Functional dysconnectivity in reward-related circuits in adolescents with major depressive disorder with and without suicidal ideation.

BackgroundAnhedonia, which is defined as the inability to feel pleasure, is considered a core symptom of major depressive disorder (MDD). It can lead to several adverse outcomes in adolescents, including heightened disease severity, resistance to antidepressants, recurrence of MDD, and even suicide. Specifically, patients who suffer from anhedonia may exhibit a limited response to selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT). Previous researches have revealed a link between anhedonia and abnormalities within the reward circuitry, making the nucleus accumbens (NAc) a potential target for treatment. However, since the NAc is deep within the brain, repetitive transcranial magnetic stimulation (rTMS) has the potential to modulate this specific region. Recent advances have enabled treatment technology to precisely target the left dorsolateral prefrontal cortex (DLPFC) and modify the functional connectivity (FC) between DLPFC and NAc in adolescent patients with anhedonia. Therefore, we plan to conduct a study to explore the safety and effectiveness of using resting-state functional connectivity magnetic resonance imaging (fcMRI)-guided rTMS to alleviate anhedonia in adolescents diagnosed with MDD.MethodsThe aim of this article is to provide a study protocol for a parallel-group randomized, double-blind, placebo-controlled experiment. The study will involve 88 participants who will be randomly assigned to receive either active rTMS or sham rTMS. The primary object is to measure the percentage change in the severity of anhedonia, using the Snaith-Hamilton Pleasure Scale (SHAPS). The assessment will be conducted from the baseline to 8-week post-treatment period. The secondary outcome includes encompassing fMRI measurements, scores on the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Montgomery Asberg Depression Rating Scale (MADRS), the Chinese Version of Temporal Experience of Pleasure Scale (CV-TEPS), and the Chinese Version of Beck Scale for Suicide Ideation (BSI-CV). The Clinical Global Impression (CGI) scores will also be taken into account, and adverse events will be monitored. These evaluations will be conducted at baseline, as well as at 1, 2, 4, and 8 weeks.DiscussionIf the hypothesis of the current study is confirmed, (fcMRI)-guided rTMS could be a powerful tool to alleviate the core symptoms of MDD and provide essential data to explore the mechanism of anhedonia.Trial registrationClinicalTrials.gov NCT05544071. Registered on 16 September 2022.

Despite being a commonly used protocol to treat major depressive disorder (MDD), the underlying mechanism of repetitive transcranial magnetic stimulation (rTMS) on dorsolateral prefrontal cortex (DLPFC) remains unclear. In the current study, we investigated the resting-state fMRI data of 100 healthy subjects by exploring three overlapping functional networks associated with the psychopathologically MDD-related areas (the nucleus accumbens, amygdala, and ventromedial prefrontal cortex). Our results showed that these networks converged at the bilateral DLPFC, which suggested that rTMS over DLPFC might improve MDD by remotely modulating the MDD-related areas synergistically. Additionally, they functionally converged at the DMPFC and bilateral insula which are known to be associated with MDD. These two areas could also be potential targets for rTMS treatment. Dynamic causal modelling (DCM) and Granger causality analysis (GCA) revealed that all pairwise connections among bilateral DLPFC, DMPFC, bilateral insula, and three psychopathologically MDD-related areas contained significant causality. The DCM results also suggested that most of the functional interactions between MDD-related areas and bilateral DLPFC, DMPFC, and bilateral insula can predominantly be explained by the effective connectivity from the psychopathologically MDD-related areas to the rTMS stimulation sites. Finally, we found the conventional functional connectivity to be a more representative measure to obtain connectivity parameters compared to GCA and DCM analysis. Our research helped inspecting the convergence of the functional networks related to a psychiatry disorder. The results identified potential targets for brain stimulation treatment and contributed to the optimization of patient-specific brain stimulation protocols.

The prefrontal cortex (PFC) is enormously important in suicide and major depressive disorder (MDD). However, little is known about the structural alterations in the brains of people with MDD and suicidal ideation. We examined the gray matter volume (GMV) of the PFC of individuals with MDD and suicidal ideation to determine if PFC volumetric differences contribute to suicidal ideation in patients with MDD. Thirty-five subjects with MDD and suicidal ideation, 38 subjects with MDD but without suicidal ideation, and 43 age- and gender-matched healthy control (HC) subjects underwent T1-weighted imaging. A voxel-based morphometric analysis was conducted to compare the PFC GMVs of the three groups. Further GMV reductions in the left and right dorsolateral PFC (DLPFC) and right ventrolateral PFC (VLPFC) were detected in the MDD with suicidal ideation group compared with those in the HC group and the MDD without suicidal ideation group, whereas the MDD without suicidal ideation group only exhibited significant differences in the left DLPFC relative to the HC group. Our findings demonstrated that left DLPFC reductions were associated with MDD and suicidal ideation, and diminished GMV reductions in the right DLPFC and right VLPFC were only associated with suicidal ideation. These results help us better understand the neuropathological changes in MDD with suicidal ideation.

Resting-state functional connectivity of the amygdala in major depressive disorder with suicidal ideation

Functional connectivity (FC) derived from resting-state functional magnetic resonance imaging has been widely applied to guide precise repetitive transcranial magnetic stimulation (rTMS). The left, right, and bilateral dorsolateral prefrontal cortices (DLPFC) have been used as rTMS treatment target regions for autism spectrum disorder (ASD), albeit with moderate efficacy. Thus, we aimed to develop an individualized localization method for rTMS treatment of ASD. We included 266 male ASDs and 297 male typically-developed controls (TDCs) from the Autism Brain Imaging Data Exchange Dataset. The nucleus accumbens (NAc) was regarded as a promising effective region, which was used as a seed and individualized peak FC strength in the DLPFC was compared between ASD and TDC. Correlation analysis was conducted between individualized peak FC strength and symptoms in ASD. We also investigated the spatial distribution of individualized peak FC locations in the DLPFC and conducted voxel-wise analysis to compare NAc-based FC between the two groups. ASD showed stronger peak FC in the right DLPFC related to TDC (Cohen's d = -.19, 95% CI: -0.36 to -0.03, t = -2.30, p = .02). Moreover, negative correlation was found between the peak FC strength in the right DLPFC and Autism Diagnostic Observation Schedule (ADOS) scores, which assessed both the social communication and interaction (r = -.147, p = .04, uncorrected significant), and stereotyped behaviors and restricted interests (r = -.198, p = .02, corrected significant). Peak FC locations varied substantially across participants. No significant differences in NAc-based FC in the DLPFC were found in the voxel-wise comparison. Our study supports the use of individualized peak FC-guided precise rTMS treatment of male ASD. Moreover, stimulating the right DLPFC might alleviate core symptoms of ASD.

Around 30% of the general population experience subjective tinnitus, characterized by conscious attended awareness perception of sound without an external source. Clinical distress tinnitus is more than just experiencing a phantom sound, as it can be highly disruptive and debilitating, leading those affected to seek clinical help. Effective tinnitus treatments are crucial for psychological well-being, but our limited understanding of the underlying neural mechanisms and a lack of a universal cure necessitate further treatment development. In light of the neurofunctional tinnitus model predictions and transcranial electrical stimulation, we conducted an open-label, single-arm, pilot study that utilized high-definition transcranial direct current stimulation (HD-tDCS) concurrent with positive emotion induction (PEI) techniques for ten consecutive sessions to down-regulate tinnitus negative valence in patients with clinical distress tinnitus. We acquired resting-state functional magnetic resonance imaging scans of 12 tinnitus patients (7 females, mean age = 51.25 ± 12.90 years) before and after the intervention to examine resting-state functional connectivity (rsFC) alterations in specific seed regions. The results showed reduced rsFC at post-intervention between the attention and emotion processing regions as follows: (1) bilateral amygdala and left superior parietal lobule (SPL), (2) left amygdala and right SPL, (3) bilateral dorsolateral prefrontal cortex (dlPFC) and bilateral pregenual anterior cingulate cortex (pgACC), and (4) left dlPFC and bilateral pgACC (FWE corrected p < 0.05). Furthermore, the post-intervention tinnitus handicap inventory scores were significantly lower than the pre-intervention scores (p < 0.05). We concluded that concurrent HD-tDCS and PEI might be effective in reducing tinnitus negative valence, thus alleviating tinnitus distress.

Dopaminergic circuitry in late-life depression and Lewy body disease.

Major depressive disorder is one of the most common psychiatric disorders, with a worldwide lifetime prevalence rate of 10%-20% in women and a slightly lower rate in men. While many patients are successfully treated using established therapeutic strategies, a significant percentage of patients fail to respond. This report describes the successful recovery of a previously treatment-resistant patient following right unilateral deep brain stimulation of Brodmann's area 25. Current therapeutic approaches to treatment-resistant patients are reviewed in the context of this case with an emphasis on the role of the right and left hemispheres in mediating disease pathogenesis and clinical recovery.

Both superior parietal lobule (SPL) of dorsolateral hemispheric surface and precuneus (PEC) of medial surface are the parts of posterior parietal cortex. The aim of this study was to determine the numerical density (Nv) of pyramidal neurons in the layer V of SPL and PEC and their potential differences. From 20 (40 hemispheres) formaline fixed human brains (both sexes; 27- 65 years) tissue blocks from SPL and PEC from the left and right hemisphere were used. According to their size the brains were divided into two groups, the group I with the larger left (15 brains) and the group II with the larger right hemisphere (5 brains). Serial Nissl sections (5 microm) of the left and right SPL and PEC were used for stereological estimation of Nv of the layer V pyramidal neurons. Nv of pyramidal neurons in the layer V in the left SPL of brains with larger left hemispheres was significantly higher than in the left SPL of brains with larger right hemisphere. Comparing sides in brains with larger left hemisphere, the left SPL had higher Nv than the right one, and then the left PEC, and the right SPL had significantly higher Nv than the right PEC. Comparing sides in brains with the larger right hemisphere, the left SPL had significantly higher Nv than left PEC, but the right SPL had significantly higher Nv than left SPL and the right PEC. Generally, there is an inverse relationship of Nv between the medial and lateral areas of the human posterior parietal cortex. The obtained values were different between the brains with larger left and right hemispheres, as well as between the SPL and PEC. In all the comparisons the left SPL had the highest values of Nv of pyramidal neurons in the layer V (4771.80 mm(-3)), except in brains with the larger right hemisphere.

Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg(-1) day(-1) × 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry.

Introduction: Addictions pose a major global health and socioeconomic challenge. Treatment strategies include pharmacological interventions, deep brain stimulation, and ablative procedures. Stereotactic radiosurgery (SRS) has emerged as a noninvasive, precise option for addiction management. nderstanding the anatomy and connectivity of the nucleus accumbens (NAc) is key to refining radiosurgical targets and improving outcomes.Method: Diffusion tensor imaging from 3T and 1.5T MRI scanners was obtained in five healthy subjects using T1 and T2 sequences. Images were fused with autosegmentation of the NAc, ventral tegmental area (VTA), amygdala, hippocampus, hypothalamus, and periventricular gray (PVG). The insula, medial/lateral orbitofrontal cortex, and dorsolateral prefrontal cortex were manually drawn. Connectivity to the NAc was visually assessed with fractional anisotropy thresholds (20–10). The five densest fiber tracts guided target selection, aligned to the anterior–posterior commissure, and transferred to Gamma Plan for radiosurgical planning.Results: The strongest connections were between the medial orbitofrontal cortex (mOFC), hypothalamus, VTA, PVG, and amygdala with the NAc. The mOFC–NAc and hippocampus–NAc tracts were the most and least robust, respectively. Derived stereotactic coordinates supported connectome-based targeting, proposing a 90 Gy dose to the NAc shell and aligning the 20 Gy isodose for neuromodulation. The right and left NAc received &gt; 20 Gy in 75.2% and 55.6% of their volumes, while the optic apparatus received ≤ 5.4 Gy (Dmax).Discussion: The NAc, within the ventral striatum, integrates limbic, cognitive, and motor inputs regulating reward and motivation. Its shell and core subregions differ functionally, with the shell showing dense dopaminergic input from the VTA and high sensitivity to reinforcement stimuli. Chronic substance exposure induces neuroplastic changes underlying compulsive behaviors, making the NAc shell a rational neurosurgical target. DBS, radiofrequency ablation, and SRS have yielded variable but promising results in refractory opioid and alcohol dependence. Advances in diffusion imaging now enable precise mapping of NAc connectivity and subregion-specific targeting. High-dose (up to 90 Gy) LINAC-based radiosurgery has shown safety and potential for radiomodulation, highlighting the therapeutic promise of anatomically informed, connectivity-guided interventions.Conclusions: Addiction remains a pervasive disorder with high relapse rates despite medical and behavioral therapies. Radiosurgery, a time-tested and safe functional technique, may offer a new treatment alternative. Connectivity-based SRS using commercial planning software allows visualization and autosegmentation of key NAc connections, supporting patient-specific, circuit-informed targeting in addiction neuromodulation.

BackgroundVisual selective attention can be categorized into top-down (goal-driven) and bottom-up (stimulus-driven) attention, with the fronto-parietal network serving as the primary neural substrate. However, fewer studies have focused on the specific roles of the right dorsolateral prefrontal cortex (DLPFC) and superior parietal lobule (SPL) in top-down and bottom-up attention. This study aimed to investigate the activity and connectivity of the right DLPFC and SPL in top-down and bottom-up attention.MethodsVisual pop-out task mainly induces bottom-up attention, while the visual search task mainly induces top-down attention. Fifty-four participants completed the pop-out and search tasks during functional magnetic resonance imaging (fMRI) scanning. We used univariate analyses, multivariate pattern analyses (MVPA), and generalized psychophysiological interaction (gPPI) to assess activity and functional connectivity.ResultsUnivariate analyses revealed stronger activation in the right DLPFC and SPL during the search > pop-out condition. The activation of the DLPFC was driven by its deactivation in the pop-out task, whereas the SPL showed significant activation in both tasks. MVPA demonstrated that activation patterns in the right DLPFC and SPL could distinguish between the pop-out and search tasks above chance level (0.5), with the right SPL exhibiting higher classification accuracy. The gPPI analyses showed that higher functional connectivity between the two seeds (right DLPFC and SPL) and bilateral precentral gyrus, left SPL, and right insula.ConclusionsThese results indicate that the right DLPFC and SPL showed stronger activity and connectivity under top-down versus bottom-up attention, allowing for neural representation of visual selective attention. This study provides evidence for understanding the role of the fronto-parietal network in visual selective attention.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12993-025-00297-8.

Postnatal growth may be associated with longitudinal brain development in children born preterm. To compare brain microstructure and functional connectivity strength with cognitive outcomes in association with postnatal growth among early school-aged children born preterm with extremely low birth weight. This single-center cohort study prospectively enrolled 38 children 6 to 8 years of age born preterm with extremely low birth weight: 21 with postnatal growth failure (PGF) and 17 without PGF. Children were enrolled, past records were retrospectively reviewed, and imaging data and cognitive assessments occurred from April 29, 2013, through February 14, 2017. Image processing and statistical analyses were conducted through November 2021. Postnatal growth failure in the early neonatal period. Diffusion tensor images and resting-state functional magnetic resonance images were analyzed. Cognitive skills were tested using the Wechsler Intelligence Scale; executive function was assessed based on a composite score calculated from the synthetic composite of the Children's Color Trails Test, STROOP Color and Word Test, and Wisconsin Card Sorting Test; attention function was evaluated using the Advanced Test of Attention (ATA); and the Hollingshead Four Factor Index of Social Status-Child was estimated. Twenty-one children born preterm with PGF (14 girls [66.7%]), 17 children born preterm without PGF (6 girls [35.3%]), and 44 children born full term (24 girls [54.5%]) were recruited. Attention function was less favorable in children with PGF than those without PGF (mean [SD] ATA score: children with PGF, 63.5 [9.4]; children without PGF, 55.7 [8.0]; P = .008). Significantly lower mean (SD) fractional anisotropy in the forceps major of the corpus callosum (0.498 [0.067] vs 0.558 [0.044] vs 0.570 [0.038]) and higher mean (SD) mean diffusivity in the left superior longitudinal fasciculus-parietal bundle (8.312 [0.318] vs 7.902 [0.455] vs 8.083 [0.393]; originally calculated as millimeter squared per second and rescaled 10 000 times as mean diffusivity × 10 000) were seen among children with PGF compared with children without PGF and controls, respectively. Decreased resting-state functional connectivity strength was observed in the children with PGF. The mean diffusivity of the forceps major of the corpus callosum significantly correlated with the attention measures (r = 0.225; P = .047). Functional connectivity strength between the left superior lateral occipital cortex and both superior parietal lobules correlated with cognitive outcomes of intelligence (right superior parietal lobule, r = 0.262; P = .02; and left superior parietal lobule, r = 0.286; P = .01) and executive function (right superior parietal lobule, r = 0.367; P = .002; and left superior parietal lobule, r = 0.324; P = .007). The ATA score was positively correlated with functional connectivity strength between the precuneus and anterior division of the cingulate gyrus (r = 0.225; P = .048); however, it was negatively correlated with functional connectivity strength between the posterior cingulate gyrus and both superior parietal lobules (the right superior parietal lobule [r = -0.269; P = .02] and the left superior parietal lobule [r = -0.338; P = .002]). This cohort study suggests that the forceps major of the corpus callosum and the superior parietal lobule were vulnerable regions in preterm infants. Preterm birth and suboptimal postnatal growth could have negative associations with brain maturation, including altered microstructure and functional connectivity. Postnatal growth may be associated with differences in long-term neurodevelopment among children born preterm.

Neurobiology of Addiction

Link between structural connectivity of the medial forebrain bundle, functional connectivity of the ventral tegmental area, and anhedonia in unipolar depression