https://orcid.org/0000-0001-8203-0032
Figures
Abstract
To assess the efficacy of horticultural therapy (HT) on anterior cingulate cortex (ACC) activity and the changes in rumination and catastrophizing scores in individuals with chronic low back pain (LBP). We conducted a randomized, controlled, cross-over, 3-week pilot study (ClinicalTrials.gov Identifier: NCT04656158). The departments of physical medicine and rehabilitation (hospital grounds and occupational therapy room) and imaging research were involved. The participants were adults with non-specific chronic LBP. All participants underwent two 90-min HT sessions and two 90-min handiwork sessions per week. The activity sequence order was randomized, and the activities were separated by a wash-out period of 1 week. Each participant underwent 3 brain MRIs: before, after the first, and after the second activity. The primary outcome was the change in ACC perfusion in ml/100g/min using arterial spin labeling MRI. The secondary outcomes were the changes in self-reported rumination and catastrophizing scores after each activity compared to baseline. Sixteen participants were included: 14 women (87.5%), LBP intensity (numeric rating scale) mean (SD) 45.1 (27.2)/100, specific activity limitation (Roland Morris disability questionnaire) 9.3 (4.1)/24. Change in ACC perfusion from baseline was -0.1 (10.7), 95% CI [-5.6, 5.8] ml (blood)/100g (tissue)/min after handiwork and -0.1 (8.7), [-4.7, 4.6] after HT and did not differ between the 2 activities (p = 0.91). Change in rumination [-0.5 (4.4) after handiwork and -0.3 (2.8) after HT] and catastrophizing scores [-2 (2.8) after handiwork and -1.4 (2.3) after HT] did not differ between activities (p = 0.99 and 0.22, respectively). Limited exposure to the interventions and the sample profile (moderate levels of pain) may explain our results. Our results highlight the need for future studies using the most appropriate outcomes to determine the exact effects of nature experiences in people with chronic musculoskeletal disease.
Citation: Rören A, Debacker C, Saghiah M, Bedin C, Fayolle A, Abdoul H, et al. (2024) Effects of horticultural therapy versus handiwork on anterior cingulate cortex activity in people with chronic low back pain: A randomized, controlled, cross-over, pilot study. PLoS ONE 19(12): e0313920. https://doi.org/10.1371/journal.pone.0313920
Editor: Stephen D. Ginsberg, Nathan S Kline Institute, UNITED STATES OF AMERICA
Received: May 3, 2024; Accepted: November 1, 2024; Published: December 17, 2024
Copyright: © 2024 Rören et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data are owned by the promotor Assistance-Publique Hôpitaux de Paris (AP-HP). Data cannot be shared publicly because of AP-HP sharing data policy. Data are available from the AP-HP Institutional Data Access (contact via Unité de Recherche Clinique (URC) Necker-Cochin laetitia.peaudecerf@aphp.fr, for researchers who meet the criteria for access to confidential data. All Data not provided in the article may be shared at the reasonable request of any qualified investigator for purposes of replicating procedures and results.
Funding: AR Fonds MSERI hôpitaux AP-HP. Centre, Université Paris Cité 2019. AR Fondation Roi Baudoin, (Fonds Luc), 2018 Belgium AR Trophées patients APHP The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: ACC, anterior cingulate cortex; ASL, arterial spin labeling; CBF, cerebral blood flow; HT, horticultural therapy; LBP, low back pain; PMR, physical medicine and rehabilitation
Introduction
The anterior cingulate cortex (ACC) is part of the neuromatrix of pain and is involved in the emotional valence of pain [1]. The ACC is activated in the case of chronic pain and may contribute to pain persistence [2]. The activity of the ACC is related to rumination, defined as the intrusion of involuntary thoughts that are difficult to “turn off” [3, 4]. A randomized controlled trial by Bratman et al. (2015) showed that both neural activation of the subgenual part of the ACC and rumination scores decreased significantly in 38 young asymptomatic individuals after a 90-minute walk in a natural setting [5].
Chronic low back pain (LBP), defined as pain persisting longer than 3 months is a common condition worldwide that limits activity and is associated with significant costs [6, 7]. Physical exercise improves pain and function in people with chronic LBP [8].
Gardening is a global physical activity involving contact with nature. When used for therapeutic purposes in people with mental, physical or social disability, supervised gardening is called horticultural therapy (HT) [9]. A recent umbrella review reported the positive impact of HT on the mental and physical well-being of people with long-term physical conditions [10]. HT seems well suited to the physical treatment of chronic LBP, as gardening activities involve spinal flexibility, spinal and limb muscle strengthening, and proprioceptive adjustments. HT meets well the criteria for long-term practice as it is associated with pleasure and creativity and can be performed at all stages of life [11].
Few studies have been conducted on the impact of HT on chronic LBP. A non-randomized controlled study of people with chronic pain (fibromyalgia and chronic LBP) found significantly larger improvements in health status, anxiety and coping strategies in the HT group (addition of 7 HT sessions to a standardized pain management program) than in the control group [12].
The main objective of this study was to compare the efficacy of supervised HT sessions with handiwork on change in ACC activation in people with chronic LBP using arterial spin labeling (ASL) perfusion MRI [5]. The secondary objectives were to assess the effect on rumination and catastrophizing scores.
We hypothesized that HT sessions would decrease ACC activation significantly more than handiwork sessions.
Methods
Design
We conducted a single-center, randomized, controlled, cross-over, open pilot study over a 3-week period (ClinicalTrials.gov Identifier: NCT04656158).
We reported our study in accordance with the Consolidated Standards of Reporting Trials (CONSORT) checklist [13] (S1 Fig) and the Template for Intervention Description and Replication (TIDieR) [14] (S2 Fig).
Substantial changes were made to the study protocol after the trial commencement to facilitate participant inclusion: recruitment was widened from people on the waiting list for the functional restoration program in our physical medicine and rehabilitation (PMR) department by the use of additional recruitment aids (posters and leaflets). In addition, the inclusion period was extended by 6 months (total duration: 12 months). We did not change any outcomes after the trial had begun.
Ethics statement
The study was approved by the Comité de Protection des Personnes SUD-EST IV, (n°19.12.17.40700). All participants provided signed informed consent.
Blinding
The principal investigator (AR), the occupational therapist who supervised the activities (handiwork and HT) (CB), the radiology technician (AF) and the participants were not blinded to activity sequence allocation. The research engineers (CD and MS) and the data analyst (HA) were blinded.
Setting and participants
The study was conducted in the physical medicine and rehabilitation (PRM) department of Cochin Hospital and the imaging research department of Saint-Anne Hospital (Paris, France). HT took place on the hospital grounds, and handiwork in the occupational therapy room of the PMR department.
Participants screened for eligibility were scheduled for the baseline face-to-face visit with the principal investigator (AR), a physiotherapist with 20 years of experience in the rehabilitation of people with chronic LBP and 10 years of experience in research.
The main inclusion criteria were 1) age ≥ 18 years, 2) non-specific chronic LBP, 3) indication for in-patient rehabilitation, 4) up-to-date tetanus vaccination and 5) being able to walk 2km. The main non-inclusion criteria were 1) contraindications to MRI, 2) sick leave for chronic LBP ≥ 3 months in the last year and 3) not in paid employment.
Study protocol
Randomization.
Randomization was centralized, and participants were randomly allocated in a 1:1 ratio to one of the 2 sequences of activities: handiwork-then-HT or HT-then-handiwork. An independent statistician provided a computer-generated randomization list with permuted blocks of 4 participants.
Intervention.
HT and handiwork activities have been part of the routine care of people with chronic LBP in our PMR department for many years (25 years for handiwork and 4 years for HT). Both activities are supervised by experienced occupational therapists with more than 25 years of experience in chronic LBP and more than 15 years of experience in the management of therapeutic workshops. HT was initiated by the individuals who attend the PMR department themselves. The handiwork activity was chosen as a comparator because of its comparable approximate energy expenditure value [15], and because during handiwork in the occupational therapy room, participants had no contact (even visual) with nature.
The dose of 2x90 min of activity was chosen in accordance with the dose of nature exposure used by Bratman et al., (2015) [5] to measure variation in ACC blood perfusion and with the recommendations for physical activity for adults with chronic conditions from the World Health Organization.
Each participant performed 2, 90-minute HT sessions (activity n°1) and 2, 90-minute handiwork sessions (activity n°2) supervised by the occupational therapist (CB). The 2 sessions of each activity were performed in the same week, interspersed with 1 week without either activity [16]. Thus, the study lasted for 3 week (S3 Fig).
Participants were asked not to change their lifestyle and usual activities during the study.
The tasks performed during HT sessions included transporting gardening tools, weeding, digging, planting and watering (S4 Fig). The tasks performed during the handiwork activity were transporting wooden boards, measuring, cutting wood with a hand saw, and assembling wood pieces (S5 Fig).
Each participant underwent 3 brain MRI scans: 1 before beginning the activities (reference MRI), 1 immediately after the second session of activity n°1 and the last immediately after the second session of activity n°2.
Outcomes.
The primary outcome was the change in ACC perfusion in ml (blood)/100g (tissue)/min after each activity compared to baseline as previously described [5].
The secondary outcomes were the change in self-reported rumination and catastrophizing scores after each activity compared to baseline. The rumination score was one of the 2 scales of the Rumination Reflection Questionnaire (0–60, 0: no rumination, 60: maximal rumination) [17], the catastrophizing score was the sub-score of the Coping Strategy Questionnaire (0–20, 0: no catastrophizing 20: maximal catastrophizing) [18].
Acceptability and satisfaction were collected after each activity using a self-administered numerical rating scale (0 = not acceptable and 100 = maximal acceptability; 0 = minimal satisfaction and 100 = maximal satisfaction).
Safety outcomes were recorded after the first activity, and after the “wash out” period and by using an open-ended question (“Did you have any adverse events?”).
Image acquisition.
Image acquisition and processing were determined according to the study by Bratman et al., (20015) [5]. Scans were acquired on a 3T whole-body MRI scanner (Vantage Galan 3T / XGO; Canon Medical Systems Corporation, Tochigi, Japan) with a 32-channel head coil. The T1-weighted MR images included 160 1.0-mm thick slices with an in-plane resolution of 1 mm2. High-resolution image acquisition was followed by a pseudo-continuous ASL sequence (pCASL) with a readout of 3D single shot Turbo Spin Echo and a postlabel delay (PLD) of 1800 ms; TR = 4910 ms; TE = 12.3 ms; FOV = 195 x 195 mm; matrix size = 64 x 64; 25 axial slices; slice thickness = 4.0 mm; voxel dimensions 3.0469 x 3.0469 x 4.0 mm, 4 averages, for a total acquisition time of 7 min and 52 s.
Image processing.
The cerebral blow flow quantification equation calculation yielded voxelwise quantitative maps reflecting milliliters of blood per 100 g tissue per minute (volume x time/mass). We coregistered arterial spin labeling (ASL) volumes to each individual’s anatomical scans and then performed a combined affine and nonlinear warping process of the anatomical data to standard space, using ASLprep (ASLprep) [19]. We applied the same warping parameters to the ASL data.
We acquired perfusion-weighted data and proton density (PD) maps and then combined information from those per the standard CBF equation quantification [20].
T1b is T1 of blood and is assumed to be 1.6 s at 3 T (10). λ (0.9 ml/g) is the brain/blood partition coefficient, ε (0.6) is overall efficiency, a combination of inversion efficiency (0.8) and background suppression efficiency (0.75). PLD (1.8s) is the post-labeling delay used for the ASL sequence, and LT (1.8s) is the labeling duration.
Statistical analysis.
Following the results of a study reporting ACC blood perfusion in asymptomatic participants after a 90-min walk in nature [5], we predicted a mean (SD) difference of 7 (4) ml (blood)/100g (tissue)/min in the ACC after HT compared with handiwork in participants with chronic LBP. With an α-risk of 5%, power of 90% and potential loss to follow-up of 20%, we sought to include 16 participants.
SAS 9.4 software was used for data analysis. Quantitative variables were described using the mean (SD) and [95%CI] or median (Q1, Q3). Qualitative variables were expressed as absolute and relative frequencies (n/N, %). The mean ACC perfusion after handiwork and HT and the mean change in ACC blood perfusion from baseline were compared between activities using a paired Student t test. We performed a sensitivity analysis using a mixed model with activity, period and sequence as fixed effects and subject as a random effect. The missing ACC perfusion value of one participant after the second activity was imputed by the median ACC perfusion after the first activity.
Results
Sixteen participants were included between May 2021 and March 2022 (Fig 1): 14 (87.5%) were women, the mean (SD) age was 49.3 (9.5) years and baseline lumbar pain intensity on NRS was 45.1 (27.2)/100 points (Table 1).
HT: horticultural therapy.
The participants randomized to the HT-then-handiwork sequence had a longer current LBP episode duration, more previous LBP-related sick leaves, higher LBP intensity scores and lower mental health scores than the other group. The mean (SD) ACC perfusion was 49.6 (10.1) ml (blood)/100g (tissue)/min after the 2 handiwork sessions and 49.5 (9.9) after the 2 HT sessions (S6 Fig).
The mean rumination score for all participants was 33.3 (8.1)/60 after the 2 handiwork sessions and 34.0 (7.4)/60 after the 2 HT sessions. The mean catastrophizing score was 11.0 (4.0)/20 after the 2 handiwork sessions and 11.8 (4.1)/20 after the 2 HT sessions (Table 2). The mean ACC perfusion score after handiwork did not differ from that after HT (Table 2). The rumination and catastrophizing scores after handiwork and HT were also very close (Table 2).
The median (Q1, Q3) duration between the end of the activity and the MRI was 40.0 min (27.5, 65.0), range 15–90.
The mean ACC perfusion, rumination and catastrophizing scores decreased very slightly after both activities, with no between-activity difference in change (Table 3).
The complementary sensitivity analysis using a mixed model found no effect of sequence (p = 0.52), period (p = 0.45) or activity (p = 0.87) on ACC perfusion.
The mean LBP intensity decreased after handiwork (mean difference: 10.3 (24.5), [-3.3, 23.8]) and after HT, mean difference (9.6 (22.6), [-2.5, 21.6]) (Table 4).
Scores for all 6 items of the credibility/expectancy questionnaire were slightly higher for handiwork than for HT (Table 5).
Mean satisfaction level was 90 (18)% for handiwork and 89 (11)% for HT. Mean acceptability level was 92 (14)% for handiwork and 91 (12)% for HT.
No adverse event was reported.
Discussion
In contrast with our hypothesis, ACC blood perfusion did not decrease after HT (S6 Fig) or handiwork.
The baseline mean ACC blood perfusion of the participants was close to the mean ACC blood perfusion measured with a PET scan in a study of asymptomatic participants [21], and the baseline rumination score was only slightly higher than that reported in young asymptomatic participants in the study by Bratman et al., (2015) [5]. Therefore, our participants may have been used to their long-lasting and stable symptoms, as shown by their moderate activity limitation scores. ACC activation has been associated with episodes of increasing pain in people with chronic LBP [22]. Another potential explanation for the similarity between the ACC blood perfusion and rumination scores found in our study of people with chronic LBP and the study of asymptomatic participants by Bratman et al. (2015) is that the asymptomatic participants may have had unassessed symptoms that could be associated with ACC activity and rumination, such as depression and anxiety [23–25].
The differences in the ACC blood flow scores between handiwork and HT and the change in ACC blood flow after both HT and handiwork was negligible; a change in cerebral blood flow (CBF) <5% may relate to measurement error [26]. The limited dose of "exposure” to nature, in terms of duration and immersion (green spaces in an urban setting) and/or the time between the intervention and the MRI may explain the lack of neurobiological effect. The physical activity involved by gardening may have counteracted the nature-related changes in ACC activity, in contrast with more passive nature exposures [5, 10]. The absence of an effect of sequence, period or activity on ACC perfusion may suggest stability in ACC blood flow, independent of challenging requirements [27].
Disparate results have been found between studies of nature-related changes in ACC activity. A study using task functional magnetic resonance imaging (fMRI) in 28 asymptomatic individuals showed greater activity in the ACC following exposure to nature scenic views compared to urban views [28]. Another study using resting-state fMRI to assess brain functional activity in 23 young asymptomatic individuals showed increased functional connectivity in several brain regions including the ACC, after participation in different horticultural tasks [29]. Therefore, the association between ACC activity and exposure to nature is not unequivocal. Moreover, the affective motivational dimension of pain involves several other brain structures that we did not evaluate [30]; their activity might have been more modified than that of the ACC in our study.
The credibility/expectancy questionnaire scores might indicate that the participants thought and felt that HT was less effective than handiwork in improving their symptoms. Both handiwork and HT may have positive effects on LBP. The changes in other clinical scores after both activities were small.
Our study has several limitations. The clinical severity of chronic LBP differed between the activity sequence groups. The sample may have been too small to draw firm conclusions about the efficacy or absence of efficacy of HT on ACC activity. Some environmental variables that were not collected (weather conditions, stress, impact of the covid-19 pandemic etc.) could also have influenced ACC perfusion. Arterial spin labeling may not be sufficiently sensitive to detect changes in ACC perfusion.
Conclusion
Our results showed that ACC blood perfusion did not decrease after 2, 90-minute HT sessions in participants with chronic low back pain. Our study emphasizes the need for future studies to specify the exact effects of nature experiences, the optimal conditions of this experience for the most common diseases, and the most suitable outcomes to measure the impact of nature on different symptoms.
Supporting information
S1 Fig. Consolidated Standards of Reporting Trials (CONSORT) checklist.
https://doi.org/10.1371/journal.pone.0313920.s002
(PDF)
S2 Fig. The Template for Intervention Description and Replication (TIDieR).
https://doi.org/10.1371/journal.pone.0313920.s003
(PDF)
S4 Fig. Example of horticultural activity: 2 participants are pulling up wilted plants under the supervision of the occupational therapist (CB).
https://doi.org/10.1371/journal.pone.0313920.s005
(TIF)
S5 Fig. Example of handiwork activity: The participant is sawing a wooden plank under the supervision of the occupational therapist (CB) (not seen on the picture).
https://doi.org/10.1371/journal.pone.0313920.s006
(TIF)
S6 Fig. Average CBF maps in MNI152 space for the 16 participants before and after HT.
The pink outline corresponds to the anterior division of the cingulate gyrus of the Harvard-Oxford cortical structural atlases with a threshold at the probability of 50%. The quality of the image is linked to the low intrinsic resolution of the ASL.
https://doi.org/10.1371/journal.pone.0313920.s007
(TIF)
Acknowledgments
We thank Léa Jilet, Camille Ollivier and Sylvain Charron for the statistical analysis, and Nadjia Hamidi and Louisa Sidhoum from the Service de Rééducation et de Réadaptation de l’Appareil Locomoteur et des Pathologies du Rachis for their help in escorting participants from one hospital to another. We acknowledge Johanna Robertson, PT, PhD for professional copy editing.
References
- 1. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288:1769–72. pmid:10846154
- 2. Bliss TVP, Collingridge GL, Kaang B-K, Zhuo M. Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Nat Rev Neurosci 2016;17:485–96. pmid:27307118
- 3. Moseley GL. A pain neuromatrix approach to patients with chronic pain. Manual Therapy 2003;8:130–40. pmid:12909433
- 4. Nolen-Hoeksema S. The role of rumination in depressive disorders and mixed anxiety/depressive symptoms. J Abnorm Psychol 2000;109:504–11. pmid:11016119
- 5. Bratman GN, Hamilton JP, Hahn KS, Daily GC, Gross JJ. Nature experience reduces rumination and subgenual prefrontal cortex activation. Proc Natl Acad Sci USA 2015;112:8567–72. pmid:26124129
- 6. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1789–858. pmid:30496104
- 7. Hartvigsen J, Hancock MJ, Kongsted A, Louw Q, Ferreira ML, Genevay S, et al. What low back pain is and why we need to pay attention. Lancet 2018;391:2356–67. pmid:29573870
- 8. Hayden JA, Cartwright J, Van Tulder MW, Malmivaara A. Exercise therapy for chronic low back pain. Cochrane Database of Systematic Reviews 2012.
- 9. Relf D, Dorn S. Horticulture: Meeting the needs of Special Populations 1995:94–103.
- 10. Panțiru I, Ronaldson A, Sima N, Dregan A, Sima R. The impact of gardening on well-being, mental health, and quality of life: an umbrella review and meta-analysis. Syst Rev 2024;13:45. pmid:38287430
- 11. Thompson R. Gardening for health: a regular dose of gardening. Clin Med (Lond) 2018;18:201–5. pmid:29858428
- 12. Verra ML, Angst F, Beck T, Lehmann S, Brioschi R, Schneiter R, et al. Horticultural therapy for patients with chronic musculoskeletal pain: results of a pilot study. Altern Ther Health Med 2012;18:44–50. pmid:22516884
- 13. Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: extension to randomised crossover trials. BMJ 2019;366:l4378. pmid:31366597
- 14. Hoffmann TC, Glasziou PP, Boutron I, Milne R, Perera R, Moher D, et al. Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014;348:g1687. pmid:24609605
- 15. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, et al. Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 2000;32:S498–504. pmid:10993420
- 16. Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 2002;31:140–9. pmid:11914310
- 17. Trapnell PD, Campbell JD. Private self-consciousness and the five-factor model of personality: Distinguishing rumination from reflection. Journal of Personality and Social Psychology 1999;76:284–304. pmid:10074710
- 18. Irachabal S, Koleck M, Rascle N, Bruchon-Schweitzer M. Stratégies de coping des patients douloureux: adaptation française du coping strategies questionnaire (CSQ-F). L’Encéphale 2008;34:47–53. pmid:18514150
- 19. Grabner G, Janke AL, Budge MM, Smith D, Pruessner J, Collins DL. Symmetric atlasing and model based segmentation: an application to the hippocampus in older adults. Med Image Comput Comput Assist Interv 2006;9:58–66. pmid:17354756
- 20. Alsop DC, Detre JA, Golay X, Günther M, Hendrikse J, Hernandez-Garcia L, et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia: Recommended Implementation of ASL for Clinical Applications. Magn Reson Med 2015;73:102–16. pmid:24715426
- 21. Fro H, Inoue K, Goto R, Kinomura S, Taki Y, Okada K, et al. Database of normal human cerebral blood flow measured by SPECT: I. Comparison between I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD as referred with O-15 labeled water PET and voxel-based morphometry. Ann Nucl Med 2006;20:131–8. pmid:16615422
- 22. Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden RN, Parrish TB, et al. Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci 2006;26:12165–73. pmid:17122041
- 23. Aldao A, Nolen-Hoeksema S, Schweizer S. Emotion-regulation strategies across psychopathology: A meta-analytic review. Clinical Psychology Review 2010;30:217–37. pmid:20015584
- 24. Berman MG, Peltier S, Nee DE, Kross E, Deldin PJ, Jonides J. Depression, rumination and the default network. Soc Cogn Affect Neurosci 2011;6:548–55. pmid:20855296
- 25. Hamilton JP, Glover GH, Hsu J-J, Johnson RF, Gotlib IH. Modulation of subgenual anterior cingulate cortex activity with real-time neurofeedback. Hum Brain Mapp 2011;32:22–31. pmid:21157877
- 26. Lassen NA. Normal Average Value of Cerebral Blood Flow in Younger Adults is 50 ml/100 g/min. J Cereb Blood Flow Metab 1985;5:347–9. pmid:4030914
- 27. Weston CSE. Another major function of the anterior cingulate cortex: the representation of requirements. Neurosci Biobehav Rev 2012;36:90–110. pmid:21554898
- 28. Kim G-W, Jeong G-W, Kim T-H, Baek H-S, Oh S-K, Kang H-K, et al. Functional neuroanatomy associated with natural and urban scenic views in the human brain: 3.0T functional MR imaging. Korean J Radiol 2010;11:507–13. pmid:20808693
- 29. Lai P-H, Li C-W, Hung S-H, Lee A-Y, Chang C-Y, Tang H-F. How Do Horticultural Activities Affect Brain Activation and Emotion? Scientific Evidence Based on Functional Connectivity. Horts 2023;58:67–78.
- 30. Dalgleish T. The emotional brain. Nat Rev Neurosci 2004;5:583–9. pmid:15208700