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Background: Emotion regulation deficits have been highlighted as a transdiagnostic feature of multiple psychiatric disorders, including premenstrual dysphoric disorder (PMDD). In this study, we hypothesized that deficient prefrontal top-down regulation of key nodes of the salience network (SN) is a characteristic of PMDD, driven by increased levels of progesterone-derived neuroactive steroids.

Methods: Functional magnetic resonance imaging was used to investigate menstrual cycle–related variations in brain activity and connectivity during 2 emotional tasks (emotion generation and regulation) in 29 women with PMDD and 27 control women. We also examined whether differential brain activation between groups was related to serum levels of progesterone-derived neuroactive steroids and premenstrual symptom severity.

Results: Women with PMDD showed increased reactivity in key nodes of the SN and, at subthreshold level, in the default mode network during the luteal phase when passively viewing negative emotional stimuli. Intriguingly, SN hyperactivity in patients with PMDD was also apparent during the follicular phase and related to premenstrual symptom severity. Women with PMDD and control women had similar network connectivity patterns and activity in regions associated with the conscious control of emotion in PMDD. No link to progesterone-derived neuroactive steroids was found.

Conclusions: Multiple network aberrations during the luteal phase may explain the development of mood symptoms during the luteal phase. Furthermore, higher baseline (follicular) SN activity may render women with PMDD more susceptible to severe mood symptoms in response to hormonal fluctuations. What drives increased SN activity in the follicular phase is unknown, but innate and neuroplastic mechanisms have been proposed.

Positron emission tomography (PET) is a powerful, non-invasive imaging technique that provides high-resolution images of physiological functions in living human tissues. PET provides high-resolution data on biological processes, including blood perfusion, metabolic activity, and the availability of neurotransmitter and hormonal receptors. Therefore, sophisticated techniques like PET are crucial to advance our mechanistic understanding of how molecular systems are impacted by both acute and regular exercise and how these changes subsequently influence cognitive function. This chapter will summarize the fundamental principles of PET imaging, with a particular focus on its application for assessing the dopamine (DA) system in the human brain. The DA system, which includes DA, its receptors, and associated neural networks, plays a critical role in mediating a variety of physiological and behavioral processes. Substantial evidence now suggests a strong link between brain DA and cognitive function. We propose that the DA system serves as a key neural mechanism through which both acute and regular exercise enhances cognitive function. Finally, we discuss the future potential and applications of hybrid PET/magnetic resonance imaging systems in this field of research.

Depressive disorders are characterized by heterogeneous symptoms and variable treatment response. Current interventions primarily aim to manage symptoms, yet their effectiveness remains limited. This highlights the need for early neurobiological markers to improve understanding of depression pathophysiology and guide treatment development. In this study, 38 healthy participants aged 18–40 years (21 females and 17 males) completed the self-report version of the Montgomery-Åsberg Depression Rating Scale (MADRS-S), followed by proton magnetic resonance spectroscopy (1H-MRS) data acquisition from the anterior cingulate cortex (ACC). Spectra were acquired from the dorsal (dACC) and pregenual (pgACC) subdivisions, and analyses focused on metabolite levels of γ-aminobutyric acid (GABA), glutamate + glutamine (Glx), total N -acetyl aspartate (tNAA), and total creatine (tCr). Simple and multiple linear regression analyses, controlling for age, sex, tobacco use, and alcohol consumption, revealed a negative association between depressive symptom scores and tNAA/tCr levels in both the pgACC and dACC. However, no significant associations were observed for GABA/tCr or Glx/tCr. These findings suggest that reduced tNAA/tCr levels in the dACC and pgACC may be associated with depressive symptom severity in non-clinical individuals. Given that tNAA reflects neuronal integrity and mitochondrial function, its reduction may reflect early neuronal and metabolic variation associated with depressive symptom scores. Thus, tNAA may represent an in vivo biomarker for early affective vulnerability, potentially enabling detection of depressive symptom scores in healthy individuals.

Studies have shown the beneficial effects of musical instrument on memory and executive function in healthy aging. However, few studies investigated these long-term benefits. In this regard, the current study tracked a cohort of older adults (n = 53) over 4 years after they have initially participated in a musical instrument training program. Out of the initial sample, 13 of them voluntarily continued participating in the musical instrument training (continue group: 77.85 ± 4.30 years, 10 female, 3 male), while 19 of them discontinued their participation in the music program and instead engaged in other forms of leisure activities (stop group: age: 76.00 ± 5.44 years, 13 female, 6 male). At baseline, behavioral measures of verbal working memory (WM), verbal memory, and executive control were collected. In addition, participants completed a visual WM task (face n-back task) during fMRI scanning. Four years later, the same battery of tests was administered, with the addition of a digit n-back task to examine changes in verbal WM. Region-of-interest structural analyses focused on the striatum and cerebellum, based on previously reported intervention effects and the advantages observed in musicians. The continue group demonstrated better preservation of verbal WM performance (a composite score of Digit Span and Verbal Fluency tasks) and right putamen gray matter volume (GMV) over 4 years. During verbal WM processing, this group exhibited lower cerebellum–pons functional connectivity (FC), which significantly correlated with improved verbal WM performance. Moreover, the continue group also showed greater cerebellar activation during the digit task, increased intra-cerebellar FC, and decreased cerebellar–cortical FC during the face task. The combined evidence suggested enhanced cerebellar function and thus reduced reliance on other brain regions such as the cortical areas and brainstem for compensation. Taken together, these results suggested the musical instrument training effects in mitigating age-related decline in verbal WM and subcortical structure (putamen) and function (cerebellum). This study provides longitudinal evidence that initiating musical instrument training in older adulthood can counteract age-related cognitive and brain decline.

The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.

While the dopaminergic system is important for cognitive processes, it is also sensitive to the influence of physical activity (PA). We summarize current evidence on whether PA-related changes in the human dopaminergic system are associated with alterations in cognitive performance, discuss recent advances, and highlight challenges and opportunities for future research.

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

Background: Autonomous motivation to exercise occurs when the activity is voluntary and with a perceived inherent satisfaction from the activity itself. It has been suggested that autonomous motivation is related to striatal dopamine D2/3-receptor (D2/3R) availability within the brain. In this study, we hypothesized that D2/3R availability in three striatal regions (nucleus accumbens, caudate nucleus, and putamen) would be positively associated with self-reported autonomous motivation to exercise. We also examined this relationship with additional exploratory analyses across a set of a priori extrastriatal regions of interest (ROI).

Methods: Our sample comprised 49 older adults (28 females) between 64 and 78 years of age. The D2/3R availability was quantified from positron emission tomography using the non-displaceable binding potential of [11C]-raclopride ligand. The exercise-related autonomous motivation was assessed with the Swedish version of the Behavioral Regulations in Exercise Questionnaire-2.

Results: No significant associations were observed between self-reported autonomous motivation to exercise and D2/3R availability within the striatum (nucleus accumbens, caudate nucleus, and putamen) using semi-partial correlations controlling for ROI volume on D2/3R availability. For exploratory analyses, positive associations were observed for the superior (r = 0.289, p = 0.023) and middle frontal gyrus (r = 0.330, p = 0.011), but not for the inferior frontal gyrus, orbitofrontal cortex, anterior cingulate cortex, or anterior insular cortex.

Conclusion: This study could not confirm the suggested link between striatal D2/3R availability and subjective autonomous motivation to exercise among older adults. The exploratory findings, however, propose that frontal brain regions may be involved in the intrinsic regulation of exercise-related behaviors, though this has to be confirmed by future studies using a more suitable ligand and objective measures of physical activity levels.

Background: Dopamine transporter (DAT) imaging is used in the diagnostic work-up in suspected parkinsonian syndromes and dementia with Lewy bodies but cannot differentiate between these syndromes, and an extra brain imaging examination of the regional cerebral blood flow (rCBF) or glucose metabolism is often needed for differential diagnosis. The requirement of two different imaging examinations is resource-consuming and inconvenient for the patients. Therefore, imaging of both cortical blood flow and DAT imaging with the same radiotracer would be more convenient and cost-effective. The aim of this study was to test whether relative regional cerebral blood flow (rCBFR) can be measured with the DAT-specific positron emission tomography (PET) tracer [18F]FE-PE2I (FE-PE2I), by validation with cerebral perfusion measured with [15O]H2O PET (H2O).

Methods: The rCBFR was quantified by kinetic modeling for FE-PE2I (R1) and H2O (F). The R1 was calculated using the simplified reference tissue model, and F was calculated with a modified Koopman double-integration method. The linear relationship and intraclass correlation (ICC) between R1 and F were tested in image data derived from 29 patients with recent onset parkinsonism and 30 healthy controls.

Results: There was a strong linear correlation across all subjects between R1 and F in the frontal, parietal, temporal, cingulate and occipital cortex as well as in the striatum (r ≥ 0.731–0.905, p < 0.001) with a good-to-excellent ICC, ranging from 0.727 to 0.943 (p < 0.001).

Conclusions: Our results suggest that FE-PE2I may be used as a proxy for cerebral perfusion, thus potentially serving as a radiotracer for assessment of both DAT availability and rCBFR in one single dynamic scan. This could be valuable in the differential diagnosis of parkinsonian syndromes.

Trial registration: EUDRA-CT 2015-003045-26. Registered 23 October 2015 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003045-26