Lisle - Post stroke depression · • Stroke is the third leading cause of disability worldwide 1 • The most recent meta-analysis found that in the first five years following a

12/2/2019

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The Contributions of the Network Sciences in Understanding Post-Stroke Depression

Benjamin N. Lisle

Currently:

Fellow in Vascular Neurology, Wake Forest Baptist Medical Center

Disclosures

• I have no conflicts of interest or financial disclosures

Objectives

•1) Basic Explanation of Network Science

•2) Review the role of Network Science in understanding Poststroke Depression (PSD)

•3) Explore the potential clinical application of the Network Sciences to Prophylaxis and Treatment of PSD

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Network Science: The Concept

• We struggle to understand emergent properties both

conceptually and technically

• In the brain, emergent properties, notably “higher” cognitive

processes, arise from interrelations between discrete elements that correspond to our classic localization paradigm.

• These networks have been and remain difficult to understand

due to limits of technology, imagination, and epistemology.


• The Origins of Network Science

• Leonhard Euler (1707-1783)

• He’s a good guy. It’s just Bell’s Palsy

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• Koningsberga Bridge Problem


• Ardmore Tower Problem


• Ardmore Tower Problem


• Ardmore Tower Graph


“Graphs” have nodes and edges.


• So you have a “graph.”

• How do you get a “network”?

• Assign attributes (names) to the discrete elements:

• Ardmore tower: food and Neurology

• North Tower: Cardiology

• Reynolds Tower: MICU

• Wattlington Hall: Nobody knows

• North tower has more edges than Ardmore tower, Reynolds tower, or the parking deck

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Network Science: The Technology

• No MRI in 1720’s Austria

• Now we have Diffusion Tensor Imaging (DTI) and functional

magnetic resonance imaging (fMRI)


• Let me offer a comforting example of diffusion weighted imaging

(DWI) sequence of MRI


• A Simplistic Explanation:

• Water molecules move randomly unless inhibited (ventricles are

dark) if impeded or directed they move non-randomly (bright

lesion on diffusion map)


• Let me offer a less comforting image of DTI and more reductive

explanation:

Network Science: The Technology • The direction of movement of water molecules within each pixel is measured in at

least 6 non-collinear directions

• Vectors are conventionally color-coded by direction

• Red for right-left

• Blue for foot-head

• Green for anterior posterior

• Anisotropy (the property of being directionally dependent) is measured and reflected in the tract’s brightness


• Example: The corticospinal tract

• Travels AP (green) and then head-foot (Blue) and has high anisotropy (bright)

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• The hottest new “–ome"

• The -ome that we have

• The human genome

• -omes we want

• The gut microbiome

• The connectome

• The Human Connectome Project

• Announced in 2010 and ungoing

• Attempt to build a “network” map that will shed light on the

anatomical and functional connectivity within the healthy

human brain

Poststroke Depression

• What you probably already know:

• Stroke is the third leading cause of disability worldwide1

• The most recent meta-analysis found that in the first five years

following a stroke, 31% developed poststroke depression (PSD) 2

Post Stroke Depression: Lesion Location

• Relation of Poststroke Depression to lesion location is

controversial

• Wong et al found no evidence to support a relationship between

lesion location and PSD in a systematic review published in Lancet Neurology in 20003

• Wei et al also failed to find evidence to support such a

relationship in a meta analysis published in JAMA Neurology in

20154

• Douven et al5 in 2017 and Zhang et al6 in 2018 reported slightly

increased frequency with left hemisphere lesions, but the former

was specific to the acute phase and another was specific to the

subacute phase. These two reviews were less comprehensive and rigorous overall.

Relation of Poststroke Depression to Lesion Location

• Nickel et al7 also found no evidence to support a relationship

between lesion location and PSD, and cite, as well as others the

following difficulties in assessing numerous studies of this

relationship:

• The general exclusion of patients with language

dysfunction

• Considerable discrepancy in the time from event

• The variability of the instrument used to measure depression

• Differing methodologies for determining lesion localization

through visual analysis

Relation of Poststroke Depression to Lesion Location

• Advanced Imaging Modalities Have Failed to Resolve the

Debate

• Statistical parametric mapping as well as multivariate lesion-

symptom mapping have produced ambivalent results similar to earlier modalities and have been included in the recently

referenced meta-analyses

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Further complicating the lesion localization…

• El Hussein et al8 and Broomfield et al found a similar pattern and

incidence of depression has been found following TIA

• This further calls into question whether the severity of brain

injury is not a primary pathophysiological mechanism for PSD

• This correlates with developing models of other mechanisms of

cerebral damage.

• Notably in the lack of correlation between severity of traumatic

brain injury (TBI) and development of Major Depressive Disorder (MDD) found by Ouellet et al9 and Ponsford et al10

• Figure1 Lisle et al

“Post-Stroke” Depression after TIA…

• Allow me a digression into the deference between an object and

a phenomenon.

• Martin Heidegger’s Da Sein paraphrased: “the thingness of the

thing does not come from the thing.”

• An example from trying to explain -1 to my daughter

Why Lesion Locatization paradigm does not work for post-stroke depression?

• It’s an emergent property, a phenomenon.

• It is not related reliably to stroke severity

• It appears to be present even in the case of TIA

Poststroke Depression: Network Alterations

• Crossley et al among others have identified that the “hubs” of

the human connectome are generally implicated in the anatomy

of brain disorder.11

• A “hub”—think of edges and nodes--is an area that is important not only for its discrete function, but also for the role it plays in

connecting other brain regions. They tend to have higher

metabolic demands and higher and longer connections along

with greater “topologic value”

• They demonstrated that computational attacks on the identified

hubs disproportionally degraded the efficiency of the brain

networks compared to random attacks.

• Nine disorders had significantly hub-concentrated lesions, including Alzheimer’s disease and schizophrenia.


• Their analysis was based upon modeling healthy adults and

simulated damage.

• It is unclear whether these areas are more likely to be damaged

because of possible metabolic sensitivity as opposed to also resulting in more severe functional disability than another area.

• This would perhaps make them even more sensitive than the

model suggests.

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Poststroke Depression: “Hub Disruption Index”

• Termenon et al have described a “hub-disruption index” to

measure alterations to the nodes in the contralateral hemisphere

regardless of the hemisphere of the lesion. They used data from

the connectome as controls.

• Applying controls from the Human Connectome Project they

developed a score based upon DTI and fMRI to assess the

deviation from “hub activity” to the healthy controls.

• They found that contralateral stroke “induces a network-wide pattern of reorganization tin the contralesional hemisphere

whatever the side of the lesion.” 12

Poststroke Depression: Non-lesional Alterations in Connectivity

• Numerous studies including Lasalle-Lagadec et al have

described alterations to the Default mode network that

correspond to the severity of poststroke depression but not the

severity of the infarct13

Poststroke Depression: Cognitive Control Network

• What is the Cognitive Control Network (CCC)

• Consensus is that the same six cortical regions are involved in many forms of cognitive control, including the following:

• Anterior cingulate cortex/presupplementary motor area

• Dorsolateral prefrontal cortex

• Inferior frontal junction

• Anterior insular cortex

• Dorsal pre-motor cortex

• Posterior parietal cortex

• It has been repeatedly demonstrated to be associated with even mildly depressed subjects compared to healthy controls

• Cole et al have also implicated dysfunction in the cognitive control network in poststroke depression independent of lesion location and severity of infarct.14


• We should think of the role of lesion location in terms of the

relationship to the connectome as well as the discrete function

and whether the resultant disability would could worse “feelings”

due to perceived loss, although this is important.

Poststroke Depression: Non-lesional Alterations in Connectivity

• It is possible that a depression-related subnetwork specific to

PSD exists as Yang et al have reported. Using the lesion index,

fractional anisotropy (from DTI), and brain structural networks

(from rfMRI) they identified seventeen nodes that had decreased local efficiency in the subnetwork in patients with PSD15

• This was a limited study with a bold claim that has not been

reproduced.

Poststroke Depression: Inflammatory markers, BDNF

• Alterations in the hypothalamic-pituitary-adrenal axis (HPA),16

the inflammatory cascade,17 and cell-mediated immune

activation,18 that follows stroke have been implicated in PSD

• Brain derived neurotrophic factor (BDNF) may be the most important of these.

• A meta-analysis found that lower peripheral levels of BDNF in

the acute stage of stroke were lower in patients who went on to

develop PSD.19

• It has been suggested that polymorphisms in BDNF genotype

lead to a propensity for PSD.

• The most definitive meta-analysis, however, found that BDNF

genotype played a role in risk of ischemic stroke, but not in the development of poststroke depression.20

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Poststroke Deprssion: Treatment and Prophylaxis

• You may already know:

• Three compelling meta-analyses, published in 2008,21 2013,22

and 201723 of randomized control trials support the use of

antidepressants in PSD.

• Three compelling meta-analyses, published in 2008, 21 2010, 25

and 2013, 26 also support prophylactic use of antidepressants to

prevent PSD in nondepressed stroke patients.

Poststroke Depression: Treatment and Prophylaxis

• Most providers agree with screening for and treating PSD upon

diagnosis.

• Most of us are uncomfortable using SSRI’s or other

antidepressants prophylactically following ischemic stroke.

• No randomized control trial has used DTI or inflammatory

markers in order to be more selective with prophylactic

treatment of PSD.

Poststroke Depression and Network Sciences: Clinical Considerations

• DTI and serological studies involving circulating peripheral levels

of BDNF could independently, or in tandem, identify an at risk

population and allow for prophylactic treatment of PSD.

• Connectome assays could also help identify patients with PSD in populations who are difficult to assay, i.e. aphasic patients.

• These studies have not been used to evaluate patients with

TIA’s for alterations in network connectivity of peripheral BDNF

levels that could lead to depression.

• TIA patients are potentially a substantially undertreated

population that could benefit from further diagnostic assays and

treatments.

Application of Network Science to Clinical Neuroscience and Poststroke Depression

• Higher order cognitive processes are difficult, or impossible to

localize as they are emergent from an interaction of discrete

nodes

• These lead to difficulties applying the typical localization paradigm even when they occur as a sequelae of a discrete

lesion

Implications for counseling and screening

• Depression after stroke is common and the guidelines currently

support screening but do not explicitly advocate for prophylactic

treatment

• It is not common to screen for depression after TIA, but we probably should if the suspicion is high for vascular TIA

• The severity of stroke, degree of deficits, and location of lesion

are not reliably predictive, and even mild strokes require vigilant

assessment

Works Cited

1) Feigin VL, Norrving B, Mensah GA: Global Burden of Diseases, Injuries and Risk Factors Study 2013 and Stroke Experts Writing Group Lancet Neurology 2016; 15:913-924.

2) Hackett ML, Pickles K: Part I: frequency of depression after stroke: an updated systematic review and meta-analysis of observational studies. International Journal of Stroke 2014; 9:1017-1025.

3) Carson AJ, MacHale S, Allen K, et al: Depression after stroke and lesion location: a systematic review. Lancet 2000; 356:122-126.

4) Wei N, Yong W, Li X, et al: Post-stroke depression and lesion location: a meta-analysis. Kaohsiung J Med Sci 2004; 20:372-380.

5) Douvan E, Kohler S, Rodriguez MMF, et al: Imaging markers of post-stroke depression and apathy: a systematic review and meta-analysis. Neuropsychol Rev 2017; 27:202-219.

6) Zhang Y, Zhao H, Fang Y, et al: The association between lesion location, sex and poststroke depression: meta-analysis. Brain Behav 2017; 7:e00788.

7) Nickel A, Thomalla G: Post-stroke depression: impact of lesion location and methodological limitations: a topical review. Front neurol 2017; 8:498.

8) El Husseini N, Goldstein LB, Peterson ED, et al: Depression and antidepressant use after stroke and transient ischemic attack. Stroke 2012; 43:1609-1616.

9) Egorova N, Cumming T, Shirbin C, et al: Lower cognitive control network connectivity in stroke participants with depressive features. Transl Psychiatry 2018; 7:4.

10) Ponsford J, Always Y, Gould KR: Epidemiology and natural history of psychiatric disorders after TBI. J Neuropsychiatry Clin Neurosci (Epub ahead of print, June 25, 2018).

11) Crossley NA, Mechelli A, Scott J, et al: The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain 2014; 137:2382-2395.

12) Termenon M, Achard S, Jaillard A, et al: The “Hub Disruption Index”: a reliable index sensitive to the brain networks reorganization: a study of the contralesional hemisphere in stroke. Front Comput Neurosci 2016; 10:84.

13) Lassalle-Lagadec S, Sibon I, Dilharreguy B, et al: Subacute default mode network dysfunction in the prediction of post-stroke depression severity. Radiology 2012; 264:218-224.

14) Cole M, Schneider W: The cognitive control network integrated cortical regions with dissociable functions. Neuroimage 2007; 37:343-360.

15) Yang S, Hua P, Shang X, et al: A significant risk factor for poststroke depression: the depression-related subnetwork. J Psychiatry Neurosci 2015; 40:259-268.

16) Broomfield NM, Quinn TJ, Abdul-Rahim AH, et al: Depression and anxiety symptoms post-stroke/TIA: prevalence and associations in cross-sectional data from a regional stroke registry BMC neurol 2014; 14:198.

17) Pascoe MC, Crewther SG, Carey LM, et al: Inflammation and depression: why poststroke depression may be the norm and not the exception. Int J Stroke 2011; 6:128-135.

18) Villa RF, Ferrari F, Moretti A: Post-stroke depression: mechanisms and pharmacological treatment. Pharmacol Ther 2018; 184:131-144.

19) Xu HB, Xu YH, He Y, et al: Decreased serum brain-derived neurotrophic factor may indicate the development of poststroke depression in patients with acute ischemic stroke: a meta-analysis. J Stroke Cerebrovasc Dis 2018; 27:709-715.

20) Boa MH, Zhu SZ, Gao XZ, et al: Meta-analysis of the association between brain-derived neurotrophic factor polymorphism rs6265 and ischemic stroke, poststroke depression. J stroke Cerebrovasc Dis 2018; 27:1599-1608.

21) Hackett ML, Anderson CS, House A, et al: Interventions for preventing depression after stroke. Chorance Databse Syst Rev 2008; (3):CD003689.

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Lisle - Post stroke depression · • Stroke is the third leading cause of disability worldwide 1 • The most recent meta-analysis found that in the first five years following a