Animals learn to approach and escape stimuli in their environment, in part through the representation of rewarding or aversive outcomes in the nucleus accumbens (NAc). The regulation of reward motivation in the NAc by dopamine signaling at DRD1 and DRD2 receptors has been the subject of extensive study. However, the process by which aversive stimuli are signaled within this system to promote motivated escape behavior is less well characterized. Conventional wisdom posits that rewarding and aversive stimuli ultimately affect DRD1 or DRD2-receptor expressing medium spiny neurons (MSNs) in an opposing manner to differentially modulate motivated behavior. However, recent studies have challenged this view and demonstrate the need to better characterize the processes that mediate aversion learning. To determine if DRD2 dopamine receptor activation disrupts escape behavior, 21 male and female Sprague Dawley rats were treated with an intra-NAc core DRD2 receptor agonist, quinpirole, while escape behavior was negatively reinforced by the termination of aversive white noise. This treatment attenuated escape, a result that is consistent with the view that aversion-induced reductions in dopamine promote escape behavior through decreased DRD2 receptor signaling in the NAc, and potential disinhibition of an aversion-sensitive striatal output circuit.
Brain Scans Reveal Dopamine Damage in Long COVID, Pointing to New Treatments
New brain imaging research has provided the strongest evidence to date that long COVID is associated with injury to the brain’s dopamine system, offering a potential biological explanation for persistent symptoms such as fatigue, slowed movement, lack of motivation, and memory problems.
The study, published in eBioMedicine by researchers at the Centre for Addiction and Mental Health in Canada, used positron emission tomography (PET) imaging to examine dopamine-releasing neurons in people with long COVID. The findings suggest that reduced dopamine nerve terminal density in key brain regions may underlie many of the neurological symptoms experienced by patients and identify a potential therapeutic target for future treatments.
Long COVID is estimated to affect approximately nine million adults in the United States and about 5% of the global population, making it one of the most common chronic conditions to emerge from the COVID-19 pandemic. The condition is characterized by symptoms that persist for at least three months after the initial SARS-CoV-2 infection and commonly includes fatigue, brain fog, memory impairment, and mood changes. Despite its prevalence, there are currently no evidence-based treatments, largely because the biological mechanisms driving these symptoms remain poorly understood.
To investigate whether the brain’s dopamine system is involved, the researchers used PET imaging to measure a well-established marker of dopamine neuron integrity in individuals with long COVID and healthy control participants.
Compared with healthy volunteers, participants with long COVID had significantly lower levels of the dopamine neuron marker throughout the striatum, a brain region that plays a central role in motivation, movement, learning, and cognition. The reduced signal indicates a loss of dopamine nerve terminal density, providing direct evidence that dopamine-releasing neurons are injured in long COVID.
The imaging findings also closely matched patients’ clinical symptoms. Lower dopamine markers in the ventral striatum were associated with greater loss of motivation, reductions in the dorsal putamen correlated with slower movement, and lower marker levels in the caudate were linked to poorer memory performance. The pattern suggests that damage within specific regions of the dopamine system may contribute to distinct neurological symptoms experienced by people with long COVID.
The findings build on the research group’s earlier work demonstrating elevated inflammation in the brains of people with long COVID, particularly in regions rich in dopamine-producing neurons. Because inflammation is known to damage dopamine neurons in other neurological disorders, the new study provides direct evidence that this inflammatory process may be accompanied by measurable injury to the brain’s dopamine system. The close relationship between dopamine neuron loss and symptom severity further strengthens the case that dopamine dysfunction plays a central role in the condition.
The study also shifts attention beyond inflammation alone and suggests that long COVID should be considered, at least in part, a disorder affecting the brain’s dopamine system. That conclusion has important therapeutic implications because several medications already approved for other neurological disorders increase dopamine availability or enhance dopamine signaling. The researchers suggest that repurposing dopamine precursors or drugs that inhibit dopamine metabolism could represent a promising strategy for treating persistent cognitive and neurological symptoms associated with long COVID.
The findings also provide biological evidence supporting the experiences of people living with long COVID, many of whom have struggled for years with debilitating symptoms despite the absence of clear diagnostic markers. By demonstrating measurable injury to dopamine-releasing neurons, the study offers objective evidence that persistent neurological symptoms have a biological basis.
Building on these results, the investigators plan to launch a clinical trial in collaboration with University Health Network to evaluate whether therapies that improve dopamine function can reduce fatigue, improve motivation, and enhance memory in people with long COVID. If successful, the trial could pave the way for one of the first mechanism-based treatment approaches for the condition.
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Impact of an Artificial Intelligence–Powered Clinical Decision Support System for Acute Kidney Injury Prevention in the Intensive Care Unit: Single-Center Uncontrolled Before-and-After Implementation Study
Background: Acute kidney injury (AKI) is a frequent and serious complication among hospitalized patients, particularly in critical care settings, where its incidence can exceed 50%. AKI is associated with increased mortality, prolonged hospitalization, dialysis dependence, and higher health care costs. Although the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines emphasize supportive care, hemodynamic optimization, and avoidance of nephrotoxins, their implementation remains inconsistent, partly due to the lack of timely risk stratification. Recent advances in artificial intelligence have enhanced early prediction and detection of AKI, offering new opportunities to improve patient outcomes and intensive care unit (ICU) efficiency. The U-Care Renal Platform (UCRP; U-Care Medical S.r.l), a Conformité Européenne (CE)–marked artificial intelligence–powered medical device, integrates directly with the ICU electronic health record to continuously analyze patient data and predict the risk of moderate or severe AKI within 24 hours, providing actionable, guideline-based recommendations. While the predictive performance of UCRP has been validated previously, its real-world impact on clinical and operational outcomes in the ICU remains underexplored. Objective: This single-center uncontrolled before-and-after implementation study aims to evaluate the association between UCRP implementation and selected ICU clinical and operational outcomes in routine practice at SCIAS Hospital, Barcelona. Methods: This study was conducted as a retrospective service evaluation of a workflow-embedded clinical decision support system between March 2023 and March 2025. It included 202 postsurgical adult ICU patients. Outcomes of interest were assessed by comparing preimplementation and postimplementation periods. Months during which the UCRP was inactive were excluded from the analysis (total excluded duration: 10 months; 5 in the preimplementation period and 5 in the postimplementation period). The outcomes included the incidence of moderate-to-severe AKI (KDIGO stages 2 and 3), the use of nephrotoxic medications, the frequency of hypotensive episodes among patients with AKI, and the ICU length of stay. Results: During the postimplementation period, lower rates of moderate-to-severe AKI (9/99, 9.1% vs 12/103, 11.7%), nephrotoxic drug administration, and hypotensive episodes among patients with AKI were observed compared with the preimplementation period. Conclusions: Integration of the UCRP into ICU workflows was associated with differences in selected AKI-related process and intermediate clinical outcomes in this single-center uncontrolled before-and-after implementation study. However, given the study design, causal relationships cannot be established, and the findings should be interpreted as preliminary signals requiring confirmation in larger, controlled, and multicenter studies, including patient-centered outcomes.
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<![CDATA[PP-01 targets CB-1 recovery and dopamine balance, aiming to ease cannabis withdrawal and boost abstinence as a fast-tracked phase 3 trial advances.]]>
Memory-focused therapy: an integrated intervention to reduce trauma symptoms, maladaptive cognitive processes, and emotional distress in Afghan youth
BackgroundAfghan youth continue to face chronic war-related trauma, terrorist violence, and severe disruptions to education and social support systems, resulting in high rates of posttraumatic stress disorder (PTSD), depression, anxiety, and hopelessness. There is a critical need for culturally responsive, low-intensity, and feasible psychological interventions that can be delivered in low-resource and unstable settings.ObjectiveThis study conducted a preliminary evaluation of the efficacy, acceptability, and mechanisms of change associated with Memory-Focused Therapy (MFT), an integrative intervention targeting autobiographical memory processing, acceptance-based regulation, and future self-construction among youth affected by the Kaaj Education Center attack in Kabul, Afghanistan.MethodsA single-group repeated-measures design was used with 26 participants assessed at baseline, post-intervention, and three-month follow-up. Standardized measures of PTSD, depression, anxiety, stress, cognitive avoidance, cognitive fusion, resilience, and posttraumatic growth were administered. MFT was delivered in 12 structured group sessions. Additionally, qualitative data from semi-structured interviews and therapist field notes were analyzed using thematic analysis.ResultsQuantitative analyses showed significant reductions in PTSD symptoms, depression, anxiety, stress, cognitive avoidance, and cognitive fusion from baseline to post-intervention, alongside significant increases in posttraumatic growth. Several of these improvements were maintained at follow-up. Qualitative findings reflected four overarching themes: (1) facilitator experiences and implementation challenges in high-risk contexts, (2) improvements in cognitive and emotional processing, (3) growth in meaning, relationships, values, and future orientation, and (4) exposure to traumatic memories and reduced avoidance.ConclusionFindings provide preliminary evidence that MFT is a feasible, acceptable, and potentially effective intervention for trauma-affected Afghan youth. By integrating trauma memory processing, present-moment emotional regulation, and future-oriented meaning-making, MFT appears to support improvements in psychological coherence, self-continuity, and resilience. Further controlled and longitudinal studies are needed to confirm these effects and examine underlying mechanisms.
Comparative meta-analysis of task-related functional brain abnormalities in nonsuicidal self-injury and suicide attempt
BackgroundNonsuicidal self-injury (NSSI) and suicide attempt (SA) are two major self-injurious behaviors causing substantial suffering and socioeconomic burden. However, it remains unclear whether NSSI and SA are characterized by common or distinct brain dysregulations. Here, we aimed to identify shared and separable neurofunctional alterations during task engagement between NSSI and SA.MethodA coordinate-based meta-analysis was employed using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) by capitalizing on task-based functional magnetic resonance imaging (fMRI) studies comparing the brain activation between NSSI/SA individuals and controls.ResultThe search identified 10 studies for NSSI (n = 200, mean age: 22.89 years) and 16 studies for SA (n = 343, mean age: 28.65 years). After threshold-free cluster enhancement correction, NSSI individuals exhibited increased right amygdala activation relative to both controls and the SA group, as well as heightened left middle frontal gyrus and reduced left paracentral lobule activation compared to the SA group. No significant activation differences were found between SA and controls, though a less conservative threshold revealed increased left postcentral gyrus activation in the SA group. No shared functional abnormalities were identified between NSSI and SA under either corrected or uncorrected thresholds. Importantly, subgroup analyses revealed that the neurofunctional abnormalities in NSSI were primarily driven by adolescent cohorts, whereas no significant clusters emerged for the SA group across age-stratified analyses.ConclusionThese results suggest that neurofunctional abnormalities are evident in adolescent NSSI, particularly in fronto−limbic regions, with no robust findings in adult NSSI or SA subgroups. This highlights a unique developmental trajectory that necessitates age-tailored risk assessment and interventions for self-injurious behaviors.
Hair cortisol as psychotherapy process parameter – an inpatient pediatric psychosomatic study
IntroductionPediatric-psychosomatic inpatient therapy is an essential part of the German health care system for the treatment of mental disorders in children and adolescents. However, empirical research in this field remains scarce and limited to psychological parameters. This longitudinal naturalistic study aimed to evaluate the efficacy and sustainability of inpatient psychosomatic therapy in children and adolescents by examining both psychological outcomes and biological markers.MethodsA total of 58 patients were assessed at seven time points before, during, and after treatment. Hair cortisol concentration (HCC) was measured as a neuroendocrine parameter of long-term stress regulation. Psychometric data were collected using five validated questionnaires.ResultsFindings indicated significant improvements in perceived stress, depressive and anxiety symptoms, family functioning and internalizing symptoms in the course of inpatient treatment. Overall, these effects remained stable at three- and six-month follow-ups, with only transient increases in depressive symptoms and family problems. HCC showed a significant decrease from admission to discharge and remained stable across follow-ups.DiscussionThese results support the efficacy of inpatient pediatric psychosomatic interventions on both psychological outcomes and neuroendocrine stress regulation and highlight the value of integrating biological markers into psychotherapy research.
Synaptic output from suprachiasmatic nucleus cholecystokinin neurons regulates locomotor rhythmicity
BackgroundThe mammalian suprachiasmatic nucleus (SCN) serves as the master circadian pacemaker, which coordinates daily behavioral and physiological rhythms through functionally diverse neuronal subtypes. Cholecystokinin (CCK) is expressed in a subset of SCN neurons; however, its role in locomotor activity rhythms remains poorly understood.MethodsTo study the functional contribution of SCN CCK-expressing (SCNCCK) neurons, we selectively blocked synaptic transmission by injecting a Cre-dependent tetanus toxin (TeNT) viral vector into the SCN of CCK-IRES-Cre mice. Before and after the virus injection, spontaneous locomotor activity was continuously recorded under a 12:12 h light–dark (LD) cycle. Subsequently, we used Cre-dependent fluorescent reporter (mYongHong) to label SCNCCK neurons and performed whole-brain projection mapping to characterize their downstream connectivity.ResultsSynaptic inhibition of SCNCCK neurons significantly attenuated the strength of locomotor rhythmicity, resulting in reduced rhythm organization and a more uniform distribution of activity. This disruption was mainly driven by a significant decrease in dark-phase locomotor activity, while light-phase activity remained unchanged. Anatomically, SCNCCK neurons are widely projected along the anterior and posterior axes to multiple hypothalamic, thalamic, and limbic regions, including the medial preoptic area (MPA), paraventricular thalamic nucleus (PVT), paraventricular hypothalamic nucleus (PVH), anterior hypothalamic area (AHC), dorsomedial hypothalamic nucleus (DMH), ventromedial hypothalamic nucleus (VMH), and medial amygdala nucleus (MeA). Quantitative analysis revealed projections to these downstream regions, with moderate variation in projection density across targets.ConclusionTogether, these findings identify SCNCCK neurons as an important neuronal subpopulation, which contributes to the robustness and consolidation of spontaneous locomotor rhythms, likely through a wide range of downstream circuits.
Associations of TNF-α, MIF, and cortisol with cognitive function in patients with bipolar disorder during acute manic episodes: a short-term follow-up study
BackgroundBipolar disorder (BD) is frequently accompanied by cognitive impairment, and growing evidence suggests that immune-inflammatory activation and hypothalamic-pituitary-adrenal axis dysregulation may contribute to its pathophysiology. This study aimed to examine the associations of tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF), and cortisol (COR) with cognitive function in patients with BD during manic episodes and to characterize their short-term changes.MethodsIn this short-term follow-up study, 53 patients with BD during manic episodes and 53 healthy controls (HCs) were enrolled. Plasma TNF-α, MIF, and COR levels were measured using enzyme-linked immunosorbent assay. Cognitive function was assessed using the Chinese Brief Cognitive Test, including information processing speed (IPS), executive function (EF), sustained attention (SAT), and working memory (WM). Patients were evaluated at baseline and after 8 weeks of treatment, whereas HCs were assessed once at baseline. Group comparisons and biomarker–cognition correlation analyses were performed. Multiple testing in the correlation analyses was controlled using the Benjamini–Hochberg false discovery rate (FDR) procedure.ResultsAt both baseline and follow-up, patients with BD had significantly lower IPS, EF, SAT, and WM scores, but significantly higher plasma TNF-α, MIF, and COR levels, than HCs. After 8 weeks of treatment, cognitive scores in the BD group improved significantly, whereas reductions in TNF-α, MIF, and COR did not reach statistical significance. In exploratory unadjusted Pearson analyses, several biomarker–cognition associations survived FDR correction. However, in the primary adjusted partial correlation analyses, only the negative association between TNF-α and WM remained significant after adjustment for covariates and FDR correction at both baseline and follow-up.ConclusionPatients with BD during manic episodes exhibited widespread cognitive impairment accompanied by elevated inflammatory and neuroendocrine markers. TNF-α showed the most robust association with working memory after adjustment for covariates and correction for multiple comparisons. Associations involving MIF or cortisol and executive function should be interpreted as exploratory and require validation in larger longitudinal studies.
Women with Parkinson’s Have More Amyloid Plaques than Men
A study led by the Mayo Clinic Arizona shows women with Parkinson’s disease have greater amyloid plaque burden than men with the condition, even after controlling for factors like carriage of the APOE4 Alzheimer’s disease susceptibility gene variant.
As reported at the European Academy of Neurology Congress in Geneva this week, 57% of women included in the study had a high amyloid plaque burden versus 40% of the men.
Amyloid-beta is a protein fragment that normally gets cleared from the brain. In Alzheimer’s disease, it misfolds and aggregates into oligomers and plaques between neurons. This disrupts synaptic signaling, activates neuroinflammation, and promotes tau protein hyperphosphorylation into neurofibrillary tangles as the disease progresses.
In contrast, Parkinson’s disease is caused by the misfolding and clumping of a protein called alpha-synuclein into toxic deposits known as Lewy bodies, which build up in and destroy the neurons that produce dopamine in a brain region called the substantia nigra. While Parkinson’s is known for its characteristic motor symptoms, at least 25% also have dementia-like symptoms similar to those seen in Alzheimer’s disease. Amyloid beta plaques are thought to worsen Parkinson’s disease and increase the risk of dementia symptoms.
There are known differences in the prevalence and symptoms shown by men and women with Parkinson’s disease. To investigate this further, 230 people enrolled in the Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program were included in this study after death. Amyloid burden in the brain was assessed during autopsy. Other clinical factors such as cognition and symptoms were recorded prior to death.
The study found that amyloid plaque burden in women was higher than in men with Alzheimer’s. For example, mean cortical total plaque score in women was 6.5/15 vs 4.9/15 in men. Neuritic plaque density was also higher in women at 1.7/3 compared with 1.3/3 in men.
After correcting for age at death and APOE4 status, women in the study were more than twice as likely to have a high plaque burden than men.
This did not seem to translate to cognitive differences between men and women in the study though. “Men and women with Parkinson’s disease had similar rates of Alzheimer’s dementia and similar results on cognitive testing. However, women showed a higher amyloid plaque burden compared with men,” explained presenting author Erika Driver-Dunckley, MD, Mayo Clinic Arizona, in a press statement.
Notably, in standard Parkinson’s disease, men are at higher risk of developing dementia than women, so it is possible women have some protection from alpha-synuclein-driven decline but not from damage linked to amyloid accumulation. Women with Parkinson’s also live longer than men with the condition, as well as being more prone to amyloid buildup and Alzheimer’s disease, which complicates understanding the meaning of these results.
“Our findings highlight the need for further research into sex differences in Parkinson’s disease and Alzheimer’s-related pathology,” concluded Driver-Dunckley. “An important next step will be to confirm these findings in additional large clinicopathological studies and better understand the biological mechanisms that may underlie these differences.
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