML) ensemble method to define the contribution of fear, interoceptive, reward, and cognitive variables to RNT, along with polygenic risk scores (PRS) for neuroticism, obsessive compulsive disorder (OCD), worry, insomnia, and headaches. We used the PRS and 20 principal components of the behavioral and cognitive variables to predict intensity of RNT. We employed the Tulsa-1000 study, a large database of deeply phenotyped individuals recruited between 2015 and 2018.
PRS for neuroticism was the main predictor of RNT intensity (R2=0.027,p<0.001). Behavioral variables indicative of faulty fear learning and processing, as well as aberrant interoceptive aversiveness, were significant contributors to RNT severity. Unexpectedly, we observed no contribution of reward behavior and diverse cognitive function variables.
This study is an exploratory approach that must be validated with a second, independent cohort. Furthermore, this is an association study, limiting causal inference.
RNT is highly determined by genetic risk for neuroticism, a behavioral construct that confers risk to a variety of internalizing disorders, and by emotional processing and learning features, including interoceptive aversiveness. These results suggest that targeting emotional and interoceptive processing areas, which involve central autonomic network structures, could be useful in the modulation of RNT intensity.
•A machine learning ensemble method identified behavioral and genetic predictors of repetitive negative thinking (RNT).•Heightened response to aversive and fear inducing stimuli are associated with RNT.•The only genetic trait associated with RNT was polygenic risk score for neuroticism.•Our results warrant the exploration of interventions that target fear learning and interoceptive aversiveness.•Our results indicate that RNT is either a component of neuroticism or a contributor to the development and stability of it.
Abstract
Background
One common denominator to the clinical phenotypes of borderline personality disorder (BPD) and major depressive disorder (MDD) is emotion regulation impairment. Although these two ...conditions have been extensively studied separately, it remains unclear whether their emotion regulation impairments are underpinned by shared or distinct neurobiological alterations.
Methods
We contrasted the neural correlates of negative emotion regulation across an adult sample of BPD patients (
n
= 19), MDD patients (
n
= 20), and healthy controls (HCs;
n
= 19). Emotion regulation was assessed using an established functional magnetic resonance imaging cognitive reappraisal paradigm. We assessed both task-related activations and modulations of interregional connectivity.
Results
When compared to HCs, patients with BPD and MDD displayed homologous decreased activation in the right ventrolateral prefrontal cortex (vlPFC) during cognitive reappraisal. In addition, the MDD group presented decreased activations in other prefrontal areas (i.e., left dorsolateral and bilateral orbitofrontal cortices), while the BPD group was characterized by a more extended pattern of alteration in the connectivity between the vlPFC and cortices of the visual ventral stream during reappraisal.
Conclusions
This study identified, for the first time, a shared neurobiological contributor to emotion regulation deficits in MDD and BPD characterized by decreased vlPFC activity, although we also observed disorder-specific alterations. In MDD, results suggest a primary deficit in the strength of prefrontal activations, while BPD is better defined by connectivity disruptions between the vlPFC and temporal emotion processing regions. These findings substantiate, in neurobiological terms, the different profiles of emotion regulation alterations observed in these disorders.
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