{"id":69074,"date":"2016-11-13T09:00:01","date_gmt":"2016-11-13T14:00:01","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=69074"},"modified":"2016-11-13T01:37:50","modified_gmt":"2016-11-13T06:37:50","slug":"another-possibility","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2016\/11\/13\/another-possibility\/","title":{"rendered":"another possibility…"},"content":{"rendered":"\n
We  live in an age of Meta-Analyses and Systematic Reviews [studies of studies]. Some, like watchdog John  Ioannidis, lament their frequency as redundant and\/or unnecessary [The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses<\/a>]. But at least in the domain of neuroscience, I see these meta-analyses as an attempt at oversight in an area where advanced technologies have been applied to clinical problems without yielding much in the way of clarity. An example:<\/div>\n
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Altered Brain Activity in Unipolar Depression Revisited<\/a><\/div>\n
Meta-analyses of Neuroimaging Studies<\/font><\/strong><\/div>\n
by Veronika I. Muller. PhD; Edna C. Cieslik. PhD; llinca Serbanescu. MSc.; Angela R. Laird. PhD; Peter T. Fox. MD; and Simon B. Eickhoff. MD<\/div>\n
JAMA Psychiatry<\/font><\/strong>. Published online November 9, 2016. <\/div>\n

<\/p>\n

Importance<\/font><\/strong><\/em><\/u> During the past 20 years, numerous neuroimaging experiments have investigated aberrant brain activation during cognitive and emotional processing in patients with unipolar depression [UD]. The results of those investigations, however, vary considerably; moreover, previous meta-analyses also yielded inconsistent findings.<\/div>\n
Objective<\/font><\/strong><\/em><\/u> To readdress aberrant brain activation in UD as evidenced by neuroimaging experiments on cognitive and\/or emotional processing.<\/div>\n
Data Sources<\/font><\/strong><\/em><\/u> Neuroimaging experiments published from January 1, 1997, to October 1, 2015, were identified by a literature search of PubMed, Web of Science, and Google Scholar using different combinations of the terms fMRI [functional magnetic resonance imaging], PET [positron emission tomography], neural, major depression, depression, major depressive disorder, unipolar depression, dysthymia, emotion, emotional, affective, cognitive, task, memory, working memory, inhibition, control, n-back, and Stroop.<\/div>\n
Study Selection<\/font><\/strong><\/em><\/u> Neuroimaging experiments [using fMRI or PET] reporting whole-brain results of group comparisons between adults with UD and healthy control individuals as coordinates in a standard anatomic reference space and using an emotional or\/and cognitive challenging task were selected.<\/div>\n
Data Extraction and Synthesis<\/font><\/strong><\/em><\/u> Coordinates reported to show significant activation differences between UD and healthy controls during emotional or cognitive processing were extracted. By using the revised activation likelihood estimation algorithm, different meta-analyses were calculated.<\/div>\n
Main Outcomes and Measures<\/font><\/strong><\/em><\/u> Meta-analyses tested for brain regions consistently found to show aberrant brain activation in UD compared with controls. Analyses were calculated across all emotional processing experiments, all cognitive processing experiments, positive emotion processing, negative emotion processing, experiments using emotional face stimuli, experiments with a sex discrimination task, and memory processing. All meta-analyses were calculated across experiments independent of reporting an increase or decrease of activity in major depressive disorder. For meta-analyses with a minimum of 17 experiments available, separate analyses were performed for increases and decreases.<\/div>\n
Results<\/font><\/strong><\/em><\/u> In total, 57 studies with 99 individual neuroimaging experiments comprising in total 1058 patients were included; 34 of them tested cognitive and 65 emotional processing. Overall analyses across cognitive processing experiments [P > .29] and across emotional processing experiments [P > .47] revealed no significant results. Similarly, no convergence was found in analyses investigating positive [all P > .15], negative [all P > .76], or memory [all P > .48] processes. Analyses that restricted inclusion of confounds [eg, medication, comorbidity, age] did not change the results.<\/div>\n
Conclusions and Relevance<\/font><\/strong><\/em><\/u> Inconsistencies exist across individual experiments investigating aberrant brain activity in UD and replication problems across previous neuroimaging meta-analyses. For individual experiments, these inconsistencies may relate to use of uncorrected inference procedures, differences in experimental design and contrasts, or heterogeneous clinical populations; meta-analytically, differences may be attributable to varying inclusion and exclusion criteria or rather liberal statistical inference approaches.<\/div>\n<\/blockquote>\n
This meta-analysis focuses on neuroimaging studies of patients where DSM\/ICD criteria were used to define the target cohort of depressed subjects. While this classification has survived for now 36 years, I know of no evidence that these criteria define anything like a discrete clinical entity. <\/div>\n
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Criteria Related to the Investigation Participants<\/font><\/strong><\/u>
Included experiments statistically contrasted neural activation between an adult [>18 years] UD group [based on DSM-IV-TR and DSM-5 or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision] and a group of healthy controls…<\/div>\n<\/blockquote>\n
The studies examined were ones that compared brain activity measured by PET scans or fMRI studies between their depressed cohort and normals. That presumes a hypothesis that the experimental subjects would have something detectable in their brains either causing or as a result of their depression. Thus there were two bedrock assumptions: [1] a unitary clinical entity [2] that has something to do with the brain. <\/div>\n
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Results<\/font><\/strong><\/u>
A total of 57 studies with 99 individual neuroimaging experiments, comprising 1058 patients were included in this analysis. There were 34 cognitive processing experiments and 75 emotional processing experiments; 50 experiments reported increased brain activity in UD, and 49 experiments reported decreased brain activity in UD.<\/div>\n

Meta-analyses Across Emotional Experiments<\/font><\/strong><\/u>
None of the 9 emotional meta-analyses revealed any significant results {all emotional: 65 experiments [P > .69]; in- creases: 33 experiments [P > .47]; decreases: 32 experiments [P > .581; negative valence: 33 experiments [P > .76]; negative valence increases: 19 experiments [P > .12]; positive valence: 19 experiments [P > .15]; emotional faces: 32 experiments [P > .80]; negative emotional faces: 18 experiments [P > .75]; sex discrimination: 17 experiments [P > .41]}. Figure 4A displays the distribution of foci of the emotional analyses.<\/p>\n

Meta-analyses Across Cognitive Experiments<\/font><\/strong><\/u>
None of the 4 cognitive meta-analyses revealed any significant results {all cognitive: 34 experiments [P > .63]; increases: 17 experiments [P > .29]; decreases: 17 experiments [P > .97]; memory: 19 experiments [P > .48]}. Figure 4B displays the distribution of foci of the cognitive analyses.<\/p>\n

Meta-analyses Controlling for Confounds<\/font><\/strong><\/u>
Analyses restricted to [1] patients not receiving medication, [2] patients without comorbidity, and [3] patients without late-life or geriatric depression revealed similar results … When restricting the analyses to experiments using corrected statistics [COR], the analyses across experiments of negative emotional processing revealed significant convergence in the left thalamus extending into hippocampus [x = -18, y = -36, z = -4; 5 experiments contributing]. All other analyses did not reveal significant convergence {COR all emotional: 38 experiments [P > .82]; COR increases emotional: 20 experiments [P > .27]; COR decreases emotional: 18 experiments [P > .23]; COR all cognitive: 23 experiments [P > .61]}…<\/div>\n
<\/div>\n<\/blockquote>\n
Said the accompanying editorial:<\/div>\n
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Müller et al provide a technically sophisticated and informative set of meta-analyses examining altered brain activity in adults with symptomatic unipolar depression. The striking overall finding of their analyses is the lack of consistent group differences across studies. The absence of replicable effects across studies remained even when they addressed a number of potentially key confounds, such as examining only patients not receiving medication, patients without comorbidities, and patients without late-life or geriatric depression…<\/div>\n<\/blockquote>\n
Don’t think that reading this blog post is the definitive take on this comprehensive and complex meta-analysis. Read  the article and its supplements. What you’ll find is a window into the heavy duty math and numerous assumptions that go into these neuroimaging studies. What the article says is that we don’t know anything about the altered brain activity in unipolar depression. Reading this, I’m not even sure that we know if<\/font><\/em> there is any altered brain activity in unipolar depression. The random scattering of hot and cold spots from the studies along with the dramatically insignificant p-values isn’t much of a confidence builder. The authors give a laundry list of possible reasons for the non-replicability and non-convergence, suspecting that methodological problems top the list. I would start my own list at the input<\/font><\/em> end of things and quote historian Edward Shorter from Before Prozac<\/a>:<\/div>\n
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"Bottom Line: Major Depression doesn’t exist in Nature. A political process in psychiatry created it…"<\/div>\n<\/blockquote>\n
Major Depressive Disorder, Unipolar Depression, hasn’t played out as an entity, it’s a symptom complex [see which nail?…<\/a>]. Is it a brain disease? So far, there’s some indirect evidence that there are perhaps several biological entities in the mix in small doses [Melancholia, Depressive Episodes in Manic Depressive Illness], and who knows what else? The point being that there may be methodological problems with these neuroimaging studies, sure enough. But that aside, the questionable diagnostic and etiological speculations before they even turn on the MRI machine are probably more to the point. I would venture that a strong possibility to be considered is that they’re chasing a biomedical etiology in a heterogeneous population of people with a symptom complex primarily generated in the biographical and psychosocial domain of living…<\/div>\n","protected":false},"excerpt":{"rendered":"

We  live in an age of Meta-Analyses and Systematic Reviews [studies of studies]. Some, like watchdog John  Ioannidis, lament their frequency as redundant and\/or unnecessary [The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses]. But at least in the domain of neuroscience, I see these meta-analyses as an attempt at oversight in […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[5],"tags":[],"class_list":["post-69074","post","type-post","status-publish","format-standard","hentry","category-opinion"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/69074","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=69074"}],"version-history":[{"count":21,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/69074\/revisions"}],"predecessor-version":[{"id":69095,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/69074\/revisions\/69095"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=69074"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=69074"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=69074"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}