Maas, B. | Search bioRxiv

bioRxiv2025

Complex Patterns of Altered White Matter Structural Connectivity within a 'subjective valuation network' in Treatment-Resistant Depression

BackgroundTreatment-resistant depression (TRD) poses a significant clinical challenge, demanding a deeper understanding of its neurobiological underpinnings to improve therapeutics. We examined white matter microstructure and structural connectivity in TRD, focusing on the subjective valuation network (SVN), which captures motivated behavior, reward processing, and emotional regulation circuits commonly altered in depression. This allowed us to identify potential neuroimaging biomarkers associated with treatment resistance. MethodsDiffusion tensor imaging (DTI) data were acquired from a sample of age-and-gender balanced individuals with TRD (n=44; female = 24, male=11, non-binary/unchecked =7) and non-depressed controls (n=42; female=27, male =12, non-binary/unchecked=5). Tract-Based Spatial Statistics were used to compare whole-brain white matter integrity differences between groups. Probabilistic tractography was then used to assess fractional anisotropy (FA) and white matter structural connectivity within the SVN across groups. SVN was defined a priori based on converging functional connectivity studies and included key regions such as the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum, and insula and their connecting white matter tracts. Additionally, correlations between clinical measures of depression severity and cognition and structural features of the networks white matter fibers (i.e. FA and structural connectivity) were explored. ResultsCompared to non-depressed controls, individuals with TRD exhibited reduced FA within the left uncinate fasciculus, left inferior fronto-occipital fasciculus, and anterior cingulum, supporting widespread white matter integrity degradations in TRD. No correlations were found between FA and depression severity, suggesting a more specific association with anhedonic features. Whole-network measures of FA and structural connectivity of the SVN did not differ between groups. However, specific subcircuits structural connectivity within the SVN differed between groups; namely, the white matter tracts connecting the insula-vmPFC, striatum-insula, and striatum-vmPFC. Hyperconnectivity emerged for patients with TRD for tracts connecting the insula-vmPFC and striatum-vmPFC region-pairs, with exhibited hypoconnectivity between the striatum-insula. Exploratory analyses for the TRD group indicated the subcircuits with altered structural connectivity within the SVN correlated with depressive severity. This indicates subcircuit network alterations may associate with greater difficulty experiencing pleasure - a core symptom of depression and a potential marker of treatment resistance. ConclusionsThis study provides evidence for wide-spread disruption of white matter microstructure and altered structural connectivity within specific subcircuits of the SVN in TRD. These findings point to an intricate pattern of structural hyper-and-hypo-connectivity within the subcircuits of the SVN which may underlie the core symptoms of TRD. The altered structural connectivity within the SVN may contribute to the pathophysiology of TRD, especially concerning the motivational and emotional deficits associated with anhedonia. Future research employing multimodal neuroimaging techniques and longitudinal designs is warranted to further elucidate the functional consequences of these structural abnormalities and their potential as predictive biomarkers for personalized treatment interventions in TRD. Specifically, investigating how these white matter alterations change with successful treatment or targeted interventions aimed at improving anhedonia could inform more effective therapies for this challenging condition.

neuroscience↗

bioRxiv2023

Sub-second Dopamine Signals during Risky Decision-Making in Patients with Impulse Control Disorder

BackgroundImpulse Control Disorder (ICD) in Parkinsons disease is a behavioral addiction arising secondary to dopaminergic therapies, most often dopamine receptor agonists. Prior research implicates changes in striatal function and heightened dopaminergic activity in the dorsal striatum of patients with ICD. However, this prior work does not possess the temporal resolution required to investigate dopaminergic signaling during real-time progression through various stages of decision-making involving anticipation and feedback. MethodsWe recorded high-frequency (10Hz) measurements of extracellular dopamine in the striatum of patients with (N=3) and without (N=3) a history of ICD secondary to dopamine receptor agonist therapy for Parkinsons disease symptoms. These measurements were made using carbon fiber microelectrodes during awake DBS neurosurgery and while participants performed a sequential decision-making task involving risky investment decisions and real monetary gains and losses. Per clinical standard-of-care, participants withheld all dopaminergic medications prior to the procedure. ResultsPatients with ICD invested significantly more money than patients without ICD. On each trial, patients with ICD made smaller adjustments to their investment levels compared to patients without ICD. In patients with ICD, dopamine levels rose or fell on sub-second timescales in anticipation of investment outcomes consistent with increased or decreased confidence in a positive outcome, respectively; dopamine levels in patients without ICD were significantly more stable during this phase. After outcome revelation, dopamine levels in patients with ICD rose significantly more than in inpatients without ICD for better-than-expected gains. For worse-than-expected losses, dopamine levels in patients with ICD remained level whereas dopamine levels in patients without ICD fell. ConclusionWe report significantly increased risky behavior and exacerbated phasic dopamine signaling, on sub-second timescales, anticipating and following the revelation of the outcomes of risky decisions in patients with ICD. Notably, these results were obtained when patients who had demonstrated ICD in the past but were, at the time of surgery, in an off-medication state. Thus, it is unclear whether observed signals reflect an inherent predisposition for ICD that was revealed when dopamine receptor agonists were introduced or whether these observations were caused by the introduction of dopamine receptor agonists and the patients having experienced ICD symptoms in the past. Regardless, future work investigating dopamines role in human cognition, behavior, and disease should consider the signals this system generates on sub-second timescales.

neuroscience↗