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Clinical Neuroscience of Depression Flashcards

Clinical Neuroscience

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1
Q

major depressive disorder (MDD) is only diagnosed if a patient exhibits 5 (or more) behaviours, what are these behaviours?

A
  • Depressed mood
  • Reduced interest in pleasure (Anhedonia)
  • Significant weight change
  • Disturbed sleep (Insomnia / hypersomnia)
  • Abnormal motor activity (Psychomotor Agitation / Psychomotor Retardation)
  • Fatigue, tiredness, or loss of energy
  • Feelings of worthlessness or excessive guilt
  • Diminished ability to think or concentrate
  • Recurrent suicidal ideas (with or without a plan)
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2
Q

what happens with each symptom?

A
  • each symptom has a complex behavioural pattern
  • involves multiple malfunctioning brain areas
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3
Q

how does diagnosis of depression happen?

A

itā€™s a judgment call by a clinician to establish whether someone is depressed
* no blood tests or easy ā€˜tests ā€˜ for depression

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4
Q

what does DBS stand for?

A

deep brain stimulation (brain surgery where electrodes are implanted into brain regions and can be turned off and on

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5
Q

what does VNS stand for?

A

vagus nerve stimulation

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6
Q

what does TMS stand for?

A

tranmissional magnetic stimulation

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7
Q

when did chlorpromazine, imipramine and iproniazid was introduced?

A

1953-1960

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8
Q

when was VNS approved?

A

2005

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9
Q

when was TMS approved?

A

2008

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10
Q

what is the main pharmacological intervention for depression?

A

SSRIs developed from an accidental discovery when working on tuberculosis treatments

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11
Q

what is beckā€™s cognitive model of depression?

A

the idea that depressive symptoms are generated and maintained by a combination of maladaptive cognitions

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12
Q

Beck suggests that individuals with depression are said to be prone toā€¦

A
  • selectively attend to negative stimuli (biased attention)
  • experience greater awareness/perception for negative stimuli (biased processing)
  • ruminate about depressive ideas (biased thought and rumination)
  • recall depressive episodes with more frequency (biased memory)
  • possess negative internal reps about the self and environment (negative schemas)
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13
Q

what is a cognitive neuroscience model of depression?

A

the idea that a number of different brain regions are involved in depression which can be mapped to the different cognitive patterns thought to trigger and sustain a depressive episode

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14
Q

a meta-analysis of reduced hippocampal volume in MDD (Videbech and Ravnkilde, 2004)

A
  • found a difference in hippcampal volume between depressed group and control group (reduced hippocampal volume in depressed individuals)
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15
Q

issues with hippocampal studies..

A

never know if an individualā€™s brain was always like that or it was different before they were diagnosed with depression

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16
Q

what is the neurotrohic hypothesis of depression?

A
  • human post-mortem data shows decreased BDNF in the hippocampus
  • this impairs memory encoding and demonstrates neuroplasticity at a very specific anatomical level
  • but we donā€™t know if itā€™s a cause or result of depression
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17
Q

what is depression associated with?

A
  • increased amygdala activity (stronger negative responses, influences memory retrieval)
  • decreased activity in right VLPFC and right DLPFC and superior parietal cortex (problems attending to positive stimuli/problems regulating amygdala response)
  • atypical fronto-striatal activity (problems with reward processing)
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18
Q

what is the neurochemistry of depression?

A
  • glucorticoids
  • brain derived neurotropic factor (BDNF)
  • Monoanimes
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19
Q

what is glucocorticoids?

A
  • (mainly cortisol in humans)
  • steroid hormone which increases blood sugar, suppresses immune system, increases metabolism
  • increased cortisol levels raise performance during stress
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20
Q

what are brain deprived neurotropic factors?

A
  • maintains and supports growth of neurons / synapses
  • expressed in many brain areas but especially related to memory formation in the hippocampus
    • Relates to the neurotrophic theory of depression (a key character)
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21
Q

what are monoanimes?

A

neurotransmitters that are released by neurones to send signals to other neurones
* Dopamine
* Serotonin
* Noradrenaline

22
Q

what is dopamine?

A

reward and motivation, supports approach and consummatory behaviors
* released from ventral tegmental area (VTA) to forebrain networks

23
Q

what is serotonin?

A

ā€œhappinessā€ molecule but also many complex behaviors (e.g. dominance)
* released from Dorsal Raphe to forebrain networks

24
Q

what is noradrenaline (also called norepinephrine)?

A

ā€œfight or flightā€ molecule that prepares the body for action
* Released to organs all over the body

25
Q

describe monamine treatmentsā€¦

A
  • have to overcome homeostatic feedback mechanisms (2-4 weeks); therefore takes 2-4wks until monoamines begin to work
  • many side effects (insomnia, restlessness, aggression, suicidal thoughts, dizziness, nausea, headaches)
  • effects can wash-out over time
  • should not be a single treatment but as part of a treatment program (i.e. antidepressants and CBT)
  • people may say that they feel better immediately after starting drug treatments ā€“ almost definitely a placebo effect, as shouldnā€™t work for 2-4 weeks.
  • Monoamine treatment by itself unlikely to help long term ā€“ should be used as part of a programme, e.g. CBT
26
Q

but what if monoamine treatments donā€™t work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). Procedure:

A

Level 1: Citalopram (SSRI) for 14 weeks (if people didnā€™t respond to this, theyā€™d be moved to level 2 and so on)

Level 2: Different anti-depressants (SSRI) + Optional CBT

Level 3: Different anti-depressants + Lithium or Thyroid Hormone

Level 4: Anti-depressants + monoamine oxidase inhibitors or serotonin-norepinephrine reuptake inhibitors (SNRI)

27
Q

but what if monoamine treatments donā€™t work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). Results:

A

Responded at Level 1 ā€“ 47% or all subjects

Remission at Level 1 ā€“ 28-33%

Remission at Level 2 ā€“ 25% (CBT seemed to work as well as drugs)

Remission at Level 3 - 12-20%

Remission at Level 4 ā€“ 7-10%

28
Q

but what if monoamine treatments donā€™t work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). what are the two variable outcomes?

A

reduction: responding to medication, yet still have depression

remission: depression symptoms drop so much, they are you are no longer considered to have depression

29
Q

but what if monoamine treatments donā€™t work? The scale of the pharmacological problems. STAR*D, a large scale test of drug efficacy using increased levels of treatment (2006). what happened with withdrawal and remission?

A
  • withdrawal rates increased at each level (side effects get worse as each level increases)
  • approx. 70% of all subjects who completed showed remission (this means 30% have drug resistant depression; this is why we need other treatments like CBT and brain stimulation)
  • some groups showed better response (women, better educated, wealthier)
30
Q

The CoBAIT study (Wiles et al., 2013) tested efficacy of CBT for two groups of participants. Usual care (n=235) OR usual care and CBT [intervention group] (n=234). Patients were monitored over 12 months and success was defined as a 50% reduction in BDI after 6 months. What did they find?

A

improvement seen in 95 participants (46%) in intervention group versus 46 (22%) in usual care (p<0Ā·001).

31
Q

what is the genetic likelihood of major depressive disorder?

A
  • highly heritable (50% chance if parents are diagnosed)
  • more in women than men
  • we ALL have at least some genes correlating (thereā€™s not one depressive gene but to what extent the gene causes depression varies)
32
Q

what is polygenomic sequencing?

A
  • about 3 billion base pairs in the human genome
  • almost all identical across all humans
  • single nucleotide polymorphisms, or SNPs (pronounced ā€œsnipsā€) result in changes across individuals and groups (bits in our genome that results in differences between us)
  • mapping these SNPs is much easier since the Human Genome Project Heritability studied in genome-wide association studies (GWAS)
  • can be used to create a genetic ā€˜roadmapā€™ of depression
33
Q

what are some of the ā€˜hot spotsā€™ genetic locations for major depressive disorder?

A
  • 44 variants argued to map onto 19 genetic pathways to depression (Wray et al, 2018)
  • weight and body size (OLFM4 and NEGR1)
  • neuron development and brain inflammation (LRFN5)
  • over-activation in the fight-flight systems (RBFOX1).
  • neurotransmitter systems for dopamine (DRD2)
  • calcium signaling (CACNA1E and CACNA2D1)
  • glutamate Neurotransmitter(GRIK5 and GRM5)
  • presynaptic vesicle trafficking (PCLO)
  • brain development (TCF4)
34
Q

what is a ā€˜roadmapā€™ and why is it useful?

A

can be used to identify an individuals likelihood of developing depression

35
Q

what is polygenic risk scores?

A

polygenomic sequences is used to compare an individualā€™s DNA to the road map and estimate how likely one is to develop depression at some point in their life
* interesting to see what co-varies with depression

36
Q

Gene SLC6A4 (commonly known as 5-HTT) regulates the expression and transportation of serotonin in the brain, yet has two versions of the gene, a short (s) version and a long (l) version, creating three variant groups: s/s, s/l and l/l. Describe the procedureā€¦

A
  • dunedin Multidisciplinary Health and Development Study of 1037 children
  • three groups on the basis of their 5-HTTLPR genotype; s/s homozygotes, s/l heterozygotes and l/l homozygotes
  • then measured number of stressful life eventsā€¦
37
Q

Gene SLC6A4 (commonly known as 5-HTT) regulates the expression and transportation of serotonin in the brain, yet has two versions of the gene, a short (s) version and a long (l) version, creating three variant groups: s/s, s/l and l/l. Describe the findings..

A
  • found that those with s/s genes who have had a higher amount of stressful life events, the higher amount of self-reported depression symptoms, suicide ideation, reports of depression, major depression episodes
  • when there is no maltreatment, groups the same but when thereā€™s severe maltreatment, those with s/s genes, have a 0.6 chance of a major depressive episode while those with l/l only had 0.3 (s/l are in the middle with about 0.45)
  • just being in the s/s group in itself is okay, itā€™s the combination with negative events where you might begin to see depression
38
Q

Gene SLC6A4 (commonly known as 5-HTT) regulates the expression and transportation of serotonin in the brain, yet has two versions of the gene, a short (s) version and a long (l) version, creating three variant groups: s/s, s/l and l/l. Describe the conclusions..

A
  • the 5HTT s/s homozygote allele variant is not enough to cause MDD
  • a combination of the 5HTT s/s variant and multiple early life stress events will increase chances of MDD diagnosis
  • the risk of MDD is thus an output of both oneā€™s genetic predisposition and oneā€™s environment
39
Q

Genetics impact brain structure..

A
  • voxel brain morphometry (VBM) used to measure gray matter volume of 5-HTT gene
  • carriers of the short-allele (s/s) variant show reduced volume in amygdala and perigenual cingulate
  • connectivity between amygdala and cingulate impaired in 5-HTT group when viewing fearful stimuli
40
Q

what does genetic variation mean for medical treatments of depression?

A
  • drug study of 102 MDD patients treated with fluvoxamine (SSRI) split into three 5-HTT groups: l/l, (long, long), l/S (long, short) and s/s (short, short). MDD measured with Hamilton depression rating scale (HDRS) found that genetics interact not just with the environment but also treatment
  • s/s have less effect on fluvoxamine alone than it has on other gene types
  • genetics interact not just with the environment but also treatment
41
Q

what are the basis of brain regions in depression?

A
  • DLPFC is hypoactive in MDD: problems with top-down regulation
  • Amygdala is hyperactive in MDD: problems with processing negative stimuli
  • Disrupted reward processing and biased memory processes
42
Q

what variant of 5HTT gene has the largest increase of depression?

A

s/s variant interacts with negative life events to increase your risk of depression (genetics + environment interact to increase your depression)
* s/s variant of the 5HTT is linked to differences in the brain regions associated with depression and may affect treatment

43
Q

how do monoamine neurotransmitters work in a healthy brain?

A

monoamine neurotransmitters are released into the synaptic cleft and bind to receptors on the post-synaptic cleft/neurone. Transmission is terminated by re-uptake of transmitter
* signal for presynaptic cell to stop releasing neurotransmitters is they start to hang around in the synaptic cleft

44
Q

how do monoamine neurotranmitters in depression work?

A

There is decreased concentration of monoamine at synaptic sites.
* they get released in synaptic cleft and there just isnā€™t enough and therefore not enough signals
* the way that SSRIs work, they block re-uptake sites (serotonin released, SSRIs plugs that sit in re-uptake site) meaning presynaptic cell keeps putting serontonin into the presynaptic cleft because itā€™s not getting the signal to stop sending it (so not getting stuff reuptaken)
* therefore, blockage of the re-uptake sites increases the concentration of monoamine neurotransmitters available at receptor sites and restores mood

45
Q

what is biased attention in depression?

A
  • amygdala important for recognition and generation of emotion
  • In healthy controls, attention is generally biased towards positive stimuli - individuals with depression instead show an attentional bias for negative stimuli
  • Problems allocated attention could contribute to dysphoria (low mood in depression - more negative input because your attend is more towards negative bias)
  • Brain regions associated with attention includeā€¦
    * Parts of the parietal cortex
    Prefrontal cortex (PFC), including the VLPFC (ventral lateral pre-frontal cortex) and DLPFC [dorsal lateral pre-frontal cortex) (these areas are particularly important for attentional disengagement
46
Q

Siegle et al 2007 used fMRI with unmedicated depression patients and healthy controls during two tasks: a digit sorting task (cognitive) and a personal relevance rating of words task (emotional) finding thatā€¦

A
  • patients with depression showed increased amygdala activity for negative words, and decreased DLPFC across the board for all tasks
  • so a negative emotional response is strongerā€¦ and less well regulated by top down-brain areas involved in attention allocation - if the amygdala is creating emotion and DLPFC is there to regulate emotions, so amygdala has a lot more emotional experience but your ability to control/down regulate that emotional response is reduced)
47
Q

what is biased processing in depression?

A
  • Reward processing affected in depression
  • Reward in the brain supported by a fronto-striatal network, neural pathways that connect frontal lobe regions with the basal ganglia (striatum)
  • Nucleus accumbens (NAcc ) is part of the reward network ā€“ it is a major input to the striatum (basal ganglia)
  • Disruption in this network has been argued to be the basis for anhedonia that we see in depression (loss of pleasure/reward)ā€¦
48
Q

Heller et al (2009) examined brain responses during emotion regulation paradigm via fMRI. Participants instructed to enhance or suppress emotional response to positive or negative images, or simply to attend

A
  • The depression sample failed to sustain Nacc (Nucleus Accumbens activation) activation when amplifying/sustain an emotional response (positive feeling) - perhaps rewatch
  • Deficits in sustaining activity in the NAcc were specific to positive emotion
  • Patients who fail to sustain NAcc activity report less intense positive emotion (feeling more depressed)
  • Difficulties sustaining NAcc activation reflect reduced prefrontal connectivity
49
Q

what biased memory in depression? what is evidence for a memory effect and what is evidence for an encoding effect? Increased awareness for negative stimuli influences likelihood that negative information will be encoded and later recalledā€¦

A
  • activity in the amygdala facilitates the encoding and retrieval of emotional stimuli in healthy individuals by modulating brain regions associated with memory
  • biased memory in depression is associated with amygdala hyperactivity, which is positively correlated with activity in the hippocampus, caudate and putamen
50
Q
A

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