Biology subjects

Nuutila, P.

Publications and source records attributed to Nuutila, P..

16 recordsLinked to original sources

bioRxiv2026

Diurnal and seasonal regulation of brain mu-opioid and dopamine D2 receptor signalling in humans

Purpose: Rhythmic regulation of human neurotransmission systems, particularly the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) signaling, remains poorly understood. Although prior studies indicate possible diurnal fluctuations in D2R signaling, potential existence of diurnal rhythms in MOR signaling has yet to be investigated. Furthermore, whether and how seasonal factors may override or interact with diurnal rhythms in either system remains unexplored. Decoding these temporal dynamics and their possible links to behavioral traits, such as anxiety, may improve mood regulation models and inspire rhythm-tailored interventions. Methods: Based on a historical PET database of healthy humans scanned with [11C]carfentanil (n = 188) and [11C]raclopride (n = 184), we investigated the diurnal patterns of MOR and D2R availability in the brain, using time-of-day (TOD) of scanning as predictor. Furthermore, we examined whether the TOD differences in receptor availability were modulated by seasonal differences in the daylength (D2R and MOR) and trait-anxiety (MOR). Results: The data revealed increased MOR and decreased D2R availability in the afternoon compared to the morning scans. Interaction with the seasonal effect was, however, observed only for MOR availability, spanning brain areas including anterior cingulate, dorsomedial and dorsolateral prefrontal cortex, insula and striatum. Besides, the diurnal variation of MOR availability in these regions was also sensitive to trait-anxiety levels. Conclusions: The current results reveal the diurnal patterns in opioidergic and dopaminergic neurotransmission with an opposing trajectory. Furthermore, the data highlight a unique role of the MOR system, mediating both types of rhythmic regulations, as well as behavioral traits.

neuroscience↗

bioRxiv2025

TURBO: Automated Total-body PET Image Processing and Kinetic Modeling Toolbox

Long axial field of view (LAFOV) PET imaging requires a high level of automation and standardization, as the large number of target tissues increases the manual workload significantly. We introduce an automated analysis pipeline (TurBO, Turku total-BOdy) for preprocessing and kinetic modelling of LAFOV [15O]H2O and [18F]FDG PET data, enabling efficient and reproducible analysis of tissue perfusion and metabolism at regional and voxel-levels. The approach employs automated processing including co-registration, motion correction, automated CT segmentation for region of interest (ROI) delineation, image-derived input determination, and region-specific kinetic modelling of PET data. MethodsWe validated the analysis pipeline using Biograph Vision Quadra (Siemens Healthineers) LAFOV PET/CT scans from 21 subjects scanned with [15O]H2O and 16 subjects scanned with [18F]FDG using six segmented CT-based ROIs (cortical brain gray matter, left iliopsoas muscle, right kidney cortex and medulla, pancreas, spleen and liver) representing different levels of blood flow and glucose metabolism. ResultsModel fits showed good quality with consistent parameter estimates at both regional and voxel-levels (R{superscript 2} > 0.83 for [15O]H2O, R{superscript 2} > 0.99 for [18F]FDG). Estimates from manual and automated input functions were in concordance (R{superscript 2} > 0.74 for [15O]H2O, and R{superscript 2} > 0.78 for [18F]FDG) with minimal bias (<4% for [15O]H2O and <10% for [18F]FDG). Manually and automatically (CT-based) extracted ROI level data showed strong agreement (R{superscript 2} > 0.82 for [15O]H2O and R{superscript 2} > 0.83 for [18F]FDG), while motion correction had little impact on parameter estimates (R{superscript 2} > 0.71 for [15O]H2O and R{superscript 2} > 0.78 for [18F]FDG) compared with uncorrected data. ConclusionOur automated analysis pipeline provides reliable and reproducible parameter estimates across different regions, with an approximate processing time of 1-1.5 h per subject. This pipeline completely automates LAFOV PET analysis, reducing manual effort and enabling reproducible studies of inter-organ blood flow and metabolism, including brain-body interactions.

neuroscience↗

bioRxiv2024

Photoperiodicity in Glucose Metabolism in the Human Brain

Photoperiodicity in the human brain function, which is a critical factor for social well-being, has been widely debated. In this study, 432 healthy males underwent fasting-state brain [18F]fluorodeoxyglucose positron emission tomography (PET) scanning twice: first at the baseline and then at the 5-year follow-up. We analyzed the effect of day length on brain glucose uptake separately for the baseline and follow-up studies and examined changes in glucose consumption as a function of the day length deviation for each participant between the repeated PET scans. Glucose uptake in the cuneus was consistently predicted by the day length on the day of scanning and by within-participant day length deviations. This longitudinal large-scale PET study provides a landmark evidence for photoperiodicity in glucose metabolism in the human brain. The cuneus may be an essential part of the visual cortex, translating environmental photoperiodic changes into temporal cues that influence cognitive function and social behavior. Significance statementPhotoperiodicity in the human brain function has been widely debated. The current study provides a landmark evidence in this regard by demonstrating how the photoperiod shapes glucose metabolism in the brain of healthy males, highlighting the crucial role of the cuneus in processing visual information related to photoperiodic changes in the environment. Understanding photoperiodicity in the function of the human brain offers insights into how humans adapt to their environments for social well-being and underscores the potential health implications of changes in the exposure of natural light.

neuroscience↗

bioRxiv2024

Reward responses to vicarious feeding depend on BMI

Eating is inherently social for humans. Yet, most neuroimaging studies of appetite and food-induced reward have focused on studying brain responses to food intake or viewing pictures of food alone. Here we used functional magnetic resonance imaging (fMRI) to measure haemodynamic responses to "vicarious" feeding. The subjects (n=97) viewed series of short videos representing naturalistic episodes of social eating intermixed with videos without feeding / appetite related content. Viewing the vicarious feeding (versus control) videos activated motor and premotor cortices, thalamus, and dorsolateral prefrontal cortices, consistent with somatomotor and affective engagement. Responses to the feeding videos were also downregulated as a function of the participants BMI. Altogether these results suggest that seeing others eating engages the corresponding motor and affective programs in the viewers brain, potentially increasing appetite and promoting mutual feeding.

neuroscience↗

bioRxiv2023

Seasonal variation in D2/3 dopamine receptor availability in the human brain

Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic in vivo dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. Here, based on historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. We found that daylength at the time of scanning was negatively correlated with availability of this type of receptors in the striatum. Likely, seasonally varying D2/3 receptor signaling also underlies the seasonality of mood, feeding, and motivational processes. Significance of the studyBrain in vivo neurotransmitter signaling demonstrates seasonal patterns. The dopamine D2/3 receptor, with both pre- and postsynaptic expressions, has been targeted by major antipsychotic and antiparkinsonian pharmaceuticals. The current study, based on a large dataset of healthy brain PET images quantifying these receptors, shows that dark seasons are associated with increased receptor availability in the striatum. Considering the previous findings of increased dopamine synthesis and lowered number of transporters, findings may suggest elevated presynaptic control of dopamine release and increased dopamine receptor sensitivity during dark seasons. The rhythmic D2/3 receptor availability may be a mechanism underlying seasonality in mood, feeding, and motivational processes.

neuroscience↗

bioRxiv2023

Quantifying stem cell derived islet graft volume and composition with FDOPA positron emission tomography

Stem cell derived islets (SC-islets) are being developed as a novel source of beta cells that would enable large scale cell replacement therapy for insulin dependent diabetes. Therapeutic use of SC-islets carries an inherent risk of unwanted growth; and multiple strategies are being explored for optimizing long-term SC-islet graft effectiveness. However, a method for noninvasive in vivo monitoring for SC-islet graft safety and efficacy is lacking, as current insulin secretion measurements are inadequate. Here, we demonstrate the potential of positron emission tomography (PET) for monitoring SC-islet grafts using two tracers: GLP1-receptor binding [18F]F-DBCO-exendin and dopamine precursor [18F]FDOPA. We could detect and longitudinally monitor human SC-islet grafts in calf muscles of immunocompromised mice. Importantly, graft volume quantified with PET strongly correlated with actual graft volume (r2=0.91 for [18F]F-DBCO-exendin). PET using [18F]F-DBCO-exendin allowed delineation of cystic structures and its uptake correlated with graft beta cell proportion, enabling study of SC-islet graft purity noninvasively. [18F]FDOPA performed similarly to [18F]F-DBCO-exendin, but with slightly weaker sensitivity. Uptake of neither tracer was biased in SC-islet grafts genetically rendered hyper- or hypoactive. Insulin secretion measurements under fasted, glucose-stimulated or hypoglycemic conditions did not correlate with graft volume. In conclusion, [18F]F-DBCO-exendin and [18F]FDOPA PET constitute powerful approaches to noninvasively assess SC-islet graft volume and composition regardless of their functionality. PET imaging could therefore be leveraged for optimizing safety and effectiveness of SC-islet grafts in patients with insulin dependent diabetes.

cell biology↗

bioRxiv2023

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort

Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls and subjects with Parkinsons disease (PD), antipsychotic-naive schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability using Bayesian mixed effects modeling. Subjects with PD showed clearest decline in D2R availability. Healthy controls and patients with PD showed high interregional correlation of D2R availability, while this pattern was weaker in schizophrenia, severe violent behavior, and depression. Subjects with pathological gambling or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also the connectivity between the regions. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region connectivity might be disrupted in affective symptoms. HighlightsWe compared human striatal and thalamic type 2 dopamine receptor (D2R) availability between healthy controls, and subjects with Parkinsons disease (PD), antipsychotic-naive schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We present the mean brain maps of group specific D2R availabilities in NeuroVault (https://neurovault.org; https://identifiers.org/neurovault.collection:12799). Dopamine type 2 receptor availability is lowered in PD in caudate nucleus, nucleus accumbens and thalamus. Antipsychotic-naive schizophrenia, severe violent behavior, and depression were associated with decreased connectivity between the striatal and thalamic D2R availability. Altered regional D2R availability in the striatum and thalamus is linked with motor disorders, while lowered regional connectivity in D2R might relate to affective disturbance.

neuroscience↗

bioRxiv2022

Secretin modulates appetite via brown adipose tissue - brain axis

Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is unknown. In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]FDG-PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin down-regulated the brain response to appetizing food images and improved inhibitory control. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling pattern promoted satiation. These findings suggest that secretin modulates the BAT-brain metabolic crosstalk and subsequent neurometabolic coupling to induce satiation, bearing potential clinical benefits for treating eating disorders. Significance of the studySecretin activates brown adipose tissue and induces satiation, but the underlying brain mechanisms are still unclear. This placebo-controlled PET-fMRI study uses brain metabolic and BOLD measures to dissect the modulatory effects of secretin on brain functions associative to satiation. Findings show that secretin i) modulates caudate glucose metabolism via the BAT-brain axis, ii) enhances BOLD response in inhibitory control, and iii) reduces reward-related BOLD response. Further evidence shows that these measured effects are tightly linked via the secretin-mediated brain neurometabolic coupling. This study significantly advances our knowledge on how secretin leads to satiation and highlights the potential role of secretin in treating eating disorders and obesity.

neuroscience↗

bioRxiv2022

Photoperiod modulates mu-opioid receptor availability in brown adipose tissue

Photoperiod drives metabolic activity of brown adipose tissue (BAT), and affects food intake and weight gain in mammals. Sympathetic innervation in BAT controls thermogenesis and facilitates physiological adaption to seasons, but the exact mechanism remains elusive. Previous studies show that the central opioid signaling tunes BAT heating and the brain muopioid receptor (MOR) levels have seasonal patterns. It is hence intriguing to know whether the peripheral MOR signaling shows seasonal variation. Here, we examined the effect of photoperiod on BAT MOR availability using [11C]carfentanil positron emission topography (PET). Adult rats (n = 9) were repeatedly imaged under changing photoperiods which simulates the local seasons. Long photoperiod downregulated MOR availability in BAT, while MOR availability in the muscles was unaffected. We confirmed the expression of MOR in BAT and muscle using immunofluorescence imaging. We conclude that photoperiod causally affects MOR availability in BAT, and sympathetic innervation of BAT may influence thermogenesis via the peripheral MOR system. Significance of the studyPhotoperiod impacts the metabolic activity of brown adipose tissue (BAT) with the exact mechanism still unclear. The current study shows that photoperiod causally affects the mu-opioid receptor (MOR) levels in BAT, with longer photoperiod leading to lower MOR availability. This possibly indicates down-regulated innervation during bright seasons. Immunofluorescence staining data reveal expression of MOR in both brain and peripheral tissues, drawing attention to the under-investigated peripheral MOR system. Also, the study highlights the feasibility of [11C]carfentanil PET in studying the peripheral MOR signaling.

molecular biology↗

bioRxiv2022

The predictive power of mRNA mapping for Cannabinoid 1 receptor protein in the human brain

Type 1 cannabinoid (CB1) receptor is expressed in cortex, hippocampus, amygdala, basal ganglia, and cerebellum. With the help of the Allen Human Brain Atlas, genomic maps visualize not only the gene expression across whole brain regions, but also the functional profile of brain structures. Therefore, it is more timely than ever to integrate genomic mapping from brain mRNA atlas with the protein expression from positron emission tomography (PET) scans for better understanding of CB1 receptor of the human brain. F18-FMPEP-d2 PET scans were retrieved from the AIVO neuroinformatics project. Autoradiography data were based on the study with H3-CP55940. mRNA expressions of CNR1 gene (Cannabinoid receptor 1) were downloaded from the Allen Human Brain Atlas. Volume of distribution (VT) from F18-FMPEP-d2 PET scans, CNR1 gene expression, and H3-CP55940 binding were calculated and Spearman correlation analysis was performed. Also, a meta-analysis was done to investigate the association between protein expression from PET and mRNA expression from the Allen Human Brain Atlas. Between VT of F18-FMPEP-d2 PET scans and CNR1 mRNA expression, moderate strength of correlation was observed (rho = 0.5026, p = 0.0354). Strong positive correlation was also found between CNR1 mRNA expression and H3-CP55940 binding (rho = 0.6727, p = 0.0281), validating the finding between F18-FMPEP-d2 PET scans and CNR1 mRNA. From the meta-analysis, the correlation coefficient ranged from -0.46 to 0.99, with a pooled effect of 0.58. In conclusion, the moderate to strong associations between gene and protein expression for CB1 receptor in the human brain were observed that CNR1 mRNA mapping might have the predictive power for in vivo CB1 receptor protein expression. From the meta-analysis, the moderate to strong correlation was observed between mRNA expression and protein expressions across multiple genes, showing the predictive power of genes to estimate protein levels of human brains. HIGHLIGHTSO_LIWe investigated the association between CNR1 gene expression from the Allen Human Brain Atlas and type 1 cannabinoid (CB1) receptor expression from F18-FMPEP-d2 PET scans. C_LIO_LIThe moderate to strong associations between gene and protein expression for CB1 receptor in the human brain were observed that CNR1 mRNA mapping might have the predictive power for in vivo CB1 receptor protein expression. C_LIO_LIFrom the meta-analysis, the moderate to strong correlation was observed between mRNA expression and protein expressions across multiple genes, showing the predictive power of genes to estimate protein levels of human brains. C_LI

neuroscience↗

bioRxiv2021

Age and sex dependent variability of type 2 dopamine receptors in the human brain: A large-scale PET cohort

BACKGROUNDThe dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved. METHODSIn this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018. RESULTSStriatal D2R availability decreased through age for both sexes and was higher in females versus males throughout age. BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135). CONCLUSIONSD2R density is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.

neuroscience↗

bioRxiv2021

Endogenous μ-opioid receptor system modulates sex drive in human males

The endogenous mu-opioid receptor (MOR) system modulates a multitude of social and reward-related functions, and exogenous opiates also influence sex drive in humans and animals. Sex drive shows substantial variation across humans, and it is possible that individual differences in MOR availability underlie interindividual of variation in human sex drive. Here we measured healthy male subjects (n=52) brains MOR availability with positron emission tomography (PET) using an agonist radioligand, [11C]carfentanil, that has high affinity for MORs. Sex drive was measured using self-reports of engaging in sexual behaviour (sex with partner and masturbating). Bayesian hierarchical regression analysis revealed that sex drive was positively associated with MOR availability in cortical and subcortical areas, notably in caudate nucleus, hippocampus, and cingulate cortices. These results were replicated in full-volume GLM analysis. These widespread effects are in line with high spatial autocorrelation in MOR expression in human brain. Complementary voxel-based morphometry analysis (n=108) provided limited evidence for association between sex drive and cortical density in the midcingulate cortex. We conclude that endogenous MOR tone is associated with individual differences in sex drive in human males.

neuroscience↗

bioRxiv2020

Cerebral μ-opioid and CB1-receptor systems have distinct roles in human feeding behavior

Eating behavior varies greatly between healthy individuals, but the neurobiological basis of these trait-like differences in feeding remains unknown. Central {micro}-opioid receptors (MOR) and cannabinoid CB1-receptors (CB1R) regulate energy balance via multiple neural pathways, promoting food intake and reward. Because obesity and eating disorders have been associated with alterations in the brains opioid and endocannabinoid signaling, the variation in MOR and CB1R system function could potentially underlie distinct eating behavior phenotypes. In this retrospective positron emission tomography (PET) study, we analyzed [11C]carfentanil PET scans of MORs from 92 healthy subjects (70 males and 22 females), and [18F]FMPEP-d2 scans of CB1Rs from 35 subjects (all males, all also included in the [11C]carfentanil sample). Eating styles were measured with the Dutch Eating Behavior Questionnaire (DEBQ). We found that lower cerebral MOR availability was associated with increased external eating - individuals with low MORs reported being more likely to eat in response to environments palatable food cues. CB1R availability was associated with multiple eating behavior traits. We conclude that although MORs and CB1Rs overlap anatomically and functionally in the brain, they have distinct roles in mediating individual feeding patterns.

neuroscience↗

bioRxiv2020

Mesolimbic opioid-dopamine interaction is disrupted in obesity but recovered by weight loss following bariatric surgery

BackgroundObesity is a growing burden to health and economy worldwide. Obesity is associated with central -opioid receptor (MOR) downregulation, and the interaction between MOR and dopamine D2 receptor (D2R) system in the ventral striatum is disrupted among obese subjects. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying subjects undergoing surgical weight loss (bariatric surgery) procedure. MethodsWe recruited 20 healthy non-obese (mean BMI 22) and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability was measured using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed to obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery. ResultsIn the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but unaltered association in dorsal caudate (r = .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss (mean total weight loss 22 %). ConclusionsBariatric surgery and concomitant weight loss recovers the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioural interventions for treating obesity. Clinical Trials RegistrationSleevePET2, NCT01373892, http://www.clinicaltrials.gov

neuroscience↗

bioRxiv2020

Seasonal variation in brain mu-opioid receptor availability

Seasonal rhythms influence mood and sociability. The brain -opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we studied the seasonal effects on brain MOR availability via analysing a dataset (n=204) of [11C]carfentanil positron emission tomography (PET) scans of healthy volunteers. We found that seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. Causal effect of daylength on brain MOR availability was further verified by a post hoc experiment with repeated PET imaging of rats (n=9) under seasonal photoperiodic simulation. Therefore, the in vivo brain MOR availability in normal humans shows significant seasonal variation, which aligns with expected seasonal variation in mood and suicidality.

neuroscience↗

bioRxiv2019

Interindividual variability and lateralization of μ-opioid receptors in the human brain

The brains {micro}-opioid receptors (MORs) are involved in analgesia, reward and mood regulation. Several neuropsychiatric diseases have been associated with dysfunctional MOR system, and there is also considerable variation in receptor density among healthy individuals. Sex, age, body mass and smoking have been proposed to influence the MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. Here we quantified in vivo MOR availability in the brains of 204 individuals with no neurologic or psychiatric disorders using positron emission tomography (PET) with tracer [11C]carfentanil. We then used Bayesian hierarchical modeling to estimate the effects of sex, age, body mass index (BMI) and smoking on [11C]carfentanil binding potential. We also examined hemispheric lateralization of MOR availability. Age had regionally specific effects on MOR availability, with age-dependent increase in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders.

neuroscience↗