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Depression - Coggle Diagram

- - - - Recovery with SSRI = 33%
        
        30% didn't get better
        
        70% recovered
        
        Some groups showed better response (women, better educated, wealthier)
      - Of those who didn't recover, 20% Recovered when CBT was added in conjunction to SSRI
      - Of those who still didn't recover, 15% recovered when they were given SSRI and Lithium/Thyroid hormone
      - Of those who STILL didn't get better, only 5% recovered when they were given SNRI/MAOI in addition to SSRIs
      - If treatments work for some people and not for others, then may depression isn't truly one unified illness
  - - - Relates to the GBA???
    - - Inhibits presynaptic neuron serotonin reuptakers
      - in 2-4 weeks serotonin levels are higher
        
        Why does it take so long?
        
        Harmer et al., 2009
        
        The second, newer antidepressant effect model suggests that downstream neuroadaptation and change in emotional bias occur simultaneously and gradually, thus explaining the gradual and delayed improvement in mood
        
        Hypothetical locations of Antidepressant Drug action (a triadic interlinked loop - mirroring Becks triad)
        
        Antidepressants effect the initial salience assessment (limbic system, amygdala)
        
        Cognitive therapies target the strategic control systems (e.g. frontoparietal attentional network)
        
        Sensory processing is also a factor
      - Some evidence that SSRIs also reduce inflammation (Wang et al. 2019)
    - - Young, 2009 - In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in the brain
        
        Brain-derived neurotrophic factor (BDNF) - plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. (Bathina & Das, 2015 )
        
        Upregulates pro-survival genes
        
        Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders
        
        https://pubmed.ncbi.nlm.nih.gov/19523343/
      - Malhi et al., 2013 - Lithium possesses unique anti-suicidal properties that set it apart from other agents.
        
        With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects
        
        At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes.
        
        Lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2
        
        Pizzino et al., 2017 - Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. An accumulation can lead to cell death
        
        Oxygen Reactive Species (ROS) - They perform some roles such as cell signalling and are typically generated as metabolic by-products [Pizzino et al., 2017]
        
        National Cancer Institute, 2011 - A type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. A build up of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins, and may cause cell death. Reactive oxygen species are free radicals.
        
        (Machado-Vieira et al., 2009) - Chronic treatment with lithium also inhibited reactive oxygen metabolite H2O2-induced cell death in rat cerebral cortex cells
        
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      - Treats the HPA
        
        Changes the way glucocorticoids (e.g. cortisol) are released into the blood in some way beginning in the adrenal cortex
    - - Monoamine oxidases are enzymes that breakdown monoamines ingested in food
        
        Link to GBA?
    - - lessening uncertainty about the future reduces anxiety and interacts with negative schemas in some way
    - - Intravenous subanaesthetic dose reduces symptoms of severe depression in hours, lasts for 7-14 days
        
        Extending effects beyond 14 days is not common
        
        Berman et al. - Study that showed that individuals’ Hamilton depression scores reduced after 2 days on ketamine treatment compared to placebo controls.
        
        But then again… of course they’ll seem better on ketamine.. Anyone would - it's a drug after all.
        
        But ketamine therapy seems to last 2 weeks which contrasts the usual short term effects of recreational ketamine.
      - The Alcohol effect - Results show family history of alcoholism increased the positive effects of Ketamine
        People with a greater sensitivity in the NMDA complex are more likely to bind ethanol, which increases glutamate
    - - (Baumeister et al., 2014) - Hallucinogens bind to the Raphe Nuclei of thalamus (releases serotonin into the serotonin pathway), which changes serotonin levels in the PFC
        
        Altered serotonin in PFC leading to altered glutamate levels to RN and hallucinogenic binding to Reticular nucleus (RN) causes altered GABA levels to the thalamus
        
        Alters sensory processing between the prefrontal cortex and thalamus
        
        In Depression, on hallucinogens, cognitive reframing is occurring by altering PFC connectivity. Particularly it is altering the connectivity between the PFC and the thalamus. NOT THE AMYGDALA!
        
        Therefore it seems as though hallucinogens are treating the cognitive aspect of depression instead of the threat response aspect.
        
        messes up the synchronicity/timing of sensory information
      - Criticisms
        
        There is a current controversy on the consensus of using hallucinogens for depression treatment due to inabilities to replicate and the exclusion of negative results/side effects
        
        “Why are all the people who say that hallucinogens help their depression are all rich straight white men?” - is it just uptight rich people who don’t care about others that are finally convinced of doing so through drugs? - suspicious …
        
        Cultural bias?
      - Metaxa & Clarke, 2024 - Psilocybin depression treatment works better in treating secondary depression - when it arises as a result of a comorbid illness. Not involved with primary serotonin imbalance model depression.
        
        Sampling bias - generally straight white men
    - - The network model of depression -
        In the MDD brain some brain networks are impaired, Drugs enhance connectivity in impaired networks, Activity dependent synaptic pruning and stabilises impaired networks. Thus making them operable even without medication
        
        Chronic Antidepressants increase neurogenesis in rat hippocampus (Malberg et al., 2000)
    - - Goldapple et al., (2004) - developed a model of brain areas and their responses to each treatment type (incorperating aspects of mayberg's model)
        
        Only CBT affects the cognitive (self-referential) aspects of MDD (medial frontal areas, ACC,OFC).
        
        Drugs/SSRIs only affect circadian vegetative areas (ventral Subgenual cingulate, anterior insula, hypothalamus, brainstem)
        
        While both CBT AND SSRIs affect the attention/salience aspect (DLPFC, Interior parietal, posterior cingulate, Hippocampus).
  - - - The Hypoactive DLPFC is a target for transcranial magnetic stimulation (TMS) (because it is on the outer layer of the brain)
        
        TMS is usually applied to the left side of the DLPFC due to the type of stimuli used - The argument there is because language function is more lateralized to the left hemisphere than the right. - in studies or Medical treatment.
      - Coil held in place over left DLPFC for up to 20 minutes
      - TMS MDD Treatment = TMS to left DLPFC, 5 days a week for 4 weeks.
      - The start of TMS - George et al., 1995 - N=1
        Hamilton score decreases after even just a day of TMS, with ups and downs but a general downwards decrease.
        
        O’Reardon et al., 2007 - Huge initial placebo effect - explains the prior studies’ results - Never fully goes away though.
        Real TMS does have a positive long term effect on MDD severity
        
        Fox et al., 2012 - Resting state Amygdala-PFC activity is asynchronous in MDD patients (indicating low connectivity).
        TMS to a variety of left DLPFC sites
        Results showed DLPFC sites with higher clinical efficacy were more inversely correlated with the Subgenual cingulate (BA25) ??????
        
        When stimulating certain parts of the DLPFC, connections to the subgenual cingulate were disrupted/unsynchronised
        
        Mitra et al. (2012) -
        MDD patients scanned with rsfMRI before and after TMS treatment to left DLPFC
        Patients who responded showed directional shifts between left DLPFC and anterior cingulate (ACC)
        Only directional shifts in the ACC predicted treatment efficacy
    - - PFC is targeted due to the electrodes being on the outer layer of the brain.
      - Abbott et al., (2014) - Depressed patients undergoing ECT gain greater hippocampal connectivity and improved symptoms
      - Using rsfMRI to predict ECT efficacy - Van Waarde et al., (2015) -
        You can predict someone will respond to ECT if they have higher connectivity of the ACC to the DLPFC
        
        Having Biomarkers for ECT responders will help increase treatment access by mitigating its stigma
    - - Hyperactive emotional areas (e.g. subgenual cingulate) can be targeted using deep brain stimulation (DBS)
      - Electrodes transplanted into the midbrain (e.g. for parkinsons)
      - Very invasive - Risks are too great for depression.
        Findings of DBS/VNS on MDD are only a secondary result of procedures for other medical problems.
      - DBS reduces neural hyperactivity in Cg25 (subgenual cingulate)
      - Mayberg et al. (2005) - Subgenual cingulate DBS worked in 4 out of 6 MDD participants (66.6%) - Subgenual cingulate goes from hyperactive to normal and hypoactive areas start to become more active again.
    - - Electrodes implanted into chest and connect to the midbrain via the spinal column (e.g. for Parkinson's)
      - Vagus nerve
        
        The vagus nerve connects the brain (sensory and motor systems) with the heart, lungs and digestive system.
        Involved with the HPA axis.
        Is responsible for causing the physical changes in the rest of your body during threatening events.
        
        Stimulation of any point of the vagus nerve works but ideally not near the brain (as that would require very invasive surgery)
      - Sackeim et al, (2001) report one third of MDD patients showed recovery after VNS.
        
        Increases concentrations of neurotransmitters (serotonin, glutamate, norepinephrine) which improves connectivity in the frontal-striatal pathway
        
        Similar to the effects of ketamine but just on a smaller scale
      - Zobel et al., (2005) report a decrease of cerebral blood flow in amygdala and hippocampus - reducing the salience response?
        
        Similar to SSRI except electrical
      - VNS causes the adrenal glands in the liver and kidneys to dump a load of glutamate into the system.
  - - - Is anxiety a milder form of depression… So that's why the algorithm was able to help?
  - - - Generally CBT is administered before medication, CBT lasts much longer than medication, CBT is also cheaper than medication
      - Operates on the idea that knowledge is power: Studies have shown that expecting pain lessens the perceived intensity of pain. This is thought to apply to when you can expect negative emotional feelings.
        
        Wager et al., 2004 - Placebo analgesic cream against Control shows DLPFC and OFC activity
      - Hollon et al., 2005 - Follow up at 12 and 24 months showed CBT group had fewest relapses compared to SSRI group
        
        Hollon et al., 2005 - cbt remission seems to stagnate at around 9-15 weeks before increasing again. How can we explain this stagnation? Maybe there is a delay where schemas need to be replenished with newly positively framed experience. Find evidence for this…
      - The CoBalT study (Wiles et al., 2013, Lancet) - CBT: Improvement seen in participants 46% in intervention group versus 22% in usual care (p<0·001).
        
        Long term effects of CoBalT (Wiles et al., 2016) - Results: Improvement seen in participants 43% in intervention group versus 27% in usual care (p<0·001)
        Demonstrates long term benefit of CBT as a supplement to ongoing treatment
      - Extinction - Offers a behavioural and neural explanation of why CBT works
        
        related to pavlovian conditioning
  - - - increased number of awakenings was also related to increased MDD levels
    - - During REM sleep, serotonin in brain stem structures is used up
        
        Missing sleep will increase available serotonin in the short term and thus improve depression symptoms
        
        prob wont positively affect structural issues though...
    - - Tailored lighting intervention for Alzheimer’s (Figueiro et al., 2019) - Tested a “circadian light” intervention (designed to maximise impact on circadian clock), Control light was below threshold for activating circadian system, Measured sleep quality (PSQI) and self-report measures of depression (CSDD) and agitation (CMAI) and the Light intervention improved ALL of the above measures
      - Sleep is involved in Emotional Regulation - Walker & Van der helm, 2009
        
        Walker & Tharani (in Walker & van der Helm, 2009) - After SD'ed individuals had 2 nights of recovery sleep, their memory was much better for negative memories, compared to the normal sleep condition, which had balanced positive and negative memory encoding. SD causes preferential Negative memory encoding
        
        relates to bias negative memories in: schema models
        
        A problematic situation could occur through repeated nights of deprived sleep, where an individual develops an overabundance of negative memories
        
        Sleep-based Preferential Emotional Memory consolidation - Payne et al, 2008 - The study found that emotional memories were selectively enhanced after sleep compared to neutral memories, suggesting a role for sleep in preferentially consolidating emotional experiences.
        
        Sleep preferentially consolidates NEGATIVE memories - Denis et al, 2022 - Sleep strengthens the negative aspects of memory, but has no impact on positive or neutral memories. Negative memories are more arousing than positive ones, which could affect memory processing during sleep. Could have an evolutionary advantage
        
        Provides evidence for Neuromodulators such as norepinephrine/noradrenaline and cortisol during waking experience, which allow these negative memories to be selectively encoded later (Mentioned in Denis et al, 2022)
        
        Cunningham et al., 2022 (I found this one) - PPs in a high cortisol condition had improved memory for negative scenes but worsened memory over time (when emotional aspects are removed from otherwise neutral scenes) for neutral scenes. Suggesting the existence of a emotional memory trade-off effect.
        
        There is direct evidence that there are distinct neural activations for arousing stimuli and emotionally valent stimuli - Kensinger & Corkin, 2004
        
        Valence - PFC-Hippocampal network
        
        Arousal: Amygdala-Hippocampal network
        
        REM (Early Sleep) - Increased Acetylcholine and Cortisol levels, reduced Noradrenaline and Serotonin. Prescence of Theta activity and PGO waves. Arguably, These all facilitate emotional memory encoding
        
        Wagner et al, 2001; 2006 Strong circadian component to REM sleep; it depends on the time of day. Late waking (i.e. having lots of REM sleep) is very important for emotional memory processing. These benefits are still seen 4 years after learning information.
        
        Nishida et al, 2009 - A nap improved memory for emotional pictures. This improvement correlated with REM sleep duration and the level Theta power in the right frontal area during REM sleep (strong oscillations). Time in REM and power of REM Theta waves is important
        
        Acetylcholine is involved with the consolidation of memories that are associated with the amygdala (emotion)
        
        SWS (Late Sleep) - Noradrenaline and serotonin levels remains the same, while Acetylcholine and Cortisol decreases. Presence of Slow waves, spindles, and ripples (sharp-wave ripples) occurs here. Good for non-emotional declarative memory
        
        Yoo et al, 2007 - Sleep regulates emotions - Sleep deprivation lead to increased amygdala reaction to emotional images and decreased functional connectivity between amygdala and mPFC (area that regulates the amygdala) This suggests the brain may reset the integrity of the brain's emotional regulation mPFC-amygdala circuit
        
        Walker & Van der Helm (2009) - Similar dysfunctions in this functional connection in mood disorders that have co-occurring abnormalities of sleep.
        
        Emotions Regulate sleep???
        
        Talamini et al, 2013 - PPs that experienced emotional distress had more early night REM and less late night REM. They also had increased overall SWS. Important to note that there was a subgroup of these participants whose sleep was consistently more resistant to emotional distress (High sleep quality responders HSQR)
        
        SWS Increase in first half of night predicted emotional attenuation
        
        HSQR participants showed swifter onset of SWS in control night. Implying this group of participants have a biological way of sleeping that lends their sleep to be more resistant against emotional disturbance. Early SWS may protect against emotional disturbance
        
        Argue that sleep, REM particularly, serves a role in stripping memories of their emotional tones while strengthening their non-emotional aspects
        
        Sleep to forget and Sleep to Remember (SFSR) Hypothesis - Walker (2009) - Sleep strips memories of their emotional tone (aka: affective tone) over the course of many sleeps as reexperiencing the emotions every time you recall a memory is unneeded, you just need to remember the lesson learned.
        
        (You don't want to reexperience memories as emotionally as you did as you experienced them but instead the lessons learned from them)
        
        Harrington et al, 2021 - Used TNT Task and found that sleep deprived individuals were less able to supressed unwanted thoughts and had more emotional responses to emotional stimuli
      - Novel sleep based treatments
        
        Lucid Dreaming - a sleep state that doesn't involve losing secondary consciousness, and involves awareness and control of dreams
        
        Model of Psychosis/Therapy for Schizophrenia (Dresler et al, 2015)
        
        Yount et al, 2023 - Lucid dream training had a benefit on PTSD symptoms, wellbeing, and mood
        
        Unclear whether or not this benefit was related to having lucid dreams - just from the training these benefits were seen. The broader schizophrenia dreaming workshop may have instead been the cause.
        
        Positive Mood - Stocks et al, 2020 - High lucidity sleepers had a more positive waking mood (n=8) than the low lucidity group (n=8)
        
        Though these newly trained lucid dreamers who had high lucidity may just be excited by the novelty of the lucid dream experience. Experiment should be done again but with experienced dreamers to confirm this idea
        
        also increase sample size
        
        Activation of the DLPFC in lucid dreaming compared to normal dreaming also present (also shown on an fMRI - Dresler et al., 2012) - makes sense as this area is associated with self-awareness
        
        DLPFC is implicated in depression...
- - - - PFC cognitive control areas are underactive
        
        Lateral Prefrontal Cortex (LPFC) is underactive.- is implicated in cognitive control and suppressing the limbic system (fear/emotion) response, regulates negative schema. it also triggers dopamine response to positive outcomes
        
        Fronto-Parietal Attention Network
        
        Dorsal Lateral Prefrontal Cortex / DLPFC - role is to come up with reasons to explain amygdala activation signals
        
        Ventral Lateral Prefrontal Cortex / VLPFC
        
        Medial Prefrontal Cortex (MPFC) - An area involved in thought, rumination, and the mental representation of the self that lies on the middle-point of the frontal-striatal pathway. It has direct projections to the amygdala. it is considered the gateway between the inner and outer world (active when reimagining or recalling a memory / taking something form memory to conscious perception)
      - Midbrain Areas are Overactive/Hyperactive
        
        Medial Temporal Lobe
        
        Amygdala - Part of the limbic system, processes emotions, prolonged response to negative emotions in MDD
        
        Victor et al., 2010 - MDD Patients vs HC patients looking at masked (to be subliminal) sad faces. MDD have increased response to sad faces. Treatment with SSRI and subsequent recovery lead to a reduction in safe face amygdala response.
        
        Overactive Amygdala / Limbic System generally - Amygdala detects threatful/salient stimuli
        
        Very low timeframe of firing (anxiety module)
        
        Overactive Nucleus Accumbens
        
        Hippocampus - Part of the Limbic system; the memory storage place. Linked to the Amygdala - the amygdala tags memories for the hippocampus
        
        if CBT is shown to reduce hippocampus responses implying a reduction in MDD and healing this could be criticised by the fact that memories are slowly transferred from there to the neocortex during sleep, so perhaps long-term schemas and memories aren't being observed here / aren't being resolved.
        
        Meta-analysis of VBM studies of MDD - Bora et al., 2012 - Reduction in volumes in hippocampus, frontal-striatal pathway (ACC->MPFC)
        
        Meta-analysis of VBM studies of MDD - Du et al., 2012 - Reduction in volume of the inferior frontal Gyrus (IFG)
      - General Evidence
        
        Wager et al., 2008 - asks participants to reappraise/supress their emotional response to disturbing/negative images. People who are able suppress negative appraisals of images have improved connectivity on the frontal-striatal pathway, in particular, the VLPFC and the connections between the dorsal and ventral PFC.
        
        Siegle et al., 2007 - Twenty-seven unmedicated patients with DSM-IV unipolar major depressive disorder and 25 never-depressed healthy control subjects completed tasks requiring executive control (digit sorting) and emotional information processing (personal relevance rating of words) during event-related functional magnetic resonance imaging (fMRI) assessment. Relative to control subjects, depressed subjects displayed sustained amygdala reactivity on the emotional tasks and decreased DLPFC activity on the digit-sorting task
      - Nucleus Accumbens - Component of the reward, motivation, and learning networks. Has increased activity (with amygdala) in response to dopamine. Highly involved in addiction; connections to and from this area is impaired in depression. Reinforces negative behaviour and doesn't reinforce positive behaviours in MDD
        
        Is in Disner's model but not Mayberg's
        
        Amygdala cannot function without the Nucleus Accumbens
        
        Something you don't like = less activity in Accumbens
        
        In depressed subjects this reward system isn't activated since you are always attending to negative stimuli; therefore positive behaviour isn't reinforced (via the reward network)
        
        Negative stimuli / behaviour IS reinforced and Nucleus Accumbens does react
        
        Heller et al., 2009 - Repeats the Wager study but with MDD participants - reduced Accumbens activity in depression PPs
        
        Analytical issues: Splitting of patients groups??? Split their patients in half
      - Anterior Cingulate Cortex (ACC) - Another inside/outside gateway brain area that is located at the front part of the CC surrounding the corpus callosum and is Divided into cognitive (dorsal) and emotional (ventral) parts
        
        Activation predicts treatment responsiveness
        
        High functional connectivity contributes to MDD (https://pubmed.ncbi.nlm.nih.gov/30418547/#:~:text=The%20high%20FC%20in%20depression,the%20ACC%2C%20contributing%20to%20depression.)
      - Thalamus - A brain area inside the corpus callosum that connects to all cortex areas. How the frontal-striatal pathway receives sensory information (except smells). In MDD the thalamus is generally underactive but is overactive/overfocused on negative stimuli due to increased amygdala / threat response
        
        The thalamus responds to both bottom-up and top-down input (involved in rumination)
        
        Thalamic Sub-areas
        
        Subareas for Vision
        
        Lateral Geniculate nucleus (LGN) - A nucleus inside the thalamus where the optic nerve initially connects to the thalamus and sends these signals to V1 / the primary visual area
        
        Pulvinar Nuclei - A collection of subthalamic nuclei. Visual salience is likely an important function of the pulvinar. connected with brain regions known to be playing a role in attentional mechanisms, such as area V4, the superior colliculus (SC), and the inferior parietal cortex (IP)
        
        Subareas for Hearing
        
        Medial geniculate nucleus (MGN)
        
        Other
        
        Superior Colliculus (SC) - Directs attention / orients body/head towards stimuli
        
        Subareas for Gustatory
      - Hypothalamus
      - Parietal Cortex (PC) - Involved in directing attention. in MDD this area is overactive for negative stimuli. [Very easy to see on a scanner]
      - Amygdala -> PFC = The Serotonergic pathway
      - Hyperactive Orbitofrontal Cortex (OFC) - codes reward expectation, morality.
        
        Uncinate fasciculus - one of several long-range white matter association fibre tracts in the human brain. It connects the orbitofrontal cortex to the anterior temporal lobes through a direct, bidirectional monosynaptic pathway.
        
        Anterior Temporal Lobe
        
        Pacheco (2009) – humans with more short 5-HTT alleles have reduced white matter in uncinate fasciculus (impairment of the emotional brain network)
- - - - Sequential treatment options list
      - Brain areas and their associated reactions with treatment
    - - MDD patients are just those who have spent too long in the downstate. When spending too long in the downstate then plasticity gets involved, negative self-fulfilling schemas develop, and serotonin gets used up.
      - Bijsterbosch et al., (2018) - Patients with attentional bias to threat showed High connectivity in limbic network - but no marked differences between anxiety and MDD patients - so this biomarker is not sufficient
        
        clinicians can differentiate GAD and MDD but rsfMRI and current machine learning models cannot
        
        Some HCs can have attentional biases towards fearful faces without having GAD or MDD, however, unlike MDD and GAD, HCs lack the high limbic connectivity, at least during resting state.
        
        Therefore differentiating between HCs and down people is easy.
        But differentiating down and depressed is less good.
    - - Stress causes release of cortisol
      - Increased immune response (via Macrophage = White Blood cells & Cytokines)
      - Reduced levels of neurotransmitters
      - Reduced levels of BDNF
      - Protein Density & Inflammation - Setiawan et al., (2015) -
        Due to hippocampus not turning off the HPA, leading to constant cortisol release, overtime having an effect on immune response leading to a heightened immune response,
        Increased immune response = increased cytokines in blood = cytokine sinto the brain = brain changes/inflammation
        
        TSPO V inflammation protein more present in PFC, ACC, Hippocampus
        
        Direct correlation between inflammation protein and MDD inventory score (r=0.63)
        
        Future studies need to be done to investigate whether the amount of this protein decreases over time when treatment is successfully responded to…
        
        Is this a form of depression that's different from the CBT form of depression?
    - - Genome-wide association studies (GWAS) - Use polygenomic sequencing to identify DNA patterns more likely to result in MDD
    - - Mayberg et al., (2000) - Patients given SSRI (fuoxetine).
        Decrease in ventral areas / increase in dorsal areas at 1 week
        Responders showed increased dorsal activity at 6 weeks
    - - Gamma Frequencies (30-100Hz) and High Gamma (100-200Hz) differ in normal and MDD
        Results are mixed (reduced gamma in some brain areas, increased in other brain areas)
        
        Successful MDD treatment does alter gamma oscillations (for more see Hamilton & Watson, 2018 on the VLE)
        
        Bailey et al., 2019 - this was failed to be replicated a year later
        
        Having an EEG marker of depression would be very effective for treatment outcomes as more places could easily have EEG treatments, due to its cheapness and portability/it doesn't take up a lot of space.
- - - - Negative views about yourself - Amygdala, PFC response that you can't turn off
        
        Leads to worsened perceptions of the world due to amygdala response / you think everyone is going to not like you / interpreting ambiguity as negative which leads to negative views about the world (Parietal Cortex - directs visual attention, responds more to negative stuff)... skewed world view .. literally
        
        This leads to biased predictions of the future (negative views about the future) - Hippocampus and leads to negative feelings / feelings of threat
        
        Hippocampus plans future behaviour using memories as a guide in conjunction with the PFC
      - being in this cycle for too long changes the neurochemistry in the brain
        
        Neurochemistry
        
        Molecular processes impaired in MDD
        
        Maletic et al., 2007 - Stress results in release of glucocorticoids and corticotropin releasing hormones (corticotropin or CRH) and pro-inflammatory cytokines. ACTH (Adrenocorticotropic hormone) then triggers cortisol release
        
        Corticotropin releasing factor (CRF/CRH) is released by the Paraventricular nucleus (PVN) of the Hypothalamus triggered by stress
        
        CRF binds to the CRF-1R receptor of the anterior pituitary gland triggering the release of Adrenocorticotropin hormone (ACTH)
        
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        Hippocampus inhibits the PVN nucleus neurons of the thalamus, which turns of this cycle in the healthy brain
        
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        Glucocorticoids (mainly cortisol in humans) is released by the adrenal cortex (adrenal gland)
        
        Cortisol increases blood sugar and aids the metabolism of fat, protein and carbohydrates
        
        (HPA Axis) Amygdala excites the PVN neurons in the hypothalamus
        
        Ploghaus et al., 2001 - Depressed / anxiety states leads to pain being perceived as being more painful
        (showing thalamus and bilateral hippocampus activation)
        
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        Diet composition and timing have a significant influence on acute cortisol secretion which will directly affect the HPA
        
        Lopresti et al., (2013) - Diet composition and timing have a significant influence on acute cortisol secretion which will directly effect the HPA
        
        Maletic et al., 2007 - Serotonin (5-HT), Norepinephrine (NE) and Dopamine (DA) are disrupted in MDD and this breaks the regulatory feedback loops that ‘turn off’ the stress response.
        
        Monoamines
        
        Dopamine - Reward and motivation, supports approach and survival behaviours
        Released from Ventral tegmental area (VTA) to forebrain networks
        
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        Serotonin - “Happiness” molecule but also many complex behaviours (e.g. dominance), Released from Dorsal Raphe to forebrain networks
        
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        Noradrenaline (also called Norepinephrine) - “Fight or flight” molecule that prepares the body for action
        Released to organs all over the body
        
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        Lopresti et al., (2013) - Mediterranean diet may increase neurotransmitters (sounds too good to be true…)
        
        Maletic et al., 2007 - Stress/Overactive Amygdala contributes to immune activation and release of inflammatory cytokines from Macrophages. Inflammatory cytokines further interfere with monoaminergic and neurotrophic signalling.
        
        Lopresti et al., (2013), Camargo et al., 2012 - Mediterranean diet reduces inflammatory markers (sounds too good to be true…) (underpowered)
        
        Inflammation model of MDD
        
        The sickness behaviour model - Depression imitates pro-survival (inflammatory) sickness behaviours due to the release of inflammatory cytokines
        Sickness behaviour represents a centrally organized suite of behaviours – depression, inactivity, anorexia, sleepiness, and reduction of grooming – that evolved in animals living in nature to conserve body resources for the high energetic costs of fever in fighting infections. (Maes et al., 2012)
        
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        Majd et al., 2020
        
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        Lipoxin A4 (LXA4) is a key anti-inflammatory protein (Potentially a: specialised pro-resolving mediator (SPM)) on the pathway that regulates inflammation.
        
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        https://www.sciencedirect.com/science/article/pii/S134786132100044X
        
        Lamon-Fava et al., 2021 - Eicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients.
        
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        Pasco et al., 2009 - Inflammation (c reactive protein) can be a biomarker for depression risk from up to 10 years prior
        
        Celecoxib may be useful treating depression (Kyoung-Sae, 2014)
        
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        Pioglitazone (anti-inflammatory diabetic drug) positively impacts depression symptoms (Sepanjnia, 2012)
        
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        Some evidence that SSRIs also reduce inflammation (Wang et al. 2019)
        
        Inflammation markers (e.g. IL-6) may be higher in depression and anxiety disorders (Ye et al. 2021)
        
        Brain derived Neurotrophic Factor (BDNF) - A growth factor protein that maintains and supports the growth of neurons / synapses
        
        Expressed in many brain areas but especially related to memory formation in the hippocampus
        
        Impaired neurotrophic support impairs the formation and maintenance of hippocampal pyramidal cells.
        
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        In MDD, Covert Attention (attending to location of interest without directing senses (i.e. moving eyes)) is always more likely to pay attention to negative stimuli
        
        Patients with bilateral amygdala damage were unable to recall emotional parts of the stories compared to controls. - Amygdala is important for emotional memory formation
  - - - Schemas become negative from depressive symptoms
      - Negative schemas biases cognition towards negativity
        
        Biased attention towards negativity - increased and sustained amygdala activity
        
        Biology of Biased Attention
        
        Frontoparietal Attention Network
        
        Due to posessing negative schemas that cause you to be more likely to process negative information
        
        Underactive dACC (cognitive control part of ACC)
        
        dACC projects to the DLPFC (the part that the dACC is closest too) and the VLPFC. Salience of stimuli Is determined here, said info goes to the Parietal cortex
        
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        Attentional Bias to Sad faces – Gotlib et al., 2004 - 3 groups. 1 MDD group, 1 GAD group, and 1 HC Group. Posner cueing task. Pairs of happy/sad/angry faces were presented [rated on emotionality (1-7)]. The pair was shown for one second and then a dot appeared behind one of the faces and PPs had to report where this dot was. Measures attentional Bias Bias in attention for sad faces in MDD
        
        Why doesn't the MDD respond more to angry faces?
        
        covert attention is directed more towards sad faces
        
        Biased Processing (predictions about other people) DLPFC hypoactivity
        
        This all leads to the manifestation of negative depressive symptoms (behavioural - not wanting to do anything etc, affective - how you feel about things, somatic - can change how your body physically feels, and motivational - it makes you lack motivation to do anything)
        
        fMRI study of cognitive / emotion processing (Siegle et al., 2002 ). - 30MDD; 28HC. 2 Tasks: One measuring Amygdala - Judging personal relevance of positive, neutral, and negative words and another task measuring the cognitive control/LPFC areas of the brain using a digit sorting task
        
        MDD show more activity for negative words over neutral words in bilateral amygdala
        
        MDD have more amygdala activity than HCs when viewing negative images
        
        Lower correlation of left DLPFC and left amygdala activity in MDD patients than in controls - implying worsened connectivity. functional connectivity analysis wasn't performed as fMRI was in its infancy here.
        
        Biology of Biased Emotional Processing
        
        Negative stimulus enters via sensory organs and feeds into the thalamus, which sends it to the amygdala
        
        Amygdala is hyperactive for negative stimuli, which projects to the Subgenual Cingulate
        
        Subgenual Cingulate is overactive to negative stimuli
        
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        Biology of Rumination
        
        Negative stimuli comes in and the amygdala is hyperactive in response
        
        Overactive Hippocampus recalls negative memories / experiences
        
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        Projects into the overactive Subgenual Cingulate
        
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        Impaired connections and underactivity of LPFC regions leads to the negative response not being stopped once the stimuli is gone
        
        Biased memory (focus on the bad stuff you can remember and make negative predictions based on them) Increased Amygdala, Hippocampus, and ACC activity and also increased striatal activity
        
        Biology of Biased Memory
        
        All areas (Hippocampus, Amygdala, Striatum) are hyperactive for negative stimuli
        
        Increased memory for negative stimuli in MDD – Hamilton et al. 2008 - MDD patients showed greater sensitivity to negative stimuli
        
        Amygdala projects to hypothalamus which causes negative memory of negative stimulus to be recalled
        
        Amygdala projects to the striatum (connection between the hippocampus and the motor system)
        
        The amygdala teaches the striatum (Caudate + Putamen) how we operate motor skills day-to-day which can lead to the physical side effects of depression too
        
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      - Environmental triggers can increase activation// development of negative Schemas
      - Genetic or personality factors can lead someone to have more negative schemas / activate them more often
      - Serotonin is inhibitory
      - Biology of Schemas
        
        ACC
        
        Dorsal ACC (closest to the PFC) is underactive [part of the salience/control network]
        
        Rostral (front of head) and Ventral ACC areas are hyperactive, as they are closer to the limbic system and are more involved in emotion/ negative emotion processing
        
        Strong connection from the Amygdala to the Ventral ACC due to negative processing
        
        Projects negative emotions to the MPFC
        
        dACC has a diminished connection to the Amygdala (Serotonin Pathway) due to the reduced brain serotonin levels, making it so control isn't as possible
        
        the low levels of serotonin is used for negative processing
        
        Negative stimuli comes in through the thalamus and projects to the amygdala which then goes into the ACC
  - - - Tells you when adrenaline/ when the symapthetic nervous system is active
    - - Good target for TMS treatment
      - For the purpose of exam/simplicity - assume the rostral ACC and Subgenual cingulate are the same thing.
        Mayberg’s study uses PET scan which has low temporal accuracy
        
        Mayberg’s was a good guess but better studies (Fox et al., 2012) have revealed that the subgenual is more likely the key area/a better predictor- she was off by about 2 cm
- - - - Stanley and Mann., 1983 - Some reports of higher 5-HT2 receptor density in Brodmann’s area 9 in the PFC in suicide victims and suicide victims with MDD episodes
        
        Lack of Serotonin -> A higher density of serotonin receptors
    - - If you have 0 stressful life events you have no difference in MDD likelihood, regardless of your genotype.
      - s/s allele requires the least number of stress events to trigger MDD
      - Pezawas et al., 2005 - VBM Study. Carriers of the short-allele variant show reduced volume in amygdala and perigenual cingulate
        
        s/s variant individuals have reduced BDNF, which compromises Frontal-striatal pathway integrity (in the way of brain area sizes and connectivity), making them more sensitive to stressful life events and more likely to develop MDD.
        
        Nestor et al., 2019 - Different combos of BDNF gene (Val66Met) and 5HTT polymorphisms determine stress sensitivity (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700400/)
        
        Val66Met - regulates BDNF levels. Short allele variant of this gene leads to a greater chance of a mood disorder
        
        Aguilera et al., 2009 - Childhood adversity predicted higher levels of adult depressive symptoms. In addition, BDNF Val66Met and 5-HTTLPR polymorphisms seemed to moderate the effect of Childhood sexual abuse on adult depressive symptoms. (https://pubmed.ncbi.nlm.nih.gov/19215635/)
        
        Stressful events are less likely to result in depression if they happen later in life.
        
        Pezawas also did DTI Study: Patients with s/s 5-HTT polymorphism had reduced Amygdala volume (DTI)
        
        DTI - Diffusion Tensor Imaging - Measures white matter tracts. If VBM measures Grey matter (cortex), then DTI measures the white matter (the computation area / highway between brain areas)
        
        Pacheco (2009) – DTI: humans with more short 5-HTT alleles have reduced white matter in uncinate fasciculus (area lying on the connection between the [Perigenual] Cingulate cortex (CC) and Amygdala)
        
        Hariri et al., 2002 - s/s allele patients had greatest hyperactivity to fear faces in amygdala (fMRI). relates to: schemas
      - Can extrapolate fear conditioning to early life stress events - Fear responses were trained to you and therefore you were classically conditioned and CSs now elicit inappropriate fear responses
        
        A model of Extinction - Myers & Davis, (2002) - 1. At relatively extended intervals following extinction, the extinguished CR reappears. The magnitude of this “spontaneous recovery” increases over time
        
        Extinction-based forgotten associative bonds are context dependent
- - - - Persons with elevated levels of neuroticism respond poorly to environmental stress, interpret ordinary situations as threatening, and can experience minor frustrations as hopelessly overwhelming
        
        Increased negative startle response – (e.g., fight or flight)
    - - So at least some MDD patients have comorbid symptoms that don’t overlap with neuroticism
        
        Essentially you cannot explain all of depression using neuroticism (the effect size would be higher)
  - - - This is saying: you have a much more severe form of MDD if you have ADHD
  - - - Is it possible that MDD questionnaire understanding/responses are different in ASD individuals.
- - - - Demonstrates why two treatments are better than one
        (better safe than sorry)
    - - SSRIS - Decreased activity: insula, right motor cortex, premotor cortex, Inferior temporal lobe. Increased in Amygdala (unpredicted.. Unclear what's going on here)
        
        In conclusion: SSRIS and CBT treat the brain area differently. They are doing very different things in the brain.
        SSRI and CBT responders seem to have directly opposite forms of MDD. i.e. differing neural underpinnings.