Rhythms Flashcards
(196 cards)
1
Q
What do biological clocks control?
A
Any single function within our bodies
2
Q
What are the physiological impacts of clocks?
A
- Sleep/wake
- Body temp
- Cardiac output
- Memory
- Energy metabolism
- Eating behaviour
- Immune response
- Detoxification
3
Q
What are the cellular impacts of clocks?
A
- Cell cycle progression
- DNA damage repair
- Cellular energy metabolism
- Cell detoxification
- Neuronal excitability
4
Q
What are the possible impacts of clocks when it goes wrong?
A
Association with disease
- Affective disorders (bipolar and depression)
- Sleep disorders
- Neurodegenerative disease (Alzheimer’s)
- Obesity/metabolic syndrome
- Inflammation (asthma, COPD)
- Cancer
5
Q
What are examples of modern lifestyles opposing natural rhythms?
A
- Chronic shift work (around 15mill people in EU)
- Sleep deprivation (phone usage before bed)
- Altered eating habits
- Jet lag
6
Q
Generally, how do clocks come about?
A
- The earth spins around the axis every 24 hours
- Every 24 hours, the environement changes
- During the day there is light, temp is higher and the opposite for night
- Every organism in the planet has adapted to this and can adjust behaviour according to this
- There is a strong relation to survival in animals
- Those with damaged biological clocks don’t live long in the wild. they get eaten by predators
7
Q
What is an exeption of an animal that does not rely on circadian rhythms?
A
Deep water fish (more than 1km) under the sea
8
Q
What is an example of a cyanobacteria rhythm?
A
Synechococcus: gene activity
9
Q
What is an example of a plant rhythm?
A
Bean: leaf movement
10
Q
What is an example of a fungi rhythm?
A
Neurospora: conidiation
11
Q
What is an example of an insect rhythm?
A
Drosophila: eclosion
12
Q
What is a circadian rhythm?
A
A rhythm around 20-28 hours
13
Q
What is an ultradian rhythm?
A
A rhythm less than 20 hours
Things that happen several times within a day such as EEG and heart-beat
14
Q
What is an infradian rhythm?
A
A rhythm more than 28 hours
There are two types:
- Circalunar (monthly- tides and menstrual cycle)
- Circannual (seasonal/annual- bird migration and hibernation)
15
Q
What are 4 main characteristics of the circadian system?
A
- It is a self-sustained oscillator
- It is entrained/synchronised by the environment
- Has a period of 24 hours relating to the rest of the clocks in an organism
- Drives rhythmical outputs
16
Q
What is the main source of entrainment for the circadian system?
A
Light
17
Q
What is the pathway of the circadian system?
A
- Eye receptors
- SCN in the hypothalamus
- Output to other brain areas
- To peripheral clocks and behavioural/physiological rhythms
18
Q
Where are the ganglion cells located?
A
Back of the retina
19
Q
What do ganglion cells detect?
A
The amount of light in the environment, whether it is light or dark
20
Q
What type of light are ganglion cells sensitive to?
A
To blue light
Has implications in modern life because looking at blue light emitters before bed
These cells are sensitive to sending information to the cells saying its day and bright when it is not
21
Q
What are the rods and cones?
A
- Classic visual photoreceptors mainly involved with vision
- Can have animals that do not have these (blind)
- However if the persons ganglion cells are still functional, they can still detect the light in the environment and synchronise to it
22
Q
What is the main pace-maker in humans clocks?
A
SCN
23
Q
What is the structure of the SCN?
A
2 nuclei on either side of the 3rd ventricle and above the optic chiasm (well located to get visual information)
24
Q
What is the core of the SCN?
A
Sits above the optic chiasm and recievs photic information about light and the environment
25
What is the shell of the SCN?
Receives input from the core and creates outputs to the other brain areas
26
What neuropeptides does the core of the SCN express?
VIP- Vasointestinal polypeptide
GRP- Gastrin-releasing peptide
27
What neuropeptide does the shell of the SCN release?
AVP- arginine vasopressin
28
What are the two photic input routes that the SCN can receive information from?
- Retina, along the retinohypothalamic tract via glutamate PACAP
- Retinal to the intergeniculate leaflet (IGL) usig glutamate and then along the IGT (tract) through NPY
29
What are 3 non-photic inputs to the SCN?
- Median raphe using serotonin to the SCN
- Other hypalamatic reigons such as the DMH or otehr populations
- Circulating factors such as glucose and leptin
30
What hormone does the pineal gland release?
Melatonin
31
What is the pineal gland closely controlled by?
The SCN
32
What is melatonin considered as and why?
- The hormone of sleep
- Is secreted in the evening before we go to bed and the levels decrease before we wake up
- Is a strong marker of sleep
33
What is the mechanism underlynig the function of the SCN?
- Transcription and translation of the clock genes which have a period of 24 hours
- The way these tick, drives the rhythm of the cells such as firing rate, neuropeptide secretion etc
34
What did bioluminescence studies show about the presence of clocks in the body?
- Expressed all over the body, not just in the SCN
- The central clock entrains peripheral clocks in cells, tissues and organs
- Such as hormonal cues (glucocorticoids), feeding and temperature
35
What is an example of an adrenal rhythm governed by the SCN?
Levels of cortisol expression
36
What is a chronotype?
Out clock dictates individual difference in circadian/sleep profiles
37
What are the 3 types of chronotype?
- Morning type (lark)
- Indifferent type
- Evening type (owl)
38
What is the population percentage, waking time and sleeping time of morning type chronotypes?
- Population- 15-20%
- Waking time- 4-6am
- Sleep time- 20-22pm
39
What is the population percentage, waking time and sleeping time of indifferent type chronotypes?
- Population- 60-70%
- Waking time- 6-8am
- Sleep time- 22-24pm
40
What is the population percentage, waking time and sleeping time of evening type chronotypes?
- Population- 15-20%
- Waking time- 8-10am
- Sleep time- 24-2am
41
What 3 things is chronotype dependent on?
- Genetic background
- Age- primary deteminant of sleep timing
- Sex- women sleep more than men and earlier
- Environment- social pressures conceal biological drives in the evening
42
Which predicts sleep duration, sleep or wake time?
Bedtime
43
What is social jet lag?
- Week days, people are forced to wake up for work earlier
- Weekends, people wake up later
- Causes chronic sleep loss due to the misalignment of biological and social rhythms
- Linked with health problems
44
What chronotype is more likely to suffer from social jet lag?
Night owls
45
What bad habits is social jet lag associated with?
- Smoking
- Increased consumption of stimulants (caffeine)
- Alcohol drinking before bed
- Depressed mood
46
What happens if a moyse can no longer detect environmental light?
- Will wake up and sleeo in its own period of less than 24 hours and awake slightly earlier everyday
- This is called freerunning
47
What is human free running cycle?
24.5
48
What are zeitgebers?
Envorinmental stimuli that cause entrainment to a circadian cycle
49
What are 4 examples of zeitgebers?
- Light levels (prinicple one)
- Food
- Temperature levels
- Social stimuli
50
What kind of pattern does a circadian rhythm show on a graph?
Sinusoidal wave
51
What are 3 circadian rhythm wave characteristics?
- Period
- Amplitude
- Phase
52
What is the period of a rhythm?
Time/distance between the two peaks or troughs
53
What is the amplitude of a rhythm?
- Size of the deviation between a trough and a peak
- Big differences in values between trough and peaks incdicate a clear difference between day and night
54
What rhythm characteristic does age decrease?
Amplitude
55
What is the phase of a rhythm?
- Timing relative to a fixed point
- Light onset to the start of activity is a phase
- Phase shifts are important in some conditions such as phase advanced and phase delayed sleep
56
What are the two phase shifts?
Phase advance- going to bed earlier than usual
- Phase delay- going to bed later than usual
57
Is it easier for humans to adjust to a phase delay or advance?
- Delay
- As we are freerunning at 24.5, so adapt to travelling westwards easier
58
Outline the feedback loops of the molecular clock genes governing circadian rhythms
- High levels of Bmal1 at the start of the day promotes Bmal1-clock heterodimers
- Bmal1 rmans high at the beginning of the subjective day and low at night
- The Bmal1-clock heterodimers bind to eboc sequences in the promotors cry, per and rev-erba genes to activate the transcription of the beginning of the circadian day
- After transcritpion and translation, the rev-erba protein enters the nucleus to supress the transcription of Bmal1 and cry genes
- As the per proteins such as per2 accumulate in the cytoplasm, they become phosphorylates by CK1 epsilon. The phosphorylated forms of per are unstable and degrade by ubiquitylation
- Late in the subjective day, cey accumulates in the cytoplasm causing stable CK1 epsilon per cry complexes which enter the nucleus at the beginning of the subjective night
- Once in the nucleus, cry1 disrupts the clock Bmal1 associated transcritptional complex- inhibition of cry, per and rev-erba transcription and the repression of Bmal1 transcription
- The Bmal1 clock heterodimer can also inhibit Bmal transcription
- It is not clear whether per and cry must dissociate from the CK1 per cry complex to inhibit the activity of the clock-Bmal1 heterodimer and stimulate Bmal1 transcription in the nucleus
- The interaction of positive and negative feedback loops of circadian genes ensures low levels of cry and per and high levels of Bmal1 at the beginning of a new circadian day
59
What are the outputs of the SCN?
- Ventral supraventricular zone (vSPZ)
- Dorsal supraventricular zone (dSPZ)
- DMH- dorsal medius of the hypothalamus
60
What do neurons in the vSPZ do?
Relay information regarding wake and sleep
61
What do neurons in the dSPZ do?
Relay information regarding temperature
62
Where are the SCZ pathways integrated?
- In the DMH
- Drives sleep activity, feeding and corticosteroid secretion
63
What is the DMH the origin of?
Of the projections to the basal forebrain, including the VLPO and LHA
64
What does the VLPO do?
Regulates sleep cycles and is active during sleep, mostly non-rem and causes the release of GABBA and galanine which inhibit neurons involved in wakefulness and arousal
65
What activates the VLPO?
Serotonin and adensoine
66
What does the LHA do?
Controls wakefulness and feeding cycles, these contain orexin and melanin concentrating hormone
67
Where do orexin and melanin project to?
- LC (NA)
- Raphe (5HT)
- TMV (histamine)
- All involved in promoting arousal
68
What do amphetamines do?
Wake provoking drigs as activate arousal areas of the brain
69
What do anti-histamines do?
Can cross the BBB and cause drowsiness by blocking the arousing influence of the histamine system
70
What do barbiturates, benzodiazepines and ethanol do?
- Barbiturates are the largest class of sleep promoting drugs
- They act on GABBAA receptors, at low doses, act on VLPO to silence the arousal system
- At higher doses they can silence much of the CNS
71
What does caffeine do?
- VLPO is activated by sleep inducing neurotransmitter adenosine
- Caffeine acts through this and inhibits activation of the VLPO, promoting wakefulness
72
What genes are advance sleep phase phenotype linked to?
- Cry1
- Per1 and 2
- Per 3
- CK1 delta, CK1 epsilon
73
What are the two common versions of per that exist in human populations?
- A long and a short allele region of the repeat region
- The long is associated with morning preference
- The short is with evening preference
74
What genes are delayed sleep phase phenotype linked to?
- Per 3
- Clock (also hypersomnia)
75
What phenotype is Bmal1 polymorphisms linked to?
Fragmented sleep
76
What phenotype is OPN4/melanopsin polymorphisms linked to?
Seasonal affective disorder
77
What does OPN4 do?
Encodes for the photopigment melanopsin in retinal ganglion cells
78
What mental health condition is associated with Fbxl3 delays cry degradation?
- Bipolar
- Mania
- Anxiety
- Depression
79
What mental health condition is associated with Per 3?
Early onset bipolar
80
What mental health condition is associated withSNAP-25 disrupts SCN AVP output?
Schizophrenia
81
What mental health condition is associated with Bmal1?
Bipolar
82
What mental health condition is associated with clock?
- Mania
- Hyperactivity
- Increased reward seeking
83
What mental health condition is associated with Vipr2 VIP receptor?
Schizophrenia
84
What are the 4 relationships between circadian rhythms and the monaminergic model of depression?
- 1. Higher MAO activity during the light phase
- 2. Higher levels of serotonin transpoerter (SERT) during active phase
- 3. 5HT levels in the synaptic cleft are higher during the light phase
- 4. Higher levels of muscarinic and adrenergic receptors during the light phase
85
What does the monamine and circadian links mean for chronopharmacodynamics of antidepressants?
Efficacy will vary according to dosing time
86
What is an example of a programmable-in-time infusion pump for chrono-delivery systems?
- Electronically engineered nonimplantable multichannel programmable pumps
- Times of onset and offset for infusion can be set and the variation of flow rate from constant to semi soluble or gradually inreasing or decreasing
- Mainly used for cancer chronotherapy
- Include IntelliJect, Melodie, OPTILIV
87
What are controlled release of oral dugs as a chrono-drug delivery system?
- Modified pills or capsules
- Reduce doses needed everyday, more effective control and reducing unwanted side effects
- Form such as the gelatine capsule which is a semi-permeable rate controlling polymer
88
What types of chrono-drug delivery systems have been developed?
- Externally and internally generated systems across a range of technologies
- Including pre-programmed systems and systems that are sensitive to modulated enzymatic and hydrolytic degredation, PH, magnetic fields, ultrasound, electric fields, light, temperature and mechanical stimulation
89
What is a rhythm sensing drug releasing nanoparticle?
- By-pass inter and intrapatient variability
- Critically impacts the tolerability and efficacy at recommended drug levels (10 fold difference between individuals)
- Nanotechnology based approaches could link drug release to relevant molecular circadian rhythm directly into the cells of interest in each patient
90
What is device-assisted transdermal drug delivery?
- Physical barriers in the skin have been overcome with nicroneedles and controlled delivery by biosensors have been developed
- Can detect body temperature and dynamic information including tremors and cardiac movements
- Signals can be used for patient customised trans-thermal delivery
91
What is three-dimensional printing?
- Used in the fabrication of complex oral dosage
- Can engineer devices with intenrnal geometries with different complexes
- Use 3D printing system
92
What are two key lessons that have been leant from the chronopharmacological studieis of anti-depressants?
- Appropriate time of administration of antidepressant drugs is key to improve their efficacy and decrease their side-effects
- Part of the pharmacological action of antidepressant drugs comes from their positive influence on the resynchronisation of disrupted circadian rhythms in patients. For example, bot ticyclic antidepressants desipramine and imipramine both increase melatonin plasma levels which can lead to improved sleep rhythms
93
What is chronotoxicology?
Is the study of time-dependent variations of the adverse effects of chemicals on living organisms. Specifically, chronotoxicology refers to the kinetics, dynamics, toxicological responses and side effects of drugs, poisons or toxic substances relative to circadian rhythms of a living organism.
94
What is chronopharmacology?
Is a branch of pharmacology studying the dependencies between the timing of drug administration and its effect. Chronopharmacology became recognised by scientists in the early 1970s.
95
What is pharmacokinetics?
Is defined as dosing time-dependent and predictable rhythmic variations in parameters used to characterise the bioavailability of a drug.
96
What are the four different aspects which change a drugs bioavailability?
- Absorption: For orally administered drugs, absorption has been shown to be affected by circadian rhythms in gastric pH, gastric motility, gastric emptying time, gastrointestinal blood flow, transporters, time for gastric emptying, etc. For parenteral administration, circadian rhythms in transdermal/ocular/pulmonary permeability will impact drug absorption.
- Distribution: Drug distribution changes according to time of day because of rhythms in blood flow through organs and binding capacity of plasma proteins.
- Metabolism: In mammals, most of the xenobiotics are metabolised in the liver. Therefore, circadian rhythms in hepatic blood flow and xenobiotic-metabolising enzymes will impact drug metabolism.
- Excretion: Drug excretion via bile flow and urine is impacted by circadian rhythms in renal blood flow, glomerular filtration, tubular reabsorption, transporters, electrolytes and urinary pH.
97
What is chronopharmacodynamics?
(Or chronesthesy) Is the study of time-related variation in effects and metabolism of drugs in healthy organisms. Rhythms in receptor number or conformation, secondary messengers, metabolic pathways and free-to-bound fraction of medications help explain this phenomenon.
98
Outline the study into chipmunks and malfunctional SCN
- Some chipmunks had a damaged SCN
- Some didn't
- They were released into the forest and tracked over a 3 month period
- Number of chipmunks with damaged SCN that died were 80%
- Number of normal chipmunks that died were 20% with functional circadian clock
- Seemed to be because they normally hide in the night but the one with broken clocks didn't
- Main predator is the weasel that was eating them at night
99
What are 3 main consequences that occur with shift work?
- Direct correlation with health problems
- Road accidents are increased- poorer reaction time at night
- Industrial accidents such as chernobyl happen more likely at night
100
What is a correlation with cancer chronotherapy and sleep?
- Quality of life of cancer patients is better in those with robust circadian rhythms
- 2-year survuval of cancer patients is better in thise with robust circadian rhythms
- Ballesta et al 2017
101
What chronotype adapts better to shift work?
Evening/owl preference- especially night shiftwork
102
Which is more dangerous, social jet lag or normal?
Social because it is chronic whereas normal only happens with flights and is a temporary adjustment
103
What links does social jet lag have with phenotype?
- Obesity
- In teenagers (have a later chronotype), more sleep deprived means more aggressiveness and poorer academic performance
104
What negative risk links do owls have?
- Mood/depression
- Eating disorder
- Smoking/drinking
105
What circadian rhythm disruptions does shift work have?
- Body temp
- Respiratory rate
- Hormonal production
- Menstrual cycle
- Urinary excretion
- Cell division
106
What brain effects does shift work have?
- Sleep loss
- REM sleep reduction
- Stage 2 sleep reduction
- Fatigue
- Reduced brain volume
107
What gastrointestinal disorders does shift work cause?
- Dyspepsia
- Heartburn
- Abdominal pains
- Flatulence
108
What cancer effects does shift work have?
- Increases breast cancer and colorectal cancer
- Followied nurses in Denmark for several years, have higher chances of developing breast cancer
- WHO has declared cirdacian upset as a direct causal link to cancer
109
What reproductive effects does shift work have?
- Spontaneous abortion
- Low birth weight
- Prematurity
110
What cardiovascular disorders does shift work cause?
- 40% increase risk for..
- Angina pectoris
- Hypertension
- Myocardial infarction
111
What mental health risks does shift work cause?
- Stress
- Anxiety
- Depression
- Neuroticism
- Reduced vigilance
- Burnout syndrome
112
Why will the misalignment of the circadian system in shift work never align?
- When they finish their shift, they are exposed to light which resets the clock
- When they don't work, they want to join in with family and friends
- Leads to health problems
113
Why is sleep necessary?
- Basic homeostatic need
- Important for learning and memory, growth and repair
- Sleep deprivation is associated with cognitive, performance and immune system impairment
114
What does a sleep EEG of cortical activity look like?
Consists of different states comprised of different brain waves
115
What are the 4 stages of sleep- as updated in 2007?
- Stage N1 (non-rem, light sleep))
- Stage N2 (deeper sleep)
- Stage N3 (deepest sleep)
- Stage R (rem)
116
What is another way of naming N3 sleep stage?
- Slow wave sleep
- Delta sleep
117
What are the normal lengths of each sleep stage and how much of the % sleep time is spent in each one?
- N1- 1-7 mins and 5%
- N2- 10-25mins and 45%
- N3- 20-40 mins and 25%
- R- 10-60mins 25%
118
What occurs during N2 sleep?
Sleep spindles form, closely related to memory function
119
What happens to the duration of N3 and R stages of sleep as the night progresses?
- N3 duration gets shorter and shorter and also decreases with age
- R gets longer and longer
120
What happens during N3 sleep?
Tissue repair, bones and muscle growth
121
What is the flip-flop cycle?
- Different parts of the brain regulate different aspects of sleep/wake
- VLPO important for slow wave sleep
- Waking, arousal centres located in the brainstem trigger waking, ascending reticular activating system
- But when go to sleep VLPO is active and arousal centres are inhibited
122
Outline the opponent process model
- Two processes controlling sleep
- Homeostatic sleep drive (process s/sleepiness) which is a simple pressure to sleep
- During the day we accumular s, amount of s is proportional to awake time
- The other is the circadian rhythms which dictate when it is the right time to go to sleep and wake up
- High levels of melatonin in the evening and drop in core tem, melatonin gets supressed, core body temp and BP go up and we wake
123
According to the opponent process model what happens when a shift worker tries to sleep when we should be awakening?
- S level will be high but melatonin will be low as well as body temp
- Quality of sleep is shorter because the two processes do not align
124
What does an actogram look like in wild type mice compared to SCN lesioned mice?
- Lesion of the SCN removes the circadian input allowing homeostatic drive to take over
- Short bouts of sleep as the s pressure builds up
- Complete loss of 24 hour rhythmicity pattern
125
What does delayed sleep syndrome do?
Person goes to bed later than normal and wakes up later
126
What does advanced sleep phase syndrome do?
Person goes to bed earlier and wakes up earlier
127
What does insomnia do?
Go to bed normally but sleep is fragmented
Periods of wakefulness during the night
128
What does hypersomnia do?
- Sleep way more than usual
- Also nap during the day
129
What RHT damage do to sleep?
- Retino-hypothalamic tract brings information from the retina to the SCN
- Cannot detect normal light so will follow their own free-running rhythm, phase delay of around 25 hours
130
What can altered sleep patterns inform us of?
- Sleep is indicative of underlying clock activity
- Sleep is altered in many diseases
131
What percentage of the population suffers from severe sleep disturbances?
More than 20%
Much higher in elderly, obese and shift-workers
132
What is the correlation between sleep and depression?
- Both populations are 20%
- Depression is characterised with sleep maintenance, insomnia and early morning wakening
133
Why is post-natal depression partly correlational with sleep?
Don't get enough sleep so more likely to suffer from depression
134
What is SAD?
- Seasonal affective disorder
- People are fine throughout the year but not in the winter (winter blues)
- Due to feeling more sleepy, lacking energy, more inclined to eating poorly
- Specific type of circadian disorder due to the shortening of day length in the winter
- When light is lower and shorter can disrupt the circadian cycle
135
What things can help overcome SAD?
- Wake up and fo to bed at the same time
- Go outside to get sun
- Morning light is more effective
- Self medications like caffeine
- Go south/on holiday
- Exercise
- Work at a window
- Enjoy social situations
- Eat a well balanced diet
136
What percentage of people suffering major depressive disorder report sleep disturbances?
Around 90%
Could be difficulties in initiating and maintaining sleep at night or sleepiness in the day
137
What can cause increase of depressive relapse?
Persistent insomnia
In bipolar patients, having insomnia can push the balance and increase the risk of a depressive relapse
138
What additional effects do antidepressants have besides (anti-depressant)
- Are sedative with strong hypnotic activity
- Some people with sleeping problems are prescribed these
- This may be a major effect within depressed people
139
What sleep problems do SZ patients report?
- If survey and ask about quality of life, they cite not being able to sleep peopertly as a key thing in making their life poorer
- Instability of circadian rhythms, sleep disturbances and fragmented rest-activity patterns are common
140
What symptoms of SZ does improvement of sleep quality improve?
Negative symptoms which don't respond well to drugs
141
What does an actogram of a SZ person look like?
Go to bed late- between 4-5am and don't wake up till 3pm (phase delay)
142
What does a SZ patient's hypnogram look like?
- Period of sleep is longer than controls
- No non-REM stage 4 throughout the night and little stage 3
- Marked decrease in slow wave sleep
143
What does an elderly persons hypnogram look like?
- Earlier bed time and waking up earlier
- Longer latency to sleep
- Frequent awakenings
- Shortening of stages 3 and 4 and REM
144
What does the amplitude of rhythms look like in elderly people?
- Is dampened
- Additionally, phase advance in sleep, cognitive performance, body temp, cortisol and blood plasma glucose rhythms (peak happens earlier)
145
What does the phase advance in elderly explain?
Earlier chronotype
146
What happens if phase advance by 4 hours in elderly compared to adult?
- Adults quickly synchronise
- 10 days to synchronise in elderly, cannot cope with jet lag aswell
147
What aspects of life effect the elderlies developing sleep disorders?
- Decreased photoreception as decreased photoreceptor function (less light being processed)
- Decreased amplitude osillator
- Decreased light exposure as less exposed to light (stay in home more) and
- Change in chronotype
- Increase of sleep disorders
- Increase in concomitant disease such as cardiovascular problems
148
What are Alzheimer's links to sleep?
- Sleep probelms due t plaques and tau accumulating in the SCN
- Marked alteration in circadian rhythmicity
- Deterioration neuronal function in the SCN
- Melatonin levels dramatically decreased and circadian ehythm is lost
149
What do AD sufferers activity rhythms look like?
- Decreased amplitude (locomotor activity, body temp, melatonin)
- Phase delay
150
What are some positive effects to establish normalised day-night patterns in AD patients?
- Morning light exposure
- Enforced daytime activity
- Consistent bedtimes
- Evening melatonin supplementation
- Landry and Liu-Ambrose 2014
151
Why has there been a push to manage sleep disruption in the elderly?
- Circadian disruption is a principal component of the disease and therefore should be part of the treatment
- Sleep problems may come first- risk vulnerability of the disease
- Musiek and Holtzman 2016
152
What is environmental/behavioural targeting of the clock?
General strategy to strengthen entrainment to the environment or to increase amplitude of rhythms
153
What are the 6 most common approaches to environmental/behavioural targeting of the clock?
- Bright light therapy
- Melatonin
- CBT
- Interpersonal and social rhythm therapy
- Scheduled exercise
- Meal patterning, similar to restrictive feeding
154
What is restricted feeding?
- Generally eat during 8 hours of the day
- The rest of the 16 hours don't eat anything
- Can drink if not giving calories
- Has positive effects on body weight and energy levels
155
What is bright light therapy?
Typically involved high intensity blue light exposure early in the day
156
What are the target conditions for bright light therapy?
- Gaining acceptance as treatment options for mood disorders
- SAD
- Unipolar and bipolar depression
- Antepartum depression
- Premenstrual depression
- Elderly, AD
- Jet lag
- Insomnia
157
What are the benefits of bright light therapy?
- Improved mood for example in mild to severe deoression, light treatment can acheive rapid remission rates in 40-67% of patients
- Enhanced sleep effciency
- Increased melatonin level gradient
158
What was CBT orignially developed for?
Insomnia but is now being used increasingly with individual with psychiatric disorders co-morbid with sleep disturbances
Has been effective in reducing the severity of depressive symptoms and suicidal ideation
159
What are the three components of CBT?
- Behavioural components (e.g. relaxation techniques, sleep restriction to around 7 hours)
- Cognitive component (correcting unhlpful attitudes about sleep)
- Educational component (sleep hygiene- same routing every evening)
160
What is interpersonal and social rhythm therapy?
- Addresses interpersonal problems and disrupted social rhythms
- Therapists monitor and improve the regularity of 5 daily activitie sover 20 week (acute intervention) or monthly (maintenance treatment)
- Effective for acute treatment of bipolar depression and for the prevention of bipolar mood episodes
- Dunster et al 2021
161
What are the 5 paramaters in interpersonal and social rhythm therapy?
- Time out of bed
- First contact with another person
- Start of daily activity
- Dinner
- Time to bed
162
What are the target conditions of melatonin?
- Blind
- Elderly
- Depression
- AD
- Jet lag
163
What happens to a mouse actogram if give melatonin during free-running?
- If give the same dose of melatonin at the same time everyday
- The mouse synchronises to a rhythm
164
What is agomelatine?
- A melatonergic MT1 and MT2 receptor agonist and serotonergic 5HT2C receptor antagonist
- Helps with depression (dual effect)
165
How does environmental and pharmacological entrainment occur in AD?
- Light therapy increases night-time sleep, higher daytime activity and lower daytime sleep
- Melatonin increases sleep time, decreases nocturnal activity and no change in daytime sleep
- Together there are some reports of cognitive benefits and care-giver benefits
166
What do reverb ligands do to treat circadian upset?
- Act on clock genes
- Reset phase, target metabolism
- Only pre-clinical at present
167
What do CRY activators do to treat circadian upset?
- Act on clock genes
- Control period , entrainment, glucocorticoid actions (via GR)
- Only pre-clinical at present
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What do CK1 inhibitors do to treat circadian upset?
- Act on clock genes
- Control period, entrainment, anti-inflammatory
- Only pre-clinical at present
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What does lithium do to treat circadian upset?
- Long-standing 'mood stabalizing' treatment
- Targets GSK3B, modulates elements of the clock (Rev-erba, Bmal1)
170
When is amitriptyline most effective?
Lower side effects (antimuscarinic action and sedation) in the evening vs the morning but no change in therapeutic effect
Silva et al 2021
171
When is lofepramine most effective?
Highest antidepressant effects with a single daily dose at midnight
Silva et al 2021
172
When is clomipramine most effective?
Highest antidepressant effects and lower side effects (tremor and mouth dryness) at midday
Silva et al 2021
173
When do diazepam and flunitrazepan work the best?
Anxiolytic effects are best given late at night (early morning)
174
When does chlorprozamine work best?
- Dose has different effects at different times of the day
- Lower dose works better when we are high in activity
- Higher dose works better around midnight
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When does citalopram work best?
- Works best in interaction with light
- Best early in the morning therefore
- The light potentiates the effect of citalopram
176
What antidepressants decrease the internal clock period?
- Desipramine
- Moclobemide
- Fluoxetine
- Clonidine
177
What antidepressants increase the internal clock period?
- Imipramine
- Clorgiline
- Lithium
178
How does haloperidol effect the internal clock period?
- Given for SZ
- Not good for the circadian system as causes a free-running of 48 hours
179
How can body temp be decreased at night in depressed patients?
- Tricyclic antidepressants
- Selective serotonin reuptake inhibitors
- These normalise the body temp at night to help with the disruption of the circadian rhythm
180
What are 3 components of chronopharmacology?
- Pharmacological effects
- Side/toxic effects
- Circadian effects
181
When is pain, lung issues and strokes most likely to occur?
- Pain at night
- Lung issues in the early hours
- Stroke, midday
182
What is an experiment into chronotoxicology of ouabain?
- Cardiac srug given to mice at different times
- When given in the morning 74% died
- When given at night 80% survived (same dose and drug)
- Demonstrated that toxic response is strongly gated by the clock
- Halberg and Stephens 1959
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What areas can chronopharmacokinetics effect?
- Distribution- GI blood flow, protein binding
- Metabolism- liver enzyme activity, hepatic blood flow
- Absorption- gastric acid secretion and PH, motility, gastric emptying time
- Elimination- urinary PH, tubular resorption
184
Outline circadian regulation of the BBB during the day in mammals
- Bmal1 and clock high during the day, they increase the expression of TRPM7 (magnesium transporter)
- Higher levels of intracellular Mg
- Activation of xenobiotic transporters (transport out foreign substances)
- Decreased levels of xenobiotics in the brain
- Zhang et al 2021
185
Outline circadian regulation of the BBB during the night in mammals
- Decreased expression of TRPM7 as Bmal and clock are repressed at night
- Lower levels of intracellular Mg
- Decrease activity of xenoviotic transporters
- Increased levels of xenobiotics in the brain
- Zhang et al 2021
186
What 5 things effect chronopharmacodynamics?
- How many receptors are expressed at a time of day (number) and how sensitive they are (conformation)
- Membrane permability
- Second messengers, metaboolic pathways
- Free-to-bound fraction of medications
- Cell, tissue, organ rhythms
187
When is it best to take statins?
- Cholesterol is produced in the night
- Take statin before bed, coincides with maximum cholesterol
- Higher therapeutic effect
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What are the 3 chronotherapy approaches?
- Clocking the drugs- optimising the time of drug administration: improve the efficacy and reduce adverse effects
- Drugging the clock- use of molecules, agents or drugs that directly target a circadian clock
- Training the clock- maintain an optimal circadian rhyth,
- Aniama-Roig et al 2022
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What is cancer chronotherapy?
Tes tthe time of day when anti-cancer drugs have the highest therpeutic effect and when have the best tolerance (they coincide)
190
Outline oxaliplatin chronotherapy
- First anticancer drug to undergo chronotherapeutic development (circadian vs constant rate)
- When reached phase 1 trials, considered too toxic
- Tried at different times during the day
- 3 fold change in the effectiveness when given at certain times of the day
- Tried in human trials, half received in notmal contrant rate and the other in chrono-modulated way
- In the constant rate there was 10 times higher incidence of neurtropenia and distal parathesias, 55% higher vomiting
- DIfference in side effects was so much that chronomodulated could be increased by 15% and this was still preferable to constant
191
How does cancer chronotherapy effect survival?
Giving anti-cancer drugs at the best time of the day can significantly improve the life span of the patient
192
What do chrono-chemotherapy and chrono-immunotherapy improve?
- Decrease drug toxicity
- Increase drug efficacy
- Increase tumour response
193
What does chrono-radiotherapy improve?
Minimise treatment related symptoms
194
What does a combination of chrono-chemotherapy, immunotherapy and radiotherapy do?
- Minimise tumour progression
- Improve patients quality of life
- Improve patients survival
- Amiama-Roig et al 2022
195
What is the objective of chronotherapy?
To deliver drugs to targeted sites in higher concentrations when they are more needed
196
What would the ideal chonotherapeutic drug be?
- Deliver drug after time interval
- Deliver drug when its more needed
- Reduce drug release when not needed
