| 1. |
- Kaltsouni, Elisavet
(författare)
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Neuroimaging progesterone receptor modulation in patients with premenstrual dysphoric disorder : Is it just in your head?
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Premenstrual dysphoric disorder (PMDD) is a menstrually related mood disorder affecting about 5% of women during their reproductive years. The disorder is cyclic, with the symptomatology namely occurring at the luteal phase of a menstrual cycle, for most ovulatory menstrual cycles and entails a series of mood and physical symptoms. A neural susceptibility to regular hormonal fluctuations is hypothesized as the neuropathophysiological mechanism. While treatment options, such as selective serotonin reuptake inhibitors and hormonal interventions, are available, the neural mechanisms underlying symptom relief remain largely unclear. In this series of studies, a multimodal neuroimaging design was approach was used to reveal the neural correlates of three-month, low-dose selective progesterone receptor modulator (SPRM) treatment in comparison to a placebo. This treatment has been demonstrated to be effective in alleviating psychological symptoms associated with PMDD. Thirty-five women with fulfilling the criteria of a PMDD diagnosis were randomized to treatment with SPRM or placebo, with structural and functional MRI scans conducted before and after randomization. Findings indicated enhanced fronto-cingulate activity during a reactive aggression task in the SPRM treatment group compared to placebo, along with a negative association between aggressive responding and brain activity in the placebo group. Resting state functional connectivity was additionally altered after treatment with SPRM in fronto-visual, temporo-insular, and temporo-cerebellar regions. Additionally, a positive correlation was observed between the reduction in cortisol levels and the decrease in temporo-insular connectivity. No treatment effects were observed on brain structure, including grey and white matter volume, as well as cortical surface architecture. Lastly, White matter microstructure integrity did not differ longitudinally but showed cross-sectional differences. In conclusion, the effects of SPRM treatment were primarily observed in brain function, specifically in terms of enhanced cognitive control processing in the context of reactive aggression and resting state functional connectivity in regions relevant to cognitive and sensorimotor processing, with no significant structural alterations noted. Taken together, these findings confirm that the fluctuations rather than absolute levels of ovarian hormones are primary contributing to premenstrual symptomatology, potentially through hormonal-state dependent functional correlates.
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| 2. |
- Nelander, Maria, 1974-
(författare)
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Preeclampsia and the Brain : Epidemiological and Magnetic Resonance Studies
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is a pregnancy specific syndrome that causes substantial maternal and fetal morbidity and mortality. One major contributor to maternal deaths is eclampsia, i.e. when seizures arise in the context of preeclampsia. The pathophysiology of eclampsia is still incompletely chartered and the long-term cerebral consequences of preeclampsia are also largely unknown.This thesis consists of a register based cohort study (n=3232, study I), and a cross-sectional neuroimaging study of pregnant women with and without preeclampsia (n=78, studies II-IV).In paper I, we compared the incidence of dementia and cardiovascular disease (CVD) between women ≥65 years with a self-reported history of hypertensive pregnancy, and women with a normotensive pregnancy. No difference was found regarding dementia, but an increased risk of CVD persisted among these elderly women.In paper II, we used phosphorus magnetic resonance spectroscopy to measure cerebral magnesium levels (Mg2+). We found lower levels of Mg2+ in women with preeclampsia than in women with normal pregnancy and non-pregnant women. Further, which was novel, we showed that lower cerebral Mg2+levels correlated with visual disturbances. The findings are interesting, since magnesium sulfate is the most effective treatment and prophylaxis for eclampsia, but with a largely unknown mechanism of action.In paper III, we measured cerebral organic osmolytes with proton magnetic resonance spectroscopy and found lower levels of osmolytes in pregnancy. Cerebral osmolytes were positively correlated with a decreased plasma osmolality, indicating that there is a joint biological mechanism. The only osmolyte that differed between women with preeclampsia and healthy pregnant women was glutamate. Glutamate is an excitatory neurotransmitter, which also functions as an osmolyte. Thus, lower cerebral glutamate levels could have implications on the pathophysiology of seizures.In paper IV, cerebral perfusion and edema were assessed with magnetic resonance imaging using intravoxel incoherent motion technique. A reduced perfusion fraction was found in a part of the basal ganglia in women with preeclampsia. No difference in edema was detected.Our findings indicate Mg2+ metabolism, plasma hypoosmolality and possibly cerebral hypoperfusion to be involved in the pathophysiology of cerebral affection in preeclampsia.
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| 3. |
- Correia de Verdier, Maria, 1983-
(författare)
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Evaluation of Intracranial Arteriovenous Malformations with Magnetic Resonance Imaging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Intracranial arteriovenous malformations (AVMs) are characterized by feeding arteries, a tangle of abnormal vessels (nidus) and draining veins. Radiological evaluation methods are used in diagnosing AVMs, treatment planning, post-treatment evaluation and monitoring stability. The general aim of our studies reviewed in this thesis was to develop and evaluate magnetic resonance imaging (MRI) techniques for the evaluation of AVMs. MethodsPaper I – In 30 patients treated with proton radiation therapy, radiation-induced MRI changes (vasogenic edema, contrast enhancement and cavitation) and their association with development of neurological symptoms and nidus obliteration were assessed. Paper II – We evaluated the effect of acquisition parameters (voxel size, number of signal averages and velocity encoding) on the accuracy and precision of phase-contrast MRI (PC-MRI)-measured flow and velocity in a small-lumen vessel phantom with constant flow. Paper III – Normal ranges and test-retest reproducibility of flow and velocity in the anterior, middle and posterior cerebral arteries were measured with PC-MRI in 30 healthy volunteers.Paper IV – We studied PC-MRI-measured flow and velocity in feeding arteries in 10 patients with AVMs and compared the values obtained with the results from paper III. We also assessed post-treatment changes in flow and velocity in three patients. Results Paper I – Radiation-induced MRI changes were found in 87% of patients after proton radiation treatment of AVMs. MRI changes were associated with neurological symptoms but not with nidus obliteration. Paper II – PC-MRI overestimated flow in a small-lumen vessel phantom. Accuracy for flow measurements improved by decreasing voxel size. Precision for both flow and velocity measurements improved by increasing voxel size. Precision for flow measurements improved by increasing the number of signal averages.Paper III – We reported normal ranges and test-retest reproducibility for PC-MRI-measured flow and velocity in the main intracranial arteries. Reproducibility was overall quite low, but higher for the middle cerebral arteries than for the anterior and posterior cerebral arteries.Paper IV – Patients with a large nidus have increased velocity measured with PC-MRI in feeding arteries compared to intracranial arteries in healthy individuals. There is a reduction in PC-MRI-measured flow and velocity after treatment. ConclusionRadiation-induced MRI changes are common after proton radiation treatment of AVMs. The accuracy and precision of PC-MRI measurements in a phantom depend on acquisition parameter settings. In patients with AVMs with a large nidus, increased velocity is observed in feeding arteries, and a decrease in flow and velocity is observed after treatment. PC-MRI can potentially be used as a clinical tool to aid treatment planning and post-treatment evaluation.
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| 4. |
- Dubol, Manon, et al.
(författare)
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Acute nicotine exposure blocks aromatase in the limbic brain of healthy women : A [11C]cetrozole PET study
- 2023
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Ingår i: Comprehensive Psychiatry. - : Elsevier. - 0010-440X .- 1532-8384. ; 123
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Tidskriftsartikel (refereegranskat)abstract
- Background: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain.Methods: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI -based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential.Results: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d =-0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend.Conclusions: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.
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| 5. |
- Kaltsouni, Elisavet, et al.
(författare)
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Selective progesterone receptor modulation and brain activity at rest in patients with premenstrual dysphoric disorder
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian hormones have been indicated to impact brain connectivity and mood. However, there is no consistent evidence on hormone-dependent functional connectivity and mental health. Alterations in resting state networks have been suggested as markers of affective disorders, but only preliminary evidence is provided on premenstrual dysphoric disorder, in which symptoms occur upon fluctuations of ovarian hormones. Recently, three-month low-dose selective progesterone receptor modulator (SPRM) administration has been associated with symptom relief and altered task-based brain reactivity during a reactive aggression condition. The present study sought to investigate the effect of this treatment on resting state functional connectivity (rs-FC) in patients with PMDD. Seed-based analyses were conducted, including including seeds from the classic resting state networks along with the functional cluster affected by SPRM treatment. Within previously identified networks related with emotional processing, rs-FC was compared between individuals with PMDD during the symptomatic luteal phase before randomization to treatment or placebo and during the end of the last treatment cycle. Seed-based rs-FC analyses yielded significant treatment by time effects on rs-FC between the left posterior superior temporal gyrus and the right insula cortex, between the posterior cerebellum and the left temporal pole, and between the right lateral visual network and left superior frontal gyrus. Visuo-frontal luteal phase connectivity decreased for the SPRM group and was positively correlated with changes in mood symptom severity in the placebo group. Cerebellar and temporal connectivity increased for the SPRM treatment group, while temporo-insular connectivity decreased and was positively correlated with cortisol levels. These findings indicate that SPRM treatment influenced rs-FC, which could be a relevant mechanism behind symptom alleviation.
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| 6. |
- Kaltsouni, Elisavet, et al.
(författare)
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White matter integrity upon progesterone antagonism in individuals with premenstrual dysphoric disorder: a randomized placebo-controlled diffusion tensor imaging study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Premenstrual dysphoric disorder (PMDD) is a depressive disorder triggered by fluctuations of progesterone and estradiol during the luteal phase of the menstrual cycle. Selective progesterone receptor modulation (SPRM), while exerting an antagonistic effect on progesterone and maintaining the estradiol on moderate levels, has shown beneficial effects on the mental symptoms of PMDD. Progesterone is also known for its neuroprotective effects, while synthetic progestins have been suggested to promote myelination. However, the impact of this treatment on white matter neuroanatomy is unexplored. Diffusion tensor imaging was used to collect data on white matter integrity in patients with PMDD, before and after treatment with ulipristal acetate (an SPRM) or placebo, as part of a double-blind randomized controlled-trial. Tract based spatial statistics were performed to investigate SPRM treatment vs. placebo longitudinal effects on fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) on the whole white matter skeleton. Voxel-wise analyses indicated no change over time in any white matter microstructure metrics in individuals treated with SPRM versus placebo. Improvement in PMDD symptoms did not correlate with changes in white matter microstructure. In secondary, cross-sectional comparisons during treatment, the SPRM group displayed lower FA and higher MD, RD, and AD in several tracts. The main findings suggest that SPRM treatment did not impact white matter microstructure. However, the between-group differences after treatment call for further investigation on the tracts potentially impacted by progesterone antagonism.
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| 7. |
- Kaltsouni, Elisavet, et al.
(författare)
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White matter volume and treatment with selective progesterone receptor modulator in patients with premenstrual dysphoric disorder
- 2024
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 163
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Tidskriftsartikel (refereegranskat)abstract
- Premenstrual dysphoric disorder (PMDD) is a mood disorder for which selective progesterone receptor modulator (SPRM) treatment has been demonstrated to be beneficial. The neural signatures of this treatment have been so far identified as greater fronto-cingulate reactivity during aggressive response to provocation, but no changes in terms of gray matter structure. White matter has recently been found to differ between patients with PMDD and healthy controls. The present study thus sought to investigate the relationship between white matter volume and SPRM treatment in patients with PMDD. A pharmaco-neuroimaging study was conducted on patients with PMDD participating in a randomized controlled trial. Participants underwent magnetic resonance imaging before and after treatment randomization to ulipristal acetate (an SPRM), or placebo, for three months. The interaction effect of treatment by time on white matter volume (WMV) was assessed. Voxel based morphometry analyses were performed on both a whole brain exploratory level and on regions of interest. No treatment effect was observed on WMV in any region, including the anterior thalamic radiations, cingulum, forceps minor, fornix, inferior fronto-occipital fasciculus, superior cerebellar peduncle, superior longitudinal fasciculus, and uncinate fasciculus. This is the first finding to indicate that no white matter volume alterations follow three-month progesterone antagonism, suggesting that white matter volume does not participate in symptom relief upon SPRM treatment for PMDD.
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| 8. |
- Katsarogiannis, Evangelos, et al.
(författare)
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Absence of Oligoclonal Bands in Multiple Sclerosis : A Call for Differential Diagnosis
- 2023
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 12:14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immunoglobulin gamma (IgG) oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) are absent in a small group of multiple sclerosis (MS) patients. According to previous research, OCB-negative MS patients differ genetically but not clinically from OCB-positive MS patients. However, whether OCB-negative MS is a unique immunological and clinical entity remains unclear. The absence of OCB poses a significant challenge in diagnosing MS. (1)Objective: The objective of this study was twofold: (1) to determine the prevalence of OCB-negative MS patients in the Uppsala region, and (2) to assess the frequency of misdiagnosis in this patient group. (2)Methods: We conducted a retrospective study using data from the Swedish MS registry (SMSreg) covering 83% of prevalent MS cases up to 20 June 2020 to identify all MS patients in the Uppsala region. Subsequently, we collected relevant information from the medical records of all OCB-negative MS cases, including age of onset, gender, presenting symptoms, MRI features, phenotype, Expanded Disability Status Scale (EDSS) scores, and disease-modifying therapies (DMTs). (3) Results: Out of 759 MS patients identified, 69 had an OCB-negative MS diagnosis. Upon re-evaluation, 46 patients had a typical history and MRI findings of MS, while 23 had unusual clinical and/or radiologic features. An alternative diagnosis was established for the latter group, confirming the incorrectness of the initial MS diagnosis. The average EDSS score was 2.0 points higher in the MS group than in the non-MS group (p = 0.001). The overall misdiagnosis rate in the cohort was 33%, with 22% of misdiagnosed patients having received DMTs. (4)Conclusions: Our results confirm that the absence of OCB in the CSF should raise suspicion of possible misdiagnosis in MS patients and prompt a diagnostic reassessment.
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| 9. |
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| 10. |
- Almqvist Téran, Nicolas, et al.
(författare)
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Posterior Fossa Volume and Dimensions : Relation to Pathophysiology and Surgical Outcomes in Classic Trigeminal Neuralgia
- 2023
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Ingår i: World Neurosurgery. - : Elsevier. - 1878-8750 .- 1878-8769. ; 179, s. e397-e403
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A small posterior fossa (PF) has been hypothesized to explain the increased incidence of trigeminal neuralgia (TN) in females and could make microvascular decompression (MVD) more challenging. The aim of this study was to investigate the association between the PF volume and dimensions in relation to biological sex, type of neurovascular conflict (NVC), and outcome after MVD in classic TN.METHODS: In this observational study, 84 patients with TN operated on with MVD with a preoperative head computed tomography(CT) scan were included. Eighty-two adults without TN who had undergone head CT for other reasons were included as controls. PF volume and dimensions (x-axis, y-axis, and z-axis) were evaluated on the CT scans. For the patients with TN, Barrow Neurological Institute (BNI) grade was evaluated 6 months after MVD.RESULTS: There was no difference in PF volume or dimensions between the patients with TN and controls. Women showed a smaller volume and narrower (x-axis) PF than men, but these differences did not manifest when comparing patients with TN and controls within each sex. Patients with an NVC involving the superior cerebellar artery had a narrower (x-axis) and shorter (y-axis) PF than did patients with an NVC resulting from other arteries. PF volume or dimensions were not associated with BNI grade after MVD.CONCLUSIONS: PF anatomy was related to the NVC type but did not differ between patients with TN and controls and was not related to the surgical outcome after MVD.
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