Search Results (14)

Background: Emotion processing is critical in the neuropathology of major depressive disorder (MDD), while its relationship with clinical treatment remains unclear. This study aims to indicate the associations between emotion processing and treatment effects following a sequential dual-site accelerated repetitive transcranial magnetic stimulation (rTMS) protocol. Methods: MDD patients were recruited to receive rTMS treatment with four sessions per day for four consecutive days, with stimulation sequentially delivered to the left dorsolateral prefrontal cortex (dlPFC) and the dorsomedial prefrontal cortex (dmPFC). Symptoms were assessed at baseline, end of treatment, and week 4 using the Montgomery–Åsberg Depression Rating Scale (MADRS), Snaith-Hamilton Pleasure Scale (SHAPS), and Fatigue Severity Scale (FSS). Emotional valence and arousal were evaluated with the Affect Rating Task (ART). Results: A total of 51 participants completed the clinical assessments and ART, with two excluded due to missing baseline data in the SHAPS and FSS. The linear mixed-effects models revealed significant improvement in depressive (p < 0.001, d = −0.343) and fatigue symptoms (p = 0.010, d = −0.572) following rTMS treatment. Neutral valence was correlated with MADRS scores at baseline (R² = 0.096, p = 0.027). In addition, changes in arousal for positive images (p = 0.047, adjusted R² = 0.097) and neutral images (p = 0.019, adjusted R² = 0.160) at treatment end were significantly correlated with MADRS improvement at week 4. Conclusions: Our study highlights the association between changes in emotional arousal and improvement in MDD following accelerated dlPFC-dmPFC dual-site rTMS treatment. Full article

Background/Objectives: Headache after a traumatic brain injury (TBI) is one of the most common post-concussive symptoms and is associated with altered pain processing and elevated disability levels. Understanding physiologic correlates of nociception in individuals with persistent post-traumatic headache (pPTH) may help identify novel treatment targets for pain-related disability. The objective of this case–control study was to compare extra- and intracranial hemodynamic responses to a noxious cold pressor task (CPT) between individuals with pPTH and healthy controls (HC) using functional near-infrared spectroscopy (fNIRS). Methods: Ten individuals with pPTH were compared to ten HC with no history of TBI, persistent headache, or chronic pain. fNIRS optodes over the medial prefrontal cortex (PFC) measured extra- and intracranial peak-to-peak hemodynamic responses during tepid- (control) and cold-water (CPT) hand immersion. Evoked pain responses during the CPT were assessed with numeric pain ratings. Linear mixed effects modeling assessed the role of group and evoked pain on hemodynamic responses. Results: pPTH group membership (p = 0.031) predicted greater extracranial hemodynamic responses to the CPT, whereas intracranial PFC responses did not differ between groups. Regardless of group membership, greater increases in pain intensity during the CPT were associated with increased hemodynamic responses for the dorsomedial PFC (p = 0.031). Conclusions: Compared to controls, individuals with pPTH responded to a noxious cold stimulus with elevated systemic hemodynamic responses regulated by the autonomic nervous system. Irrespective of group, hemodynamic responses within the dmPFC were associated with evoked pain responses to the CPT and may provide a useful biomarker for individual variations in cortical pain processing for healthy and clinical populations. Full article

Social anxiety disorder (SAD) is characterized by fear and avoidance of social situations. Considering the reduced availability of conventional therapies, we aimed to improve our understanding of the biological mechanisms in SAD by evaluating gamma-aminobutyric acid (GABA) and other neurometabolites (including glutamate + glutamine/glutamix (Glx), N-acetyl aspartate (NAA), myo-inositol (mI), total choline (tCho), and total creatine (tCr) in the dorsomedial prefrontal cortex/anterior cingulate cortex (dmPFC/ACC), dorsolateral prefrontal cortex (dlPFC), and the insula). In this pilot study, we recruited 26 (age: 25.3 ± 5.0 years; 61.5% female) individuals with SAD and 26 (age: 25.1 ± 4.4 years; 61.5% female) sex-age-matched controls. Using proton magnetic resonance spectroscopy, we found that compared to the controls, GABA+ macromolecular signal (GABA+) in dlPFC (t = 2.63; p = 0.012) and Glx in the insula (Mann–Whitney U = 178.3; p = 0.024) were higher in the participants with SAD. However, no between-group differences were observed in dmPFC/ACC (t = 0.39; p = 0.699). Increased GABA+ in dlPFC could be explained by aberrant GABA transporters. In the insula, increased Glx may be associated with the dysfunction of glutamate transporters or decreased activity of glutamic acid decarboxylase in the GABAergic inhibitory neurons. However, these proposed mechanisms need to be further investigated in SAD. Full article

The dorsomedial caudate–putamen (dmCPu), a key input structure of the basal ganglia, plays a crucial role in goal-directed behaviors and the transition to habits. The functional specialization of the dmCPu along its anteroposterior axis suggests that distinct prefrontal cortex (PFC) subregions may differentially contribute to these processes. However, the precise topographical organization of PFC and adjacent areas projections to the anterior and posterior dmCPu remains poorly understood. We employed retrograde tracing using Fluoro-Gold to map the projections from PFC subregions and adjacent areas to the anterior and posterior dmCPu in male Sprague Dawley rats. Histological verification and immunohistochemical labeling were conducted to confirm injection sites and neuronal labeling. Quantitative analyses were performed to assess the effects of injection site placement (anterior vs. posterior dmCPu), laterality (ipsilateral vs. contralateral), and cortical subregion on projection density. The posterior dmCPu received significantly higher projection densities than the anterior dmCPu, with a pronounced ipsilateral dominance across all cortical subregions. Among the subregions examined, the cingulate cortex exhibited the highest number of labeled neurons projecting to the dmCPu, with distinct patterns of connectivity between anterior and posterior injection sites. Notably, motor and somatosensory cortical projections were more prominent in the posterior dmCPu, whereas cingulate projections demonstrated robust anteroposterior and lateralized differences. These findings provide a comprehensive map of the topographical organization of cortical inputs to the dmCPu, highlighting differential connectivity patterns that may underlie distinct functional roles in goal-directed and habitual behaviors. This work advances our understanding of corticostriatal circuits and their relevance to adaptive behaviors and neuropsychiatric disorders. Full article

Functional neuroimaging studies of neuropsychiatric disorders and cognitive impairment are commonly conducted in the clinic setting but less so in the acutely medically ill while hospitalized. This is largely due to technical and logistical limitations, given the lack of portable devices with high spatial and temporal resolutions. This exploratory study reports on the development and implementation of a novel diffuse optical tomography (DOT) system that can be employed for bedside three-dimensional functional neuroimaging. To test this portable DOT system, our protocol included a task-based sequence involving the Months Backwards Test with imaging centered on the bilateral prefrontal cortex. Fifteen subjects were recruited from intensive care units and the general wards of a single tertiary academic hospital and included in our final analysis. Volumetric hemoglobin analyses of the dorsolateral prefrontal cortex (DLPFC) and dorsomedial prefrontal cortex (DMPFC) were reliably captured in all our subjects. The peak value was calculated to be 3.36 µM and 0.74 µM for oxygenated-hemoglobin (HbO) and total-hemoglobin (HbT) (p < 0.042, [HbT]), respectively. The standard error was calculated to be 4.58 uM and 3.68 uM for (HbO) and (HbT). We additionally developed a seed-based correlation analysis to demonstrate the capability of DOT in studying functional connectivity. The right DLPFC was found to be moderately associated with the left DLPFC in all our subjects (r = 0.656). The DMPFC was observed to be associated with the left DLPFC but less so (r = 0.273) at the group level. Overall, the contribution of left-to-right DLPFC connectivity was significantly higher than left DLPFC to DMPFC in our group (p = 0.012). Future studies should investigate the potential of such a DOT system in the research of neuropsychiatric and neurocognitive disorders within the hospital to study different types of mechanisms, pathophysiology, and interventions that occur acutely and can advance our knowledge of these disorders. Full article

Exposure to opioids can lead to the alteration of several neurotransmitters. Among these neurotransmitters, glutamate is thought to be involved in opioid dependence. Glutamate neurotransmission is mainly regulated by astrocytic glutamate transporters such as glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT). Our laboratory has shown that exposure to lower doses of hydrocodone reduced the expression of xCT in the nucleus accumbens (NAc) and the hippocampus. In the present study, we investigated the effects of chronic exposure to hydrocodone, and tested ceftriaxone as a GLT-1 upregulator in mesocorticolimbic brain regions such as the NAc, the amygdala (AMY), and the dorsomedial prefrontal cortex (dmPFC). Eight-week-old male mice were divided into three groups: (1) the saline vehicle control group; (2) the hydrocodone group; and (3) the hydrocodone + ceftriaxone group. Mice were injected with hydrocodone (10 mg/kg, i.p.) or saline for 14 days. On day seven, the hydrocodone/ceftriaxone group was injected with ceftriaxone (200 mg/kg, i.p.) for last seven days. Chronic exposure to hydrocodone reduced the expression of GLT-1, xCT, protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal Kinase (JNK) in NAc, AMY, and dmPFC. However, hydrocodone exposure increased the expression of G-protein-coupled metabotropic glutamate receptors (mGluR5) in the NAc, AMY, and dmPFC. Importantly, ceftriaxone treatment normalized the expression of mGluR5, GLT-1, and xCT in all these brain regions, except for xCT in the AMY. Importantly, ceftriaxone treatment attenuated hydrocodone-induced downregulation of signaling pathways such as AKT, ERK, and JNK expression in the NAc, AMY, and dmPFC. These findings demonstrate that ceftriaxone has potential therapeutic effects in reversing hydrocodone-induced downregulation of GLT-1 and xCT in selected reward brain regions, and this might be mediated through the downstream kinase signaling pathways such as AKT, ERK, and JNK. Full article

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter implicated in neuropsychiatric disorders. The best method for quantifying GABA is proton magnetic resonance spectroscopy (¹H MRS). Considering that accurate measurements of GABA are affected by slight methodological alterations, demonstrating GABA reproducibility in healthy volunteers is essential before implementing the changes in vivo. Thus, our study aimed to evaluate the back-to-back (B2B) and day-to-day (D2D) reproducibility of GABA+ macromolecules (GABA+) using a 3 Tesla MRI scanner, the new 32-channel head coil (CHC), and Mescher–Garwood Point Resolved Spectroscopy (MEGA-PRESS) technique with the scan time (approximately 10 min), adequate for psychiatric patients. The dorsomedial pre-frontal cortex/anterior cingulate cortex (dmPFC/ACC) was scanned in 29 and the dorsolateral pre-frontal cortex (dlPFC) in 28 healthy volunteers on two separate days. Gannet 3.1 was used to quantify GABA+. The reproducibility was evaluated by Pearson’s r correlation, the interclass-correlation coefficient (ICC), and the coefficient of variation (CV%) (r/ICC/CV%). For Day 1, B2B reproducibility was 0.59/0.60/5.02% in the dmPFC/ACC and 0.74/0.73/5.15% for dlPFC. For Day 2, it was 0.60/0.59/6.26% for the dmPFC/ACC and 0.54/0.54/6.89 for dlPFC. D2D reproducibility of averaged GABA+ was 0.62/0.61/4.95% for the dmPFC/ACC and 0.58/0.58/5.85% for dlPFC. Our study found excellent GABA+ repeatability and reliability in the dmPFC/ACC and dlPFC. Full article

The present study aimed to characterize the phenomenon of behavioral sensitization to cocaine and to identify neuroanatomical structures involved in the induction and expression phases of this phenomenon. For this, in experiment 1 (induction phase), mice were treated with saline or cocaine every second day for 15 days (conditioning period), in the open-field or in their home-cages. In experiment 2 (expression phase), the same protocol was followed, except that after the conditioning period the animals were not manipulated for 10 days, and after this interval, animals were challenged with cocaine. Neuroanatomical structures involved in the induction and expression phases were identified by stereological quantification of c-Fos staining in the dorsomedial prefrontal cortex (dmPFC), nucleus accumbens core (NAc core and shell (NAc shell), basolateral amygdala (BLA), and ventral tegmental area (VTA). Neuroanatomical analysis indicated that in the induction phase, cocaine-conditioned animals had higher expression of c-Fos in the dmPFC, NAc core, BLA, and VTA, whereas in the expression phase, almost all areas had higher expression except for the VTA. Therefore, environmental context plays a major role in the induction and expression of behavioral sensitization, although not all structures that compose the mesolimbic system contribute to this phenomenon. Full article

Metacognition has only scarcely been investigated in brain tumor patients. It is unclear if and how the tumor-lesioned brain might be able to maintain an adequate sense-of-self. As cortical midline structures (CMS) are regarded as essential for self-referential mental activity, we investigated resting-state fMRI connectivity (FC) of CMS to the default-mode network (DMN) and to the whole brain, comparing glioma patients and matched controls. Subjects furthermore performed a trait judgement (TJ), a trait recall task (TR), and neuropsychological testing. In the TJ, adjectives had to be ascribed as self- or non-self-describing, assessing the self-serving effect (SSE), a normally observed bias for positive traits. In the TR, the mnemic neglect effect (MNE), a memory advantage for positive traits, was tested. The groups were compared and partial correlations between FC and test metrics were analyzed. Although patients were significantly impaired in terms of verbal memory, groups did not differ in the SSE or the MNE results, showing preserved metacognitive abilities in patients. FC of CMS to the DMN was maintained, but was significantly decreased to whole brain in the patients. FC of the dorsomedial prefrontal cortex (DMPFC) to whole brain was correlated with the MNE in patients. Preserving the DMPFC in therapeutic interventions might be relevant for maintaining self-related verbal information processing in the memory domain in glioma patients. Full article

Previous studies demonstrated sex-related differences in several areas of the human brain, including patterns of brain activation in males and females when observing their own bodies and faces (versus other bodies/faces or morphed versions of themselves), but a complex paradigm touching multiple aspects of embodied self-identity is still lacking. We enrolled 24 healthy individuals (12 M, 12 F) in 3 different fMRI experiments: the vision of prototypical body silhouettes, the vision of static images of the face of the participants morphed with prototypical male and female faces, the vision of short videos showing the dynamic transformation of the morphing. We found differential sexual activations in areas linked to self-identity and to the ability to attribute mental states: In Experiment 1, the male group activated more the bilateral thalamus when looking at sex congruent body images, while the female group activated more the middle and inferior temporal gyrus. In Experiment 2, the male group activated more the supplementary motor area when looking at their faces; the female group activated more the dorsomedial prefrontal cortex (dmPFC). In Experiment 3, the female group activated more the dmPFC when observing either the feminization or the masculinization of their face. The defeminization produced more activations in females in the left superior parietal lobule and middle occipital gyrus. The performance of all classifiers built using single ROIs exceeded chance level, reaching an area under the ROC curves > 0.85 in some cases (notably, for Experiment 2 using the V1 ROI). The results of the fMRI tasks showed good agreement with previously published studies, even if our sample size was small. Therefore, our functional MRI protocol showed significantly different patterns of activation in males and females, but further research is needed both to investigate the gender-related differences in activation when observing a morphing of their face/body, and to validate our paradigm using a larger sample. Full article

The default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. 1400 genes differed using log2FC > ±1 and adjusted p-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Protein–protein interaction and co-expressional networks coupled with gene set enrichment analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated, while glutamatergic synaptic signaling upregulated genes in suicidal individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding protein 2 (NECAB2). In situ hybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in two different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims. Full article

(1) Objective: Considering that current knowledge of mechanisms involved in the molecular pathogenesis of Social Anxiety Disorder (SAD) is limited, we conducted a systematic review to evaluate cumulative data obtained by Proton Magnetic Resonance Spectroscopic (¹H MRS) studies. (2) Methods: A computer-based literature search of Medline, EMBASE, PsycInfo, and ProQuest was performed. Only cross-sectional studies using ¹H MRS techniques in participants with SAD and healthy controls (HCs) were selected. (3) Results: The search generated eight studies. The results indicated regional abnormalities in the ‘fear neurocircuitry’ in patients with SAD. The implicated regions included the anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), insula, occipital cortex (OC), as well as the subcortical regions, including the thalamus, caudate, and the putamen. (4) Conclusions: The evidence derived from eight studies suggests that possible pathophysiological mechanisms of SAD include impairments in the integrity and function of neurons and glial cells, including disturbances in energy metabolism, maintenance of phospholipid membranes, dysregulations of second messenger systems, and excitatory/inhibitory neurocircuitry. Conducting more cross-sectional studies with larger sample sizes is warranted given the limited evidence in this area of research. Full article

In day-to-day life, we often choose between pursuing familiar behaviors that have been rewarded in the past or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for flexibly arbitrating between old and new behavioral strategies. The way in which DMS neurons host stable connections necessary for sustained flexibility is still being defined. An entry point to addressing this question may be the structural scaffolds on DMS neurons that house synaptic connections. We find that the non-receptor tyrosine kinase Proline-rich tyrosine kinase 2 (Pyk2) stabilizes both dendrites and spines on striatal medium spiny neurons, such that Pyk2 loss causes dendrite arbor and spine loss. Viral-mediated Pyk2 silencing in the DMS obstructs the ability of mice to arbitrate between rewarded and non-rewarded behaviors. Meanwhile, the overexpression of Pyk2 or the closely related focal adhesion kinase (FAK) enhances this ability. Finally, experiments using combinatorial viral vector strategies suggest that flexible, Pyk2-dependent action involves inputs from the medial prefrontal cortex (mPFC), but not the ventrolateral orbitofrontal cortex (OFC). Thus, Pyk2 stabilizes the striatal medium spiny neuron structure, likely providing substrates for inputs, and supports the capacity of mice to arbitrate between novel and familiar behaviors, including via interactions with the medial-prefrontal cortex. Full article

Overgeneral autobiographical memory (AM) manifests in individuals with major depressive disorder (MDD) tested during depressed (dMDD) or remitted phases (rMDD), and healthy individuals at high-risk (HR) for developing MDD. The current study aimed to elucidate differences in hemodynamic correlates of AM recall between rMDDs, HRs, and controls (HCs) to identify neural changes following previous depressive episodes without the confound of current depressed mood. HCs, HRs, and unmedicated rMDDs (n = 20/group) underwent fMRI while recalling AMs in response to emotionally valenced cue words. HRs and rMDDs recalled fewer specific and more categorical AMs relative to HCs. During specific AM recall, HRs had increased activity relative to rMDDs and HCs in left ventrolateral prefrontal cortex (VLPFC) and lateral orbitofrontal cortex. During positive specific AM recall, HRs and HCs had increased activity relative to rMDDs in bilateral dorsomedial prefrontal cortex (DMPFC) and left precuneus. During negative specific AM recall HRs and HCs had increased activity in left VLPFC and right DMPFC, while rMDDs had increased activity relative to HRs and HCs in right DLPFC and precuneus. Differential recruitment of medial prefrontal regions implicated in emotional control suggests experiencing a depressive episode may consequently reduce one’s ability to regulate emotional responses during AM recall. Full article