Abnormal habenula functional connectivity characterizes treatment-resistant depression

Barreiros, Ana Rita; Breukelaar, Isabella A.; Mayur, Prashanth; Andepalli, Jagadeesh; Tomimatsu, Yoshiro; Funayama, Kenta; Foster, Sheryl; Boyce, Philip; Malhi, Gin S; Harris, Anthony; Korgaonkar, Mayuresh S.

doi:10.1016/j.nicl.2022.102990

Cited by 22 publications

(18 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The left orbital area of the middle frontal gyrus is located in the prefrontal lobe and constitutes the reward network (47,48). A core symptom of TRD is the inability to feel pleasure, and abnormalities in the reward network are important in the pathogenesis of TRD (49). The orbital frontal cortex (OFC) participates in emotion regulation, sensory integration, pain regulation, and reward prediction in the human body (50,51).…”

Section: Discussionmentioning

confidence: 99%

Immediate Modulation of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Imaging Study

Sun

et al. 2022

Front. Psychiatry

View full text Add to dashboard Cite

BackgroundPrevious studies found that transcutaneous auricular vagus nerve stimulation (taVNS) was clinically effective in treating a case of treatment-resistant depression (TRD). However, the brain neural mechanisms underlying the immediate effects of taVNS treatment for TRD have not been elucidated.Materials and MethodsDifferences in the amplitude of low-frequency fluctuations (ALFF) between TRD and healthy control (HC) groups were observed. The TRD group was treated with taVNS for 30 min, and changes in ALFF in the TRD group before and after immediate treatment were observed. The ALFF brain regions altered by taVNS induction were used as regions of interest to analyze whole-brain functional connectivity (FC) changes in the TRD group.ResultsA total of 44 TRD patients and 44 HCs completed the study and were included in the data analysis. Compared with the HC group, the TRD group had increased ALFF in the left orbital area of the middle frontal gyrus. After taVNS treatment, ALFF in the left orbital area of the middle frontal gyrus and right middle frontal gyrus decreased in the TRD group, while ALFF in the right orbital area of the superior frontal gyrus increased. The FC in the left orbital area of the middle frontal gyrus with left middle frontal gyrus and the right inferior occipital gyrus was significantly increased.ConclusionTranscutaneous auricular vagus nerve stimulation demonstrates immediate modulation of functional activity in the emotional network, cognitive control network, and visual processing cortex, and may be a potential brain imaging biomarker for the treatment of TRD.

show abstract

Section: Discussionmentioning

confidence: 99%

Immediate Modulation of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Imaging Study

Sun

et al. 2022

Front. Psychiatry

View full text Add to dashboard Cite

show abstract

“…Although the brain's social behavior circuitry is complex and numerous brain areas are impacted in disordered social processing, here, we turn our focus to studies of upstream control of DA signaling by the LHb. LHb dysfunction is one of the most robust correlates of adult psychopathology across preclinical and clinical models (Fakhoury, 2017 ; Yang et al, 2018 ; Barreiros et al, 2022 ; Mondoloni et al, 2022 ), yet causal experiments that leverage animal models of early adversity to study developmental impacts on this system are limited (Nakamura et al, 2021 ; Langlois et al, 2022 ). Below, we summarize some of the key clinical evidence supporting a focus on this area in future work on the pathogenesis of disordered social processing.…”

Section: Early Adversity Social Behavior and Psychopathologymentioning

confidence: 99%

“… MDD and Schizophrenia: Links to habenula dysfunction, early life adversity, and social anhedonia. The clinical literature has demonstrated links between MDD and schizophrenia and habenula dysfunction, including hyperactivity and its connectivity with other brain regions (Shepard et al, 2006 ; Proulx et al, 2014 ; Fakhoury, 2017 ; Zhang et al, 2017 ; Barreiros et al, 2022 ). Early adversities such as emotional neglect, maternal separation and sexual trauma are contributing factors conferring increased risk for both of these disorders (Kessler et al, 2010 ; Bentall et al, 2012 ; Heim and Binder, 2012 ; Akdeniz et al, 2014 ; Wickham and Bentall, 2016 ).…”

Section: Early Adversity Social Behavior and Psychopathologymentioning

confidence: 99%

Rodent models of early adversity: Impacts on developing social behavior circuitry and clinical implications

Packard

Opendak

2022

Front. Behav. Neurosci.

View full text Add to dashboard Cite

Flexible and context-appropriate social functioning is key for survival across species. This flexibility also renders social behavior highly plastic, particularly during early development when attachment to caregiver can provide a template for future social processing. As a result, early caregiving adversity can have unique and lasting impacts on social behavior and even confer vulnerability to psychiatric disorders. However, the neural circuit mechanisms translating experience to outcome remain poorly understood. Here, we consider social behavior scaffolding through the lens of reward and threat processing. We begin by surveying several complementary rodent models of early adversity, which together have highlighted impacts on neural circuits processing social cues. We next explore these circuits underlying perturbed social functioning with focus on dopamine (DA) and its role in regions implicated in social and threat processing such as the prefrontal cortex (PFC), basolateral amygdala (BLA) and the lateral habenula (LHb). Finally, we turn to human populations once more to examine how altered DA signaling and LHb dysfunction may play a role in social anhedonia, a common feature in diagnoses such as schizophrenia and major depressive disorder (MDD). We argue that this translational focus is critical for identifying specific features of adversity that confer heightened vulnerability for clinical outcomes involving social cue processing.

show abstract

“…Moreover, the authors provide evidence that, unlike patients responding to ADs, TRD patients are characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard-to-treat depression [ 22 ]. Therefore, it seems that the therapy based on inhibition of habenula hyperactivity may have a significant impact on the success in the treatment of TRD.…”

Section: Introductionmentioning

confidence: 99%

Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

et al. 2022

View full text Add to dashboard Cite

The mechanisms of treatment-resistant depression (TRD) are not clear and are difficult to study. An animal model resembling human TRD is the Wistar Kyoto rat strain. In the present study, we focused on selecting miRNAs that differentiate rats of the WKY strain from Wistar Han (WIS) rats in two divisions of the habenula, the lateral and medial (LHb and MHb, respectively). Based on our preliminary study and literature survey, we identified 32 miRNAs that could be potentially regulated in the habenula. Six miRNAs significantly differentiated WKY rats from WIS rats within the MHb, and three significantly differentiated WKY from WIS rats within the LHb. Then, we selected relevant transcripts regulated by those miRNAs, and their expression in the habenular nuclei was investigated. For mRNAs that differentiated WKY rats from WIS rats in the MHb (Cdkn1c, Htr7, Kcnj9, and Slc12a5), their lower expression correlated with a higher level of relevant miRNAs. In the LHb, eight mRNAs significantly differentiated WKY from WIS rats (upregulated Htr4, Drd2, Kcnj5, and Sstr4 and downregulated Htr2a, Htr7, Elk4, and Slc12a5). These data indicate that several important miRNAs are expressed in the habenula, which differentiates WKY rats from WIS rats and in turn correlates with alterations in the expression of target transcripts. Of particular note are two genes whose expression is altered in WKY rats in both LHb and MHb: Slc12a5 and Htr7. Regulation of KCC2 via the 5-HT7 receptor may be a potential target for the treatment of TRD.

show abstract

Abnormal habenula functional connectivity characterizes treatment-resistant depression

Cited by 22 publications

References 43 publications

Immediate Modulation of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Imaging Study

Immediate Modulation of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Imaging Study

Rodent models of early adversity: Impacts on developing social behavior circuitry and clinical implications

Habenula as a Possible Target for Treatment-Resistant Depression Phenotype in Wistar Kyoto Rats

Contact Info

Product

Resources

About