Editorial
Imaging evidence for depression: Is there biology in the bibliography?
Evidencia sobre la depresión con técnicas de imagen: ¿hay biología en la bibliografía?
John Suckling
Department of Psychiatry, University of Cambridge, Herchel Smith Building, Cambridge, United Kingdom
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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "5" "paginaFinal" => "7" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "John Suckling" "autores" => array:1 [ 0 => array:3 [ "nombre" => "John" "apellidos" => "Suckling" "email" => array:1 [ 0 => "js369@cam.ac.uk" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Department of Psychiatry, University of Cambridge, Herchel Smith Building, Cambridge, United Kingdom" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Evidencia sobre la depresión con técnicas de imagen: ¿hay biología en la bibliografía?" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Medical imaging has undoubtedly had a profound influence on clinical practice. Although this technology has been successfully translated to imaging the brain−<span class="elsevierStyleItalic">neuroimaging</span>− there has been disappointingly little impact on the management of individual patients presenting at psychiatry clinics. Neuroimaging, or to be more precise its interpretation, has been derided as merely a new phrenology, but it remains a central pillar of an evolving evidence base putting psychiatry on a convergent course with other disciplines, as medical practice becomes medical science.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Major depressive disorder (MDD) is the fourth leading cause of disease burden worldwide, and is associated with chronic physical illnesses placing it to become second only to heart disease in terms of disease burden.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The aetiology of MDD is far from a complete understanding, although it might be hoped that its biological loci could be described with some precision by the wide range of structural and functional imaging techniques at our disposal. The physical principles that underpin these techniques and the corresponding measurements they make are varied and distinct. What unites them is that when distinguishing pathological changes in anatomy and physiology, the observed effect sizes are small. Consequently, even for such a prevalent disorder, the prospects for imaging as a diagnostic or prognostic test look unlikely in the foreseeable future.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Notwithstanding this gloomy analysis, much has been learnt about the neurobiological basis of MDD from imaging and other techniques. Indeed, it is now clear from these direct observations that there is a neurobiological basis for the disorder favouring the unitarian model codified in DSM-III. Much of the convincing evidence for this has come the synthesis of published work as meta-analyses, a technique recently reframed for imaging studies.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, whether the brain differences associated with MDD represent a cogent model requires careful examination. Here we see if pieces really do fall into place.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">The hypothalamus–pituitary–adrenal axis</span><p id="par0020" class="elsevierStylePara elsevierViewall">HPA axis hyperactivity, leading to prolonged hypercortisolemia is a potentially powerful model of MDD that predicts cellular changes of brain areas that have a high concentration of glucocorticoid receptors such as the hippocampus, amygdala and cingulate cortex; areas of the limbic system involved in mood regulation.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The mainstay of studies of the HPA axis has been structural MRI using manual tracing of regions with hypothesised involvement. Perhaps surprisingly, the eponymous regions of the model have been the least-well studied, with a recent attempt at a meta-analysis being described as “futile”.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In contrast, meta-analyses have confirmed a highly significant reduction in the volume of the hippocampus and anterior cingulate associated with MDD<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> that is not replicated in combined volume measurements of the amygdale.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> The hippocampus is also sensitive to prolonged illness, with longer durations associated with smaller volumes.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> At the cellular level, neurogensis in the hippocampus mediated by selective serotonin reuptake inhibitor (SSRI) treatment<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a> has been shown to arise through accelerated maturation of immature granule cells.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> However, observing the predictions of these animal model data of increased hippocampal volumes in medicated patients is restricted by the small quantity of source data, although greater volume loss with moderate rather than severe duration of illness may indicate a restorative effect by chronic treatment.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The amygdala has a similarly uneven (although distinct) pattern of volume change. Several meta-analyses have failed to find overall differences<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> and no relationship has been found with chronicity.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However, stratifying according to medication status reveals a decrease in amgydala volume in drug naive patients. Conversely, treated patients have an increase in volume paralleling increased activity that accompanies acute administration of SSRI in a dose-responsive manner.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Furthermore, chronicity is strongly confounded with medication history, potentially masking its effect.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The overall picture therefore is of differential sensitivities of the components of the HPA axis to hypercortisolemia induced by depressive episodes. It is interesting to note that when studies looking at the entire cortex (rather than just a few regions) are combined, the only area that significantly characterises MDD is the anterior cingulated,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> suggesting small effects and/or variable results across studies. The down-regulation activity by SSRI treatment<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> has analogous heterogeneity across the HPA axis. Whether volume reductions predate clinical symptoms remains unknown. Meta-analysis of children with MDD provides no evidence either way,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> although an article published subsequently<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> found that morphologic changes might be evident initially and that genetic differences may increase vulnerability to early-life stress, and thus the risk of MDD.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">The fronto-limbic model</span><p id="par0040" class="elsevierStylePara elsevierViewall">A simple but influential systems-level model for depression is that enhanced “bottom-up” limbic activation by negative stimuli, in the absence of effective “top-down” inhibitory control by prefrontal cortex, may predispose to ruminative amplification of negatively valenced events, attentional bias to negative stimuli, and reduced capacity to reconstruct negative cognitions, leading to the emergence of depressive symptoms.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> This cognitive model predicts over-activation of the (para)limbic system (particularly amygdala and anterior cingulate cortex) by negative emotional stimuli in conjunction with under-activation of prefrontal cortical areas that are reciprocally connected to limbic structures and are thought to play an important role in mood regulation.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Meta-analyses of cross-sectional functional MRI studies of patients with MDD generally support the predicted patterns of increased limbic and decrease prefrontal activity. However, there is limited overlap of significant effects between studies.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16,17</span></a> It would be easy to dismiss this as a result of differences in methodologies, however a lack of consistency in the location of activation may in fact be a marker of MDD.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Effective pharmacotherapy with SSRI is associated with “normalization” of initial over-activation of limbic regions and the opposite trend, toward increased activation following treatment, in regions of prefrontal and cingulate cortex.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">An observation arising from the meta-analyses is the emergence of other regions outside of the fronto-limbic system with reduced activation in patients.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Whilst interesting, this is not unexpected given that most studies are explorative and thus report effects from across the entire cortex. These additional regions include the posterior cingulate and other components of the so-called default mode network, frequently linked to self-monitoring.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Abnormal activation in these regions can easily be envisaged as playing a key role in ruminative behavior. Meta analyses of resting cerebral blood flow with positron emission tomography has also demonstrated the sensitivity of these regions to SSRI treatment.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In this brief overview of the current evidence for a neurobiology substrate to MDD we have necessarily had to narrow our focus to just two models. Summarizing the findings takes us in two apparently contradictory routes. On the one hand, there is good support for the consistent involvement of HPA axis and fronto-limbic brain systems in MDD; a significant achievement compared to our knowledge only a decade ago. On the other hand, there are clearly additional complexities in the data that are not adequately accounted for by the existing models as they are described. In short, it looks unlikely that a reductionist approach will lead to a sufficient or useful description of MDD. Indeed, this is the case more generally across the inventory of mental health disorders. Compartmental models in which areas are imbued with specific functions and sensitivities do not acknowledge the distributed and integrative nature of the brain function. As the techniques to measure the brain mature, an evolution is also needed in our conceptualization of its organization, function and dsyfunction.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The author has no conflict of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:3 [ "identificador" => "sec0010" "titulo" => "The hypothalamus–pituitary–adrenal axis" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "The fronto-limbic model" ] ] ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of interest" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Suckling J. Evidencia sobre la depresión con técnicas de imagen: ¿hay biología en la bibliografía? Rev Psiquiatr Salud Ment (Barc.). 2012;5:5–7.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Depression, chronic diseases, and decrements in health: results from the World Health Surveys" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Moussavi" 1 => "S. Chatterji" 2 => "E. Verdes" 3 => "A. Tandon" 4 => "V. Patel" 5 => "B. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 0 | 4 | 4 |
| 2024 September | 11 | 17 | 28 |
| 2024 August | 17 | 15 | 32 |
| 2024 July | 11 | 7 | 18 |
| 2024 June | 13 | 3 | 16 |
| 2024 May | 17 | 6 | 23 |
| 2024 April | 23 | 5 | 28 |
| 2024 March | 14 | 8 | 22 |
| 2024 February | 20 | 3 | 23 |
| 2024 January | 7 | 2 | 9 |
| 2023 December | 14 | 6 | 20 |
| 2023 November | 9 | 3 | 12 |
| 2023 October | 24 | 3 | 27 |
| 2023 September | 24 | 3 | 27 |
| 2023 August | 8 | 1 | 9 |
| 2023 July | 6 | 7 | 13 |
| 2023 June | 4 | 0 | 4 |
| 2023 May | 13 | 6 | 19 |
| 2023 April | 6 | 1 | 7 |
| 2023 March | 13 | 1 | 14 |
| 2023 February | 12 | 4 | 16 |
| 2023 January | 12 | 3 | 15 |
| 2022 December | 12 | 8 | 20 |
| 2022 November | 12 | 10 | 22 |
| 2022 October | 19 | 3 | 22 |
| 2022 September | 14 | 16 | 30 |
| 2022 August | 13 | 6 | 19 |
| 2022 July | 15 | 8 | 23 |
| 2022 June | 6 | 11 | 17 |
| 2022 May | 13 | 11 | 24 |
| 2022 April | 13 | 12 | 25 |
| 2022 March | 16 | 14 | 30 |
| 2022 February | 16 | 12 | 28 |
| 2022 January | 12 | 9 | 21 |
| 2021 December | 22 | 13 | 35 |
| 2021 November | 20 | 9 | 29 |
| 2021 October | 12 | 19 | 31 |
| 2021 September | 13 | 12 | 25 |
| 2021 August | 15 | 12 | 27 |
| 2021 July | 9 | 10 | 19 |
| 2021 June | 17 | 12 | 29 |
| 2021 May | 20 | 11 | 31 |
| 2021 April | 64 | 11 | 75 |
| 2021 March | 18 | 6 | 24 |
| 2021 February | 12 | 13 | 25 |
| 2021 January | 16 | 6 | 22 |
| 2020 December | 15 | 7 | 22 |
| 2020 November | 12 | 14 | 26 |
| 2020 October | 11 | 5 | 16 |
| 2020 September | 15 | 27 | 42 |
| 2020 August | 8 | 22 | 30 |
| 2020 July | 6 | 13 | 19 |
| 2020 June | 7 | 13 | 20 |
| 2020 May | 8 | 6 | 14 |
| 2020 April | 12 | 7 | 19 |
| 2020 March | 14 | 2 | 16 |
| 2020 February | 13 | 14 | 27 |
| 2020 January | 24 | 7 | 31 |
| 2019 December | 10 | 11 | 21 |
| 2019 November | 8 | 2 | 10 |
| 2019 October | 10 | 1 | 11 |
| 2019 September | 10 | 6 | 16 |
| 2019 August | 12 | 5 | 17 |
| 2019 July | 5 | 9 | 14 |
| 2019 June | 14 | 10 | 24 |
| 2019 May | 62 | 28 | 90 |
| 2019 April | 7 | 4 | 11 |
| 2019 March | 6 | 7 | 13 |
| 2019 February | 9 | 1 | 10 |
| 2019 January | 1 | 6 | 7 |
| 2018 December | 9 | 2 | 11 |
| 2018 November | 4 | 0 | 4 |
| 2018 October | 16 | 4 | 20 |
| 2018 September | 24 | 11 | 35 |
| 2018 August | 8 | 2 | 10 |
| 2018 July | 4 | 3 | 7 |
| 2018 June | 11 | 4 | 15 |
| 2018 May | 16 | 9 | 25 |
| 2018 April | 5 | 2 | 7 |
| 2018 March | 5 | 1 | 6 |
| 2018 February | 43 | 0 | 43 |
| 2018 January | 27 | 1 | 28 |
| 2017 December | 47 | 0 | 47 |
| 2017 November | 21 | 2 | 23 |
| 2017 October | 7 | 3 | 10 |
| 2017 September | 11 | 15 | 26 |
| 2017 August | 18 | 3 | 21 |
| 2017 July | 17 | 3 | 20 |
| 2017 June | 7 | 10 | 17 |
| 2017 May | 9 | 1 | 10 |
| 2017 April | 18 | 7 | 25 |
| 2017 March | 12 | 19 | 31 |
| 2017 February | 8 | 6 | 14 |
| 2017 January | 5 | 2 | 7 |
| 2016 December | 16 | 5 | 21 |
| 2016 November | 13 | 3 | 16 |
| 2016 October | 28 | 6 | 34 |
| 2016 September | 17 | 4 | 21 |
| 2016 August | 15 | 2 | 17 |
| 2016 July | 20 | 1 | 21 |
| 2016 June | 34 | 7 | 41 |
| 2016 May | 33 | 15 | 48 |
| 2016 April | 16 | 10 | 26 |
| 2016 March | 22 | 15 | 37 |
| 2016 February | 22 | 15 | 37 |
| 2016 January | 21 | 15 | 36 |
| 2015 December | 17 | 13 | 30 |
| 2015 November | 19 | 8 | 27 |
| 2015 October | 19 | 13 | 32 |
| 2015 September | 16 | 8 | 24 |
| 2015 August | 12 | 2 | 14 |
| 2015 July | 8 | 4 | 12 |
| 2015 June | 2 | 2 | 4 |
| 2015 May | 14 | 3 | 17 |
| 2015 April | 10 | 8 | 18 |
| 2015 March | 12 | 6 | 18 |
| 2015 February | 20 | 3 | 23 |
| 2015 January | 26 | 4 | 30 |
| 2014 December | 39 | 6 | 45 |
| 2014 November | 13 | 6 | 19 |
| 2014 October | 32 | 4 | 36 |
| 2014 September | 21 | 0 | 21 |
| 2014 August | 15 | 1 | 16 |
| 2014 July | 20 | 3 | 23 |
| 2014 June | 9 | 2 | 11 |
| 2014 May | 17 | 2 | 19 |
| 2014 April | 9 | 4 | 13 |
| 2014 March | 14 | 3 | 17 |
| 2014 February | 11 | 3 | 14 |
| 2014 January | 12 | 3 | 15 |
| 2013 December | 25 | 1 | 26 |
| 2013 November | 22 | 5 | 27 |
| 2013 October | 19 | 1 | 20 |
| 2013 September | 21 | 4 | 25 |
| 2013 August | 24 | 4 | 28 |
| 2013 July | 17 | 2 | 19 |
Show all