Altered cerebral blood flow patterns associated with pathologic worry in the elderly
Open accessAbstract
BACKGROUND: Generalized anxiety disorder (GAD) is the most prevalent anxiety disorder among the elderly and has high functional and cognitive morbidity. However, late-life GAD is relatively understudied and its functional neuroanatomy is uncharted. Several imaging studies have suggested abnormalities in the cognitive control systems of emotion regulation in anxiety disorders in young adults. The aim of this study was to examine the neural correlates of emotion regulation in late-life GAD. METHOD: We compared 7 elderly GAD subjects and 10 elderly nonanxious comparison subjects using functional MRI. Regional cerebral blood flow (rCBF) was measured using pulsed arterial spin labeling perfusion MRI at rest and during an emotion regulation paradigm. RESULTS: Relative to the rest condition, elderly nonanxious comparison subjects had increased rCBF during worry induction (WI) in the right insula, bilateral amygdala, and associative temporooccipital areas. Elderly GAD subjects had increased rCBF during WI in the associative temporooccipital areas, but not in the insula or the amygdala. During worry suppression (WS), elderly nonanxious comparison subjects had increased rCBF in the prefrontal cortex (PFC) and dorsal ACC. Elderly GAD subjects had no changes in rCBF during WS in the PFC. CONCLUSIONS: When attempting to regulate their emotional responses, elderly anxious subjects failed to activate prefrontal regions involved in the downregulation of negative emotions. These results, showing that elderly anxious subjects are not effectively engaging the PFC in suppressing worry, may be clinically relevant for developing personalized therapeutic strategies for the treatment of late-life GAD.
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Individuals with GAD may respond poorly to motivational conflict, demonstrating deficits in attentional and cognitive elaborative regulation strategies.
“these individuals may respond poorly to this motivational conflict, demonstrating deficits in different systems of regulation30 encompassing attentional (e.g., attentional flexibility in processing both interoceptive and exteroceptive emotional stimuli31–33, 11) and more cognitive elaborative strategies (e.g., meta-cognitive awareness, cognitive reappraisal34, 35).”
From AN OPEN TRIAL OF EMOTION REGULATION THERAPY FOR GENERALIZED ANXIETY DISORDER AND COOCCURRING DEPRESSION. (2015) · cites this paper as [35]
The Conclusion reports impaired top-down regulation of worry in elderly people with GAD and discusses automatic and instructed emotion regulation. It does not test responses to motivational conflict, and its finding is limited to elderly participants rather than people with GAD generally. The attentional and cognitive-elaborative examples carry other citations in the citing sentence. (LLM, conf=0.82)
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Cites
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“These two latter areas have been cited frequently in the literature in connection with emotion processing.[24,44,45] It is unclear why elderly GAD subjects engage less the insula/amygdala during WI.”
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“Elderly GAD subjects had no changes in rCBF during WS in the PFC. Conclusions: When attempting to regulate their emotional responses, elderly anxious subjects failed to activate prefrontal regions involved in the downregulation of negative emotions.”
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“[46] The model considers worry a cognitive process designed to avoid the anxiogenic images that induce somatic activation through increased noradrenergic discharge.[2,46] Thus, as worry represents an avoidance process of anxious experiences, activation of amygdala during WI is unlikely in pathological worriers.”
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“Our results indicate that during WI, elderly GAD subjects have increased rCBF in the posterior associative temporooccipital areas, most likely due to the role of these areas in the required mental visual imagery of the worry modulation task.[42,43] Nonanxious elderly also engage the associative temporooccipital areas…”
ResultEtkin, A., Prater, K. E., Hoeft, F., Menon, V., & Schatzberg, A. F. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2009.09070931 · Cited by 550 · cited 5× · see citing works
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“[15,51] We can speculate that WI triggers unconscious appraisal of threat and spontaneous response of areas, such as the ACC, involved in automatic emotion regulation,[52] whereas WS (a prototypical topdown, conscious instruction) increases rCBF to areas involved in instructed emotion regulation.[52,53] During WS, eld…”
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MethodSelf-citationEmpirical optimization of ASL data analysis using an ASL data processing toolbox: ASLtbx
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“[17] Other data reported in young adults show that GAD is associated with deficits in emotion regulation through failure to engage the ACC,[18] exaggerated amygdala reactivity to warning cues preceding aversive/neutral pictures,[19] disrupted connectivity patterns of the amygdala subregions (basolateral and centromedi…”
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Generalized Anxiety Disorder in Stroke Patients: A 3-Year Longitudinal Study
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“[3,4] Late-life GAD is associated with decreased quality of life,[5,6] cognitive impairment,[7,8] increased health care utilization,[5] and poorer recovery after disabling medical events.[5,9] Elderly GAD subjects have a three-fold increase in risk of health-related activity limitation, compared to nonanxious elderly,…”
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“[21] Furthermore, alterations have been described in other structures, such as insula[24] and the bed nucleus of stria terminalis.[22,23] Overall though, the brain circuits altered in GAD and anticipatory anxiety are less well known at this time as the ones involved in fear and panic.”
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Pediatric perfusion imaging using pulsed arterial spin labeling
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MethodIncreased Amygdala and Insula Activation During Emotion Processing in Anxiety-Prone Subjects
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BackgroundTreatment of generalized anxiety disorder in older adults.
Wetherell, J. L., Gatz, M., & Craske, M. G. (2003) · Journal of Consulting and Clinical Psychology · doi:10.1037/0022-006x.71.1.31 · Cited by 205 · cited 3× · see citing works
“[4,10] Due in part to our lack of understanding of GAD in the elderly, treatment response in late-life GAD is highly variable[11] and established treatments for midlife GAD, such as CBT, have failed to prove advantageous in late-life GAD.[12,13] Emotion regulation facilitates adaptive behavior and decision-making in r…”
BackgroundTreatment of generalized anxiety disorder in older adults.
Wetherell, J. L., Gatz, M., & Craske, M. G. (2003) · Journal of Consulting and Clinical Psychology · doi:10.1037//0022-006x.71.1.31 · Cited by 198 · see citing works
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ResultCognitive Impairment in Late-Life Generalized Anxiety Disorder
Mantella, R. C., Butters, M. A., Dew, M. A., Mulsant, B. H., Begley, A. E., Tracey, B., Shear, M. K., Reynolds, C. F., & Lenze, E. J. (2007) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e31803111f2 · Cited by 189 · cited 1× · see citing works
“[3,4] Late-life GAD is associated with decreased quality of life,[5,6] cognitive impairment,[7,8] increased health care utilization,[5] and poorer recovery after disabling medical events.”
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Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder
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“Our results indicate that during WI, elderly GAD subjects have increased rCBF in the posterior associative temporooccipital areas, most likely due to the role of these areas in the required mental visual imagery of the worry modulation task.[42,43] Nonanxious elderly also engage the associative temporooccipital areas…”
ResultThe Rostral Anterior Cingulate Cortex Modulates the Efficiency of Amygdala-Dependent Fear Learning
Bissière, S., Plachta, N., Hoyer, D., McAllister, K. H., Olpe, H.-R., Grace, A. A., & Cryan, J. F. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.10.022 · Cited by 151 · see citing works
Functioning of neural systems supporting emotion regulation in anxiety-prone individuals
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Meta-analysis comparing different behavioral treatments for late-life anxiety
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“[47] Recent data support a possible malfunction of the amygdalar complex, reporting disrupted amygdalar subregions connectivity in midlife GAD.”
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Berkowitz, R. L., Coplan, J. D., Reddy, D. P., & Gorman, J. M. (2007) · Reviews in the Neurosciences · doi:10.1515/revneuro.2007.18.3-4.191 · Cited by 106 · cited 1× · see citing works
“[31,45,54–57] Elderly GAD subjects did not present any increased lateral prefrontal rCBF during WS.”
BackgroundWorry content reported by older adults with and without generalized anxiety disorder
Diefenbach, G. J., Stanley, M. A., & Beck, J. G. (2001) · Aging & Mental Health · doi:10.1080/13607860120065069 · Cited by 95 · cited 1× · see citing works
“Generalized anxiety disorder (GAD) is centrally defined by chronic, uncontrollable worry that causes significant distress and impairment in functioning.[1,2] With an estimated community prevalence of 7.”
BackgroundMennin, D. S., Heimberg, R. G., Fresco, D. M., & Ritter, M. R. (2008) · Depression and Anxiety · doi:10.1002/da.20493 · Cited by 91 · see citing works
Caudle, D. D., Senior, A. C., Wetherell, J. L., Rhoades, H. M., Beck, J. G., Kunik, M. E., Snow, A. L., Wilson, N. L., & Stanley, M. A. (2007) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e31803c550d · Cited by 62 · cited 1× · see citing works
“[3,4] Late-life GAD is associated with decreased quality of life,[5,6] cognitive impairment,[7,8] increased health care utilization,[5] and poorer recovery after disabling medical events.”
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“[3] Despite its prevalence and clinical impact, GAD is the least studied, the least understood, and arguably the least treated mental disorder in the elderly.[4,10] Due in part to our lack of understanding of GAD in the elderly, treatment response in late-life GAD is highly variable[11] and established treatments for…”
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“However, the neural network abnormalities described in younger adults might not be entirely translatable into the elderly, given the anatomical and pathophysiological changes observed in the aging brain.[25] One particular gap in our understanding of late-life GAD concerns the underlying structural and functional neur…”
BackgroundFear and Anxiety: Possible Roles of the Amygdala and Bed Nucleus of the Stria Terminalis
Young, M. D., & Lee, L. (1998) · Cognition & Emotion · doi:10.1080/026999398379619 · Cited by 45 · see citing works
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“CBT) in elderly with GAD.[13,60] This distinctive feature may be relevant for novel treatment development (i.”
BackgroundGeneralized Anxiety Disorder Severity Scale validation in older adults
Andreescu, C., Belnap, B. H., Rollman, B. L., Houck, P., Ciliberti, C., Mazumdar, S., Shear, M. K., & Lenze, E. J. (2008) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e31817c6aab · Cited by 35 · cited 1× · see citing works
“Participants were further assessed using the self-report Penn State Worry Questionnaire[34] and the GAD Severity Scale (GADSS).[35] Cognitive status was evaluated with a comprehensive battery of neuropsychological measures widely used for older adults.”
MethodSelf-citationArterial spin labeling: Validity testing and comparison studies
Ewing, J. R., Cao, Y., Knight, R. A., & Fenstermacher, J. D. (2005) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.20451 · Cited by 34 · cited 1× · see citing works
“[29,38–40] The water saturation pulse was applied at 800 msec after the global (corresponding to the control) or slice selective inversion (corresponding to the label).”
MethodKoziak, A. M., Winter, J. D., Lee, T., Thompson, R. T., & Lawrence, K. S. (2007) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2007.10.005 · Cited by 33 · cited 1× · see citing works
“[29,38–40] The water saturation pulse was applied at 800 msec after the global (corresponding to the control) or slice selective inversion (corresponding to the label).”
MethodViviani, R., Sim, E.-J., Lo, H., Richter, S., Haffer, S., Osterfeld, N., Thöne, J., & Beschoner, P. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.01.041 · Cited by 29 · cited 1× · see citing works
“the modest sample size and the variance components in brain perfusion, we obtained a weaker signal during the between-group comparison.[64] The comparison group was significantly older than the GAD group; however, our results did not change when we controlled the age difference.”
ResultWetherell, J. L., Stoddard, J. A., White, K. S., Kornblith, S. J., Nguyen, H., Andreescu, C., Zisook, S., & Lenze, E. J. (2010) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2619 · Cited by 25 · cited 15× · see citing works
“[47] Recent data support a possible malfunction of the amygdalar complex, reporting disrupted amygdalar subregions connectivity in midlife GAD.”
ResultInfluentialSelf-citationEscitalopram for Older Adults With Generalized Anxiety Disorder: A Randomized Controlled Trial
Lenze, E. J., Rollman, B. L., Shear, M. K., Dew, M. A., Pollock, B. G., Ciliberti, C., Costantino, M., Snyder, S., Shi, P., Spitznagel, E., et al. (2009) · JAMA · doi:10.1001/jama.2008.977 · Cited by 5 · cited 15× · see citing works
“[47] Recent data support a possible malfunction of the amygdalar complex, reporting disrupted amygdalar subregions connectivity in midlife GAD.”
BackgroundMethodInfluentialSelf-citationAnxiety disorders in later life: a report from the Longitudinal Aging Study Amsterdam
Beekman (1998) · Pure Amsterdam UMC · doi:10.1002/(sici)1099-1166(1998100)13:10 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- [30]Paulesu E Sambugaro T Torti L Danelli F Scialfa G Sberna M Ruggiero GM Bottini G Sassaroli S Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study. Psychol Med 2009 epub ahead of print doi: 10.1017/S00332917090005649 19419593 · DOI
- [32]First MSR Gibbon M Williams JBW Structured clinical interview for DSM-IV Axis I Disorders - Patient Edition (SCID-I/P) 1995 2.0 ed.
- [59]Thorp SR Ayers CR Nuevo R Stoddard JA Sorrell JT Wetherell JL Meta-analysis comparing different behavioral treatments for late-life anxiety. Am J Geriatr Psychiatry 2009 17 2 105 15 19155744 PMC2794407
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Sex differences in the developing brain: insights from multimodal neuroimaging
Kaczkurkin, A. N., Raznahan, A., & Satterthwaite, T. D. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-018-0111-z · Cited by 403 · see citing works
Mochcovitch, M. D., da Rocha Freire, R. C., Garcia, R. F., & Nardi, A. E. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.06.041 · Cited by 206 · see citing works
“One of them presents a PFC failure in top-down control (similarly to emotion regulation tasks) while the other shows maintenance of PFC hyper-activation (Paulesu et al., 2010; Andreescu et al., 2011).”
BackgroundResultKolesar, T. A., Bilevicius, E., Wilson, A. D., & Kornelsen, J. (2019) · NeuroImage Clinical · doi:10.1016/j.nicl.2019.102016 · Cited by 157 · see citing works
Mennin, D. S., Fresco, D. M., Ritter, M., & Heimberg, R. G. (2015) · Depression and Anxiety · doi:10.1002/da.22377 · Cited by 149 · see citing works
“meta-cognitive awareness, cognitive reappraisal[34, 35]).”
Hilbert, K., Lueken, U., & Beesdo‐Baum, K. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.01.022 · Cited by 144 · see citing works
“…Price et al. (2011) 16 (11) 63.1 (3.1) Not stated SCID No Strawn et al. (2012a) 10 (6) 14.3 (2) Not stated K-SADS NS Functional neuroimaging: ACCb Andreescu et al. (2011) 7 (5) 63.3 (3.9) Not stated SCID ANX Blair et al. (2012) 17 (13) 36.1 (11.8) Not stated SCID No Chen and Etkin (2013) 39…”
BackgroundMethodInfluentialAnxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat
Balderston, N. L., Vytal, K. E., O’Connell, K., Torrisi, S., Letkiewicz, A. M., Monique Ernst, D., & Grillon, C. (2016) · Depression and Anxiety · doi:10.1002/da.22518 · Cited by 106 · see citing works
Structural and functional neuroimaging studies in generalized anxiety disorder: a systematic review
Madonna, D., Delvecchio, G., Soares, J. C., & Brambilla, P. (2019) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2018-0108 · Cited by 99 · see citing works
Weber-Goericke, F., & Muehlhan, M. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.09.049 · Cited by 97 · see citing works
The neural correlates of worry in association with individual differences in neuroticism
Servaas, M. N., Riese, H., Ormel, J., & Aleman, A. (2014) · Human Brain Mapping · doi:10.1002/hbm.22476 · Cited by 96 · see citing works
“[2010] and other studies demonstrating the involvement of the default mode network and brain regions related to emotion processing and regulation in state as well as trait worry and rumination [Andreescu et al., 2011; Berman et al., 2011; Cooney et al., 2010; Hamilton et al., 2011; Marchetti et al., 2012; Paul et al.,…”
BackgroundElevated Amygdala Perfusion Mediates Developmental Sex Differences in Trait Anxiety
Kaczkurkin, A. N., Moore, T. M., Ruparel, K., Ćirić, R., Calkins, M. E., Shinohara, R. T., Elliott, M. A., Hopson, R. D., Roalf, D. R., Vandekar, S., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.04.021 · Cited by 96 · see citing works
“The results of this study are convergent with and extend results from prior studies that link elevated perfusion to clinically-diagnosed anxiety disorders (39,40) or to task-induced anxiety/stress (41,42).”
BackgroundResultZainal, N. H., & Newman, M. G. (2017) · Psychological Medicine · doi:10.1017/s0033291717003579 · Cited by 92 · see citing works
“Inhibition issues may also reflect abnormalities in neural coupling between the ventromedial PFC and dorsal raphe nucleus that regulates anxiety (Munakata et al. 2011) and cerebral blood flow patterns (Andreescu et al. 2011).”
BackgroundAndreescu, C., Sheu, L. K., Tudorascu, D., Gross, J. J., Walker, S. E., Banihashemi, L., & Aizenstein, H. J. (2014) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2014.05.003 · Cited by 97 · see citing works
Self-citationFonzo, G. A., Ramsawh, H. J., Flagan, T., Sullivan, S. G., Simmons, A. N., Paulus, M. P., & Stein, M. B. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.07.031 · Cited by 91 · see citing works
“Prefrontal–limbic interactions may be particularly relevant to the pathophysiology of GAD given the role of these regions in worry behavior (Paulesu et al., 2010; Andreescu et al., 2011), existing findings for abnormal prefrontal– limbic connectivity in GAD during both a resting state (Etkin et al.”
BackgroundNew Research on Anxiety Disorders in the Elderly and an Update on Evidence-Based Treatments
Andreescu, C., & Varon, D. (2015) · Current Psychiatry Reports · doi:10.1007/s11920-015-0595-8 · Cited by 85 · see citing works
Self-citationKaczkurkin, A. N., Moore, T. M., Calkins, M. E., Ciric, R., Detre, J. A., Elliott, M. A., Foa, E. B., Garcia de la Garza, A., Roalf, D. R., Rosen, A., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.174 · Cited by 86 · see citing works
Buff, C., Brinkmann, L., Neumeister, P., Feldker, K., Heitmann, C. Y., Gathmann, B., Andor, T., & Straube, T. (2016) · NeuroImage Clinical · doi:10.1016/j.nicl.2016.09.023 · Cited by 86 · see citing works
“, 2012) or in worry-induction tasks (Andreescu et al., 2011; Paulesu et al., 2010).”
BackgroundMental health in the UK Biobank: A roadmap to self‐report measures and neuroimaging correlates
Dutt, R., Hannon, K., Easley, T. O., Griffis, J. C., Zhang, W., & Bijsterbosch, J. D. (2021) · Human Brain Mapping · doi:10.1002/hbm.25690 · Cited by 71 · see citing works
“These inherent limitations of meta-analyses may explain why disagreement persists within even meta-analytical work, with a recent study showing hypo-(rather than hyper-) connectivity in the core DMN in patients with depression [Tozzi et al., 2021].”
BackgroundInfluentialFitzgerald, J. M., Phan, K. L., Kennedy, A. E., Shankman, S. A., Langenecker, S. A., & Klumpp, H. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.05.013 · Cited by 68 · see citing works
Dotson, V. M. (2014) · Journal of Depression & Anxiety · doi:10.4172/2167-1044.s1-003 · Cited by 66 · see citing works
“Functional imaging studies in older adults have found that compared to depression without anxiety, mixed depression and anxiety is associated with greater activation in the right hemisphere dorsal anterior cingulate cortex (ACC), posterior cingulate, and precentral gyrus during an executive task, and with lower defaul…”
BackgroundDiefenbach, G. J., Assaf, M., Goethe, J. W., Gueorguieva, R. V., & Tolin, D. F. (2016) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2016.07.002 · Cited by 58 · see citing works
Application of a cognitive neuroscience perspective of cognitive control to late-life anxiety
Beaudreau, S. A., MacKay‐Brandt, A., & Reynolds, J. R. (2013) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2013.03.006 · Cited by 60 · see citing works
Rabany, L., Diefenbach, G. J., Bragdon, L. B., Pittman, B. P., Zertuche, L., Tolin, D. F., Goethe, J. W., & Assaf, M. (2017) · Brain Connectivity · doi:10.1089/brain.2017.0497 · Cited by 58 · see citing works
“…in several brain regions, with some similarities between the two disorders, including within the PFC (Andreescu et al., 2011; Ball et al., 2013; Gaebler et al., 2014), ACC (Andreescu et al., 2011; Etkin et al., 2010; Goldin et al., 2009), and amygdala (Burklund et al., 2015; Etkin et al., 2010).”
Treating Anxiety Disorders in Older Adults: Current Treatments and Future Directions
Bower, E. S., Wetherell, J. L., Mon, T., & Lenze, E. J. (2015) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000064 · Cited by 88 · see citing works
“Similar to the general population, anxiety disorders in the elderly frequently co-occur with depression.15,19,24,25,28,38–41 In the National Comorbidity Survey Replication, 2.8% of adults 55 years of age and older had experienced cooccurring mood and anxiety disorders over the past year.19 Of those with a current anxi…”
BackgroundInfluentialSelf-citationZainal, N. H., & Newman, M. G. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.11.084 · Cited by 54 · see citing works
“Across a diversity of paradigms, worry led individuals with GAD to show vigilance toward social threats (Bar-Haim et al., 2007).”
Anxiety in Late Life: An Update on Pathomechanisms
Hellwig, S., & Domschke, K. (2019) · Gerontology · doi:10.1159/000500306 · Cited by 49 · see citing works
Executive skills in older adults with GAD: Relations with clinical variables and CBT outcome
Mohlman, J. (2013) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2012.12.001 · Cited by 49 · see citing works
“Because the neural circuitry of worry involves frontal activation (Andreescu et al., 2011) and”
BackgroundInfluentialBlay, S. L., & Marinho, V. (2012) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e3283578cdd · Cited by 49 · see citing works
Resting State Correlates of Subdimensions of Anxious Affect
Bijsterbosch, J. D., Smith, S. M., Forster, S., John, O. P., & Bishop, S. J. (2013) · Journal of Cognitive Neuroscience · doi:10.1162/jocn_a_00512 · Cited by 49 · see citing works
“…of cognitive, emotional, and homeostatic processes including salience detection, awareness of bodily state, response to pain, and risky decision-making (Andreescu et al., 2011; Levens & Phelps, 2010; Paulus & Stein, 2010; Xue, Lu, Levin, & Bechara, 2010; Craig, 2002, 2009; Wiech & Tracey, 2009).”
Brain structural changes in late-life generalized anxiety disorder
Andreescu, C., Tudorascu, D., Sheu, L. K., Rangarajan, A., Butters, M. A., Walker, S. E., Berta, R., Desmidt, T., & Aizenstein, H. J. (2017) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2017.08.004 · Cited by 48 · see citing works
“Other exclusion criteria were lifetime psychosis or bipolar disorder, increased suicide risk, medical instability according to review of medical chart data, ongoing psychotherapy, and current antidepressant or anxiolytic use (Andreescu et al., 2011).”
Self-citationBordner, K. A., Kitchen, R. R., Carlyle, B. C., George, E. D., Mahajan, M. C., Mane, S., Taylor, J. R., & Simen, A. A. (2011) · Experimental Gerontology · doi:10.1016/j.exger.2011.03.003 · Cited by 41 · see citing works
Steffens, D. C., Wang, L., Manning, K. J., & Pearlson, G. D. (2017) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2017.03.017 · Cited by 40 · see citing works
“[49], who found that older depressed subjects with high anxiety, when compared to nonanxious depressed older adults, exhibited increased functional connectivity in the precuneus Steffens et al.”
BackgroundKarim, H. T., Tudorascu, D., Butters, M. A., Walker, S., Aizenstein, H. J., & Andreescu, C. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.180 · Cited by 38 · see citing works
Self-citationPrefrontal-limbic connectivity during worry in older adults with generalized anxiety disorder
Mohlman, J., Eldreth, D. A., Price, R. B., Staples, A. M., & Hanson, C. (2015) · Aging & Mental Health · doi:10.1080/13607863.2015.1109058 · Cited by 32 · see citing works
“Regardless, ratings indicate a degree of success equivalent to previous investigations that only included post scanning questionnaires of anxiety severity (Andreescu et al., 2011).”
ResultZanos, P., Bhat, S., Terrillion, C. E., Smith, R. J., Tonelli, L. H., & Gould, T. D. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.12952 · Cited by 28 · see citing works
“gait speed effects of ageing in humans (Andreescu et al., 2011).”
BackgroundInefficient Involvement of Insula in Sensorineural Hearing Loss
Xu, X., Jiao, Y., Tang, T., Zhang, J., Salvi, R., & Teng, G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00133 · Cited by 32 · see citing works
“Others have noted a relationship between the perfusion of the insula and anxiety (Andreescu et al., 2011).”
BackgroundDemertzis, K. H., & Craske, M. G. (2006) · Springer eBooks · doi:10.1007/978-0-387-28370-8_30 · Cited by 27 · see citing works
Emotion Reactivity and Cerebrovascular Burden in Late-Life GAD: A Neuroimaging Study
Karim, H. T., Tudorascu, D., Aizenstein, H. J., Walker, S. E., Good, R., & Andreescu, C. (2016) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2016.07.015 · Cited by 27 · see citing works
“Late-life GAD is relatively understudied, and, in particular, the underlying structural and functional neuroanatomy has received little attention.(1,7,8) Community-based studies have indicated that generalized anxiety is the most prevalent anxiety disorder in the elderly, due to a second peak of incidence in late life…”
Self-citationChen, Y., Cui, Q., Sheng, W., Tang, Q., Lu, F., Pang, Y., Nan, X., He, Z., Li, D., Lei, T., et al. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110379 · Cited by 22 · see citing works
Cognitive processes across anxiety disorders related to intolerance of uncertainty: Clinical review
Haegen, M. V., & Étienne, A.-M. (2016) · Cogent Psychology · doi:10.1080/23311908.2016.1215773 · Cited by 22 · see citing works
“Indeed, individual with GAD have emotional reactions that occur more easily and intensely than non-anxious people and they have significant difficulties in their ability to identify and clarify their emotional experience (Andreescu et al., 2011).”
BackgroundLi, H., Zhang, B., Hu, Q., Zhang, L., Jin, Y., Wang, J., Cui, H., Pang, J., & Li, C. (2020) · General Psychiatry · doi:10.1136/gpsych-2019-100057 · Cited by 20 · see citing works
Altered Task-Evoked Corticolimbic Responsivity in Generalized Anxiety Disorder
Kim, N., & Kim, M. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073630 · Cited by 17 · see citing works
“In a worry regulation task with scripts, worry induction state elicited greater rostral ACC reactivity in geriatric GAD patients [67].”
BackgroundPrice, R. B., Cummings, L. R., Gilchrist, D., Graur, S., Banihashemi, L., Kuo, S. S., & Siegle, G. J. (2018) · Journal of Consulting and Clinical Psychology · doi:10.1037/ccp0000309 · Cited by 18 · see citing works
Experimental examination of worry among older and young adults
Gould, C. E., Gerolimatos, L. A., & Edelstein, B. A. (2014) · International Psychogeriatrics · doi:10.1017/s1041610214000891 · Cited by 15 · see citing works
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“Moreover, healthy young and older adult individuals also exhibit altered brain perfusion in response to clinically elevated levels of pathological worry, anxiety, or both.(22,23) The effect of anxiety on CBF in CVD populations has yet to be examined, and no study has simultaneously examined the impact of anxiety on ce…”
BackgroundAdvances in psychotherapy for generalized anxiety disorder.
Garfinkle, E. J., & Behar, E. (2012) · Current Psychiatry Reports · doi:10.1007/s11920-012-0263-1 · Cited by 12 · see citing works
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Imaging trait anxiety in high anxiety F344 rats: Focus on the dorsomedial prefrontal cortex
Prinssen, E. P. M., Nicolas, L. B., Klein, S., Grundschober, C., Lopez‐Lopez, C., Kessler, M. S., Bruns, A., von Kienlin, M., Wettstein, J. G., Moreau, J., et al. (2011) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2011.11.001 · Cited by 10 · see citing works
“It is quite likely that these areas are part of an emotional processing network with the dmPFC as a major component (Andreescu et al., 2011; Canteras et al., 2010; Ding et al., 2011; Qiu et al., 2011; Schneier et al., 2009).”
BackgroundMcDowell, C. P., Newman, L., Monroe, D. C., O’Connor, J. D., Knight, S. P., Kenny, R. A., & Herring, M. P. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab090 · Cited by 9 · see citing works
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“Изменения церебральной перфузии в ответ на повышенный уровень тревоги выявляются как у молодых лиц, так и людей пожилого возраста [60, 61].”
Puccetti, N. A., Stamatis, C. A., Timpano, K. R., & Heller, A. S. (2024) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-024-01239-z · Cited by 11 · see citing works
“…in worry and rumination may indicate a heightened salience of negative endogenous stimuli (i.e., thoughts and memories) and feeling “stuck” in RNT (Andreescu et al., 2011; Burrows et al., 2017; Kalisch & Gerlicher, 2014; Kühn et al., 2012; Nejad et al., 2013; Paulesu et al., 2010; Piguet et al.,…”
Guo, Z., Feng, L., Yan, X., Yang, L., Huang, S., Xing, Y., & Yang, Y. (2017) · BMC Psychiatry · doi:10.1186/s12888-017-1428-6 · Cited by 8 · see citing works
“It has been reported that patients with GAD may display abnormal cerebral blood flow [2], however the mechanism is still unclear.”
BackgroundAdvances and Barriers for Clinical Neuroimaging in Late-Life Mood and Anxiety Disorders
Ly, M. J., & Andreescu, C. (2018) · Current Psychiatry Reports · doi:10.1007/s11920-018-0870-6 · Cited by 7 · see citing works
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“between-group difference was observed between the patients and healthy control (Andreescu et al., 2011).”
BackgroundMRI Studies in Late-Life Mood Disorders
Andreescu, C., & Aizenstein, H. J. (2011) · Current topics in behavioral neurosciences · doi:10.1007/7854_2011_175 · Cited by 6 · see citing works
Self-citationCerebral hemodynamic response to generalized anxiety disorder
Harandi, A. A., Kimia, N., Medghalchi, A., Sharifipour, E., Pakdaman, H., Siavoshi, F., Barough, S. S., Esfandani, A., & Hosseini, M. H. (2023) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2023.111654 · Cited by 4 · see citing works
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Self-citationOlder and wiser? The neural correlates of worry induction and reappraisal in older adults
Karim, H. T., Gross, J. J., Mennin, D. S., Gerlach, A., Tudorascu, D., Butters, M. A., Ladouceur, C. D., & Andreescu, C. (2025) · Neuropsychopharmacology · doi:10.1038/s41386-025-02193-1 · Cited by 6 · see citing works
Self-citationAdvances in neuroscience research and big data's analysis on anxiety disorder
Yu, Q., Ruan, M., Chen, Y., & Wang, C. (2024) · Wiley Interdisciplinary Reviews Cognitive Science · doi:10.1002/wcs.1692 · Cited by 3 · see citing works
Cognitive, Emotional, and Behavioral Inflexibility and Perseveration in Neuropsychiatric Illness
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Structural and Functional Neuroanatomy of Generalized Anxiety Disorder
Schienle, A., & Wabnegger, A. (2020) · Wiley eBooks · doi:10.1002/9781119189909.ch8 · Cited by 3 · see citing works
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Effects of Jie Yu Wan on Generalized Anxiety Disorder: A Randomized Clinical Trial
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Self-citationThe effects of virtual reality technology on negative emotions in the elderly: a meta-analysis
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Trait Worry and Neural Correlates of Emotion Regulation
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“…p er so na l u se o f t he in di vi du al u se r a nd is n ot to b e di ss em in paradigms found altered activation especially in PFC and ACC regions and the insula (Andreescu et al., 2011; Paulesu et al., 2010; Schienle, Schaefer, Pignanelli, & Vaitl, 2009; Steinfurth, Alius, Wendt, & Hamm, 2017).”
BackgroundNeuroimaging of anxiety disorders
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A Gender-Based Point of View in Pediatric Neurology
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The Scientific Autobiography of a Traveler
Andreescu, C. (2021) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2021.01.008
Self-citationLate-Life Anxiety and Comorbid Depression
Bower, E. S., & Wetherell, J. L. (2021) · Cambridge University Press eBooks · doi:10.1017/9781139087469.007
Rangarajan, A., Karim, H. T., Tudorascu, D., Walker, S. E., Aizensteina, H., & Andreescu, C. (2019) · doi:10.31234/osf.io/6c8gz
Self-citationMohlman, J., & Bryant, C. (2015) · The Encyclopedia of Adulthood and Aging · doi:10.1002/9781118521373.wbeaa272
Molaie, A. M., von Walter, H. F., & Yarns, B. C. (2024) · Springer eBooks · doi:10.1007/978-3-031-55711-8_21
Cerebral blood flow as a mechanistic framework across neurological disease
Patel, S., Nischal, S. A., & Patel, N. K. (2026) · Discover Neuroscience · doi:10.1186/s13064-026-00269-2 · Cited by 1 · see citing works
“Further studies have demonstrated altered neural activity amongst elderly patients with anxiety, where a failure to activate the PFC (involved in the downregulation of negative emotions) may provide an opportunity for clinical targeting in this sub-population of GAD patients [236].”
Mertens, A. T., & Doucet, G. E. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1797635
“Additionally, all these studies either did not assess sex differences (27, 28) or controlled for them (29, 30).”
- Authors
- Andreescu, C., Gross, J. J., Lenze, E., Edelman, K. D., Snyder, S., Tanase, C., & Aizenstein, H.
- Affiliations
- University of Pittsburgh (US)
- Stanford University (US)
- Washington University in St. Louis (US)
- Corresponding author
- Andreescu, Carmen
- Venue
- Depression and Anxiety
- Publisher
- Wiley
- Published
- 2011-03
- Volume
- 28
- Issue
- 3
- Pages
- 202-209
- ISSN
- 1091-4269 (ISSN-L)
- PMC
- PMC3225118
- OpenAlex
- W2102039394
- Cited by
- 81
- References
- 63
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 11 · 2016: 8 · 2015: 6 · 2014: 9 · 2013: 5 · 2012: 3
- FWCI
- 8.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Depression and Anxiety (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P30AG024827)
- National Institute of Mental Health (R01MH076079, MH086680, MH070547, R01MH070547, R34MH086680, K23MH086686)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Keywords
- generalized anxiety disorder, late-life anxiety, older adults, emotion regulation, regional cerebral blood flow, prefrontal cortex, anterior cingulate cortex, amygdala, insula, cognitive control
- MeSH terms
- Adaptation, Psychological, Aged, Amygdala, Anxiety Disorders, Arousal, Brain, Brain Mapping, Cerebral Cortex, Cognition Disorders, Dominance, Cerebral, Emotions, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Occipital Lobe, Reference Values, Regional Blood Flow, Temporal Lobe, Down-Regulation, Prefrontal Cortex, Magnetic Resonance Angiography
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