Tuuli Maria Hietamies

All Publications

• UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Rijsketic, D. R., Casey, A. B., Barbosa, D. A., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M. B., Halpern, C. H., Williams, L. M., Malenka, R. C., Heifets, B. D. 2023

  Abstract

  The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2+/-;Ai14+ mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse.

  View details for DOI 10.1038/s41386-023-01613-4

  View details for PubMedID 37248402

  View details for PubMedCentralID 7007572

• The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis. Journal of affective disorders Hietamies, T. M., McInnes, L. A., Klise, A. J., Worley, M. J., Qian, J. J., Williams, L. M., Heifets, B. D., Levine, S. P. 2023

  Abstract

  Ketamine intravenous therapy (KIT) appears effective for treating depression in controlled trials testing a short series of infusions. A rapidly proliferating number of clinics offer KIT for depression and anxiety, using protocols without a strong evidence basis. Controlled comparison of mood and anxiety from real-world KIT clinics, and the stability of outcomes, is lacking.We performed a retrospective controlled analysis on patients treated with KIT in ten community clinics across the US, between 08/2017-03/2020. Depression and anxiety symptoms were evaluated using the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS) and the Generalized Anxiety Disorder 7-item (GAD-7) scales, respectively. Comparison data sets from patients who did not undergo KIT were obtained from previously published real-world studies.Of 2758 patients treated, 714 and 836 met criteria for analysis of KIT induction and maintenance outcomes, respectively. Patients exhibited significant and concordant reduction in both anxiety and depression symptoms after induction (Cohen's d = 1.14 and d = 0.9, respectively). Compared to two external datasets of KIT-naive depressed patients or patients starting standard antidepressant therapy, KIT patients experienced a significantly greater reduction in depression symptoms at eight weeks (Cohen's d = -1.03 and d = -0.62 respectively). Furthermore, we identified a subpopulation of late-responders. During maintenance, up to a year post-induction, increases in symptoms were minimal.Due to the retrospective nature of the analyses, interpreting this dataset is limited by incomplete patient information and sample attrition.KIT treatment elicited robust symptomatic relief that remained stable up to one year of follow-up.

  View details for DOI 10.1016/j.jad.2023.04.141

  View details for PubMedID 37201900

• Brain-Wide Activity Mapping Reveals a Required Role for the Dorsal Endopiriform Nucleus in MDMA-Evoked Prosocial Behavior Heifets, B., Rijsketic, D., Salgado, J., Wall, N., Ramirez-Ovalle, G., Llorach, P., Lopez, R., Casey, A., Hietamies, T., Rastegar, Z., Barbosa, D., Beier, K., Malenka, R. ELSEVIER SCIENCE INC. 2023: S57-S58

  View details for Web of Science ID 000993018500139

• UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. bioRxiv : the preprint server for biology Rijsketic, D. R., Casey, A. B., Barbosa, D. A., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M., Halpern, C. H., Williams, L. M., Malenka, R. C., Heifets, B. D. 2023

  Abstract

  The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos + cell density measurements. Psilocybin increased c-Fos expression in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus and decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum. Main effects of context and psilocybin-treatment were robust, widespread, and spatially distinct, whereas interactions were surprisingly sparse.

  View details for DOI 10.1101/2023.02.19.528997

  View details for PubMedID 36865251

  View details for PubMedCentralID PMC9980055

• Diagnostic test accuracy of remote, multidomain cognitive assessment (telephone and video call) for dementia. The Cochrane database of systematic reviews Beishon, L. C., Elliott, E., Hietamies, T. M., Mc Ardle, R., O'Mahony, A., Elliott, A. R., Quinn, T. J. 2022; 4: CD013724

  Abstract

  Remote cognitive assessments are increasingly needed to assist in the detection of cognitive disorders, but the diagnostic accuracy of telephone- and video-based cognitive screening remains unclear.To assess the test accuracy of any multidomain cognitive test delivered remotely for the diagnosis of any form of dementia. To assess for potential differences in cognitive test scoring when using a remote platform, and where a remote screener was compared to the equivalent face-to-face test.We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, LILACS, and ClinicalTrials.gov (www.gov/) databases on 2 June 2021. We performed forward and backward searching of included citations.We included cross-sectional studies, where a remote, multidomain assessment was administered alongside a clinical diagnosis of dementia or equivalent face-to-face test.Two review authors independently assessed risk of bias and extracted data; a third review author moderated disagreements. Our primary analysis was the accuracy of remote assessments against a clinical diagnosis of dementia. Where data were available, we reported test accuracy as sensitivity and specificity. We did not perform quantitative meta-analysis as there were too few studies at individual test level. For those studies comparing remote versus in-person use of an equivalent screening test, if data allowed, we described correlations, reliability, differences in scores and the proportion classified as having cognitive impairment for each test.The review contains 31 studies (19 differing tests, 3075 participants), of which seven studies (six telephone, one video call, 756 participants) were relevant to our primary objective of describing test accuracy against a clinical diagnosis of dementia. All studies were at unclear or high risk of bias in at least one domain, but were low risk in applicability to the review question. Overall, sensitivity of remote tools varied with values between 26% and 100%, and specificity between 65% and 100%, with no clearly superior test. Across the 24 papers comparing equivalent remote and in-person tests (14 telephone, 10 video call), agreement between tests was good, but rarely perfect (correlation coefficient range: 0.48 to 0.98).Despite the common and increasing use of remote cognitive assessment, supporting evidence on test accuracy is limited. Available data do not allow us to suggest a preferred test. Remote testing is complex, and this is reflected in the heterogeneity seen in tests used, their application, and their analysis. More research is needed to describe accuracy of contemporary approaches to remote cognitive assessment. While data comparing remote and in-person use of a test were reassuring, thresholds and scoring rules derived from in-person testing may not be applicable when the equivalent test is adapted for remote use.

  View details for DOI 10.1002/14651858.CD013724.pub2

  View details for PubMedID 35395108

• Brain wide mapping of neuronal activity evoked by MDMA, a rapid-acting therapy for post-traumatic stress disorder Ryskamp, D., Llorach, P., Schlozman, S., Rastegar, Z., Salgado, J. S., Hietamies, T., Barbosa, D. A., Pinto, D., Neuman, P., Hell, M., Beier, K., Malenka, R. C., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2021: 583-584

  View details for Web of Science ID 000752526600251

• Brain-wide unbiased mapping of neuronal activity pinpoints ketamine's interaction with the opioid system in mice Ryskamp, D., Hietamies, T., Schlozman, S., Llorach, P., Salgado, J. S., Barbosa, D. A., Heifets, B. D. LIPPINCOTT WILLIAMS & WILKINS. 2021: 582

  View details for Web of Science ID 000752526600250

• UK consensus on pre-clinical vascular cognitive impairment functional outcomes assessment: questionnaire and workshop proceedings JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM McFall, A., Hietamies, T. M., Bernard, A., Aimable, M., Allan, S. M., Bath, P. M., Brezzo, G., Carare, R. O., Carswell, H., Clarkson, A. N., Currie, G., Farr, T. D., Fowler, J. H., Good, M., Hainsworth, A. H., Hall, C., Horsburgh, K., Kalaria, R., Kehoe, P., Lawrence, C., Macleod, M., McColl, B. W., McNeilly, A., Miller, A. A., Miners, S., Mok, V., O'Sullivan, M., Platt, B., Sena, E. S., Sharp, M., Strangeward, P., Szymkowiak, S., Touyz, R. M., Trueman, R. C., White, C., McCabe, C., Work, L. M., Quinn, T. J. 2020; 40 (7): 1402–14

  Abstract

  Assessment of outcome in preclinical studies of vascular cognitive impairment (VCI) is heterogenous. Through an ARUK Scottish Network supported questionnaire and workshop (mostly UK-based researchers), we aimed to determine underlying variability and what could be implemented to overcome identified challenges. Twelve UK VCI research centres were identified and invited to complete a questionnaire and attend a one-day workshop. Questionnaire responses demonstrated agreement that outcome assessments in VCI preclinical research vary by group and even those common across groups, may be performed differently. From the workshop, six themes were discussed: issues with preclinical models, reasons for choosing functional assessments, issues in interpretation of functional assessments, describing and reporting functional outcome assessments, sharing resources and expertise, and standardization of outcomes. Eight consensus points emerged demonstrating broadly that the chosen assessment should reflect the deficit being measured, and therefore that one assessment does not suit all models; guidance/standardisation on recording VCI outcome reporting is needed and that uniformity would be aided by a platform to share expertise, material, protocols and procedures thus reducing heterogeneity and so increasing potential for collaboration, comparison and replication. As a result of the workshop, UK wide consensus statements were agreed and future priorities for preclinical research identified.

  View details for DOI 10.1177/0271678X20910552

  View details for Web of Science ID 000523805200001

  View details for PubMedID 32151228

  View details for PubMedCentralID PMC7307003

• Variability of functional outcome measures used in animal models of stroke and vascular cognitive impairment - a review of contemporary studies JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Hietamies, T. M., Ostrowski, C., Pei, Z., Feng, L., McCabe, C., Work, L. M., Quinn, T. J. 2018; 38 (11): 1872–84

  Abstract

  Despite promising preclinical data, few novel stroke therapies have shown efficacy in man. Efforts to improve standards in conduct and reporting of preclinical research are ongoing. In clinical trials, inconsistency in outcome measures led to regulatory agencies and funders mandating use of a core set of functional outcomes. Our aim was to describe functional outcome measures in preclinical stroke and vascular cognitive impairment (VCI) studies. From 14 high impact journals (January 2005-December 2015 inclusive), 91,956 papers were screened with 1302 full texts analyzed for stroke (ischemic and hemorrhagic) and 56 for VCI studies. In total, 636 (49%) stroke and 37 (66%) VCI papers reported functional outcome measures. There were 74 different functional assessments reported in stroke and 20 in VCI studies. Neurological deficit scores (74%) and Morris water maze (60%) were most commonly used in stroke and VCI, respectively. However, inconsistencies in methods used to assess and score recovery were noted. Neurological and behavioural functional outcome measures are increasingly used in preclinical stroke or VCI studies; however, there is substantial variation in methods. A strict standardized outcome set may not be suitable for translational work, but greater consistency in choice, application and reporting of outcomes may improve the science.

  View details for DOI 10.1177/0271678X18799858

  View details for Web of Science ID 000450149200002

  View details for PubMedID 30203705

  View details for PubMedCentralID PMC6259321