Autism L1-Introduction

The DSM: Diagnostic and Statistical Manual of Mental Disorder.

=>a tool used for communication between clinicians
=>until 1973, homosexuality was in the DSM
=>In DSM 1 & 2, autism was not mentioned, but it was mentioned under schizophrenia.
=>In DSM 3+, pervasive development disorders/autism was mentioned (Disorders usually first diagnosed in infancy, childhood or adolescence).
     ->Disorders usually diagnosed in infancy, childhood or adolescence includes (1)Mental retardation, (2)Learning disorders, (3) Motor skills disorder, (4) Communication disorders, (5) Pervasive developmental disorders, (6) Attention-deficit and disruptive behaviour disorders (7)Feeding & eating disorders of infancy or early childhood, (8)Tic disorders, (9)Elimination disorders, and (10)Other disorders of infancy, childhood/adolescence.

Childhood disorders in DSM-5:
-acquired through brain damage
-happened in developmental stage (that there is no evidence of neurological injury)--abnormal cognitive development (i.e. deviant developmental path)
-one kind of disorder: Pervasive Developmental Disorders (inclusive of Autism, Asperger Syndrome, Pervasive Developmental Disorder not otherwise Specified <PDD-NOS>, Rett's disorder, Childhood Disintegrative Disorder...)

In DSM-4, social features of autism were originally regarded as the triad of impairments (Wing & Gould, 1979). The triad includes three components: socialisation, imagination, and communication.
All autistic people share difficulties as in three aspects, inclusive of socialisation, communication, and restricted interests/repetitive behaviours.
A patient could be diagnosed with autism if there is/are delay(s) or abnormal functioning in at least one of the areas: (1)social interaction, (2) language as used in social communication, (3) symbolic or imaginative play, with onset prior to age 3 years. **The disturbance is not better accounted for by Rett's disorder of Childhood Disintegrative Disorder.

Note:
Rett's syndrome is a rare genetic neurological and developmental disorder that affects the way the brain develops, leading to a progressive inability to use muscles for eye and body movements and speech, which happens exclusively in girls at the age of 6 months old.
Childhood disintegrative disorder is also known as Heller's syndrome/ disintegrative psychosis. It is a rare condition characterised by the late onset of developmental delays/stunning reversals--in language, social function, and motor skills. CDD is a form of regressive autism--where children experience dramatic regression (typically after 3 years of normal development).


DSM-4: triad of impairments
1. Qualitative impairment in social interaction:

• marked impairment in the use of multiple nonverbal behaviours such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction
• failure to develop peer relationships appropriate to developmental level
• lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g. by a lack of showing, bringing or pointing out objects of interests)
• lack of social or emotional reciprocity

2. Qualitative impairments in communication (as manifested by at least one of the following):

• delay in/total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime)
• (in individuals with adequate speech) marked impairment in the ability to initiate or sustain a conversation with others
• stereotyped and repetitive use of language or idiosyncratic language
• lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level

3. Restricted, repetitive and stereotyped patterns of behaviour, interests, and activities (as manifested by at least one of the following):

• encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus
• apparently inflexible adherence to specific, non-functional routines or rituals
• stereotyped and repetitive motor mannerisms (e.g. hand or finger flapping/twisting/complex whole-body movement)
• persistent preoccupation with parts of objects

In May of 2013, DSM-5 was published. The main changes were the removal of Asperger's syndrome, the combination of social and communication symptoms and the introduction of Autism Spectrum Disorder.

Note:

Asperger's syndrome is a form of milder autism (also characterised by significant difficulties in social interaction and non-verbal communication, along with restricted and repetitive patterns of behaviour and interests), it differs from other forms of ASD with relatively normal language and intelligence. Physical clumsiness and unusual use of language are common in patients. The symptoms usually begin before 2y/o and last a lifetime.

The description and diagnostic criteria have changed for ASD.

1. Persistent deficits in social communication and social interaction across contexts, not accounted for by general developmental delays, and manifest ALL 3 of the following:

• Deficits in social-emotional reciprocity
• Deficits in nonverbal communicative behaviours used for social interaction
• Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers)

2. Restricted, repetitive patterns of behaviours, interests, or activities as manifested by AT LEAST 2 of the following:

• Stereotyped/repetitive speech, motor movements, or use of objects
• Excessive adherence to routines, ritualised patterns of verbal or nonverbal behaviour, or excessive resistance to change
• Highly restricted, fixated interests that are abnormal in intensity or focus
• Hyper-/hypo- reactivity to sensory input or unusual interest in sensory aspects of environment

3. Symptoms MUST be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)

4. Symptoms limit and impair everyday functioning

The criteria for diagnosis changed from triad to dyad, that the previous "socialisation, communication and imagination" triad of impairments was adjusted to the dyad of "(1)social communication, and (2)restricted, repetitive behaviours/interests".

Social communication is inclusive of social communication and interaction; while behaviours refer to restricted, repetitive patterns of behaviour, interests/activities (including sensory abnormalities).

Autism Spectrum Disorder (ASD) was introduced to encompass a range of conditions classified as neurodevelopmental disorders, including autism, Asperger's syndrome, PDD-NOS, and CDD.

The DSM-5 emphasizes on individual needs, which ASD was divided into three levels of severity: (Level1) requiring support, (Level2) requiring substantial support, and (Level3) requiring very substantial support.

The changes were made to refrain the inconsistent use of diagnostic categories by clinicians, and to improve diagnosis without limiting sensitivity. With the new criteria, 91% of previous cases gained ASD diagnosis.

The diagnosis of Autism

According to Bradley-Johnsen et al.(2008), the diagnosis of autism requires three levels of examination. 

The first level of the examination was carried out as in interviews and record review. Patients or caregiver will be questioned about the current concerns, how long has been the situation going on, the initiative of seeking help. Additional information would be retrieved from the third party such as school and any circumstances which may concern will be recorded (family functioning, school functioning and/or any recent seemingly unrelated events).

Next, initial screenings will be taken in the form of questionnaire/checklist by clinicians. The screening comes in different methods but they are not intended for diagnosis.

The final level of examination is formal testing, which is inclusive of direct assessment (either autism-related or others), detailed study of case history, behavioural observation and other testings (e.g. neuropsychological, personality, IQ, and comorbidities).

The Autism Diagnostic Interview (ADI-R) (Rutter, LeCouteur & Lord, 2003)
->studies the case history in details
->sturctured interview with parents up to 3 hours
->requires training
->not really useful for adults
->examines the current behaviours and 4-5 years behaviour
->scored by clinician in three subscales (language/communication, reciprocal social interactions and restricted, repetitive & stereotyped behaviours & interests)

The Autism Diagnostic Observation Schedule (ADOS) (Lord, Rutter, DiLavore & Risi, 1999)
->4/5 modules depending on verbal ability/age of individual
->requires training
->individual is put into a series of scenarios in which his/her behaviour is observed
->Young children activities include: responding to their own name, make-believe play with standardised set of objects, joint attention to attention-grabbing toy, demonstrating familiar action (using gesture), telling a story from a book, describing picture etc
->Older children/adults activities include: demonstrating familiar action, telling story from a book, creating a story using objects, interview (about emotions, current work/school, social difficulties & annoyance, friend & marriage, loneliness, plans & hopes) etc
->Participants are scored afterwards based on behaviours observed throughout the activities.
->Take into account both what they say & do and how:

• Aspects of language (e.g. use of stereotyped words, unusual volume/rate etc; offering/asking for information, conversational flow, gesture)
• Aspects of social interaction (e.g. eye contact, facial expressions towards others, empathy, insight into social relationships, quality of close relationships)
• Stereotyped behaviours (e.g. excessive interest in certain topics, compulsions & rituals, hand & finger mannerisms, unusual sensory interest in items)

Some other formal testings:

>Behavioural observation

->Psychiatrist: interaction, screening, observation

->Psychologist: neuropsychological tasks, personality tasks (sentence completion/drawing/storytelling), IQ tests, comorbidities, ToM

ADOS & ADI are 'gold standard' but are still fallible and need to be combined with clinical judgement.

今日也不好

一早起来 仗着昨晚流泪 赖了30分钟的床

匆匆准备忘了擦妆前隔离 用上了新买的很喜欢的眼影

急着出门 换了侧背的小包 把止痛药都留在了家里 那个时候我还不知道今天一整天会有多后悔

课都提早结束了 experiment好辛苦 眼睛花了头也痛了 

去了小雪社团办的女仆咖啡厅 却被拒绝待客 赶快到长颈鹿餐厅吃饭 食物不好饮料不好

回到学校 心情依旧不好 今天唯一的好事大概是两个老师都给我回了信 做了一点工作

我突然想到 昨天我什么都没做 就是弹弹琴 我很快乐

但今天我做了好多事 却一点都高兴不起来

大家今天兴致都不高 小贤还被后车厢的盖子砸到 决定要去小雪家倾诉一下

回家的路上 我把小雪小贤赶快赶下车 却忘了后车厢载着餐厅用具 只因为车里刚好有青峰在唱「我好想你」差点就憋不住了

我以为回家路上我会哭 但是没有 今日高速公路上非常大雾 车镜比我双眼还模糊 只好硬生生憋回去好好嘶吼一首「我管你」

差不多到家的路上 不懂事的弟弟打来 我说我好累就马上把电话挂了 我怕忍不住就讲出我其实不止累 我难过得要死

就在小区里我遇上父皇大人 我直接回家了 父皇大人把车子停在路边打给我 我说我不想吃饭 大概父皇大人也感受到我的疲惫

车子停好 赖在车里听了一首「故事」 还是青峰 浅浅吟唱抚平了我内心的涟漪

人生一场大梦 也无风雨也无晴 已忘言语已忘我 叶落不觉晓

非常怕黑的我 居然在车里呆了快五分钟 全程只有仪表板与收音机的小光

脱了高跟鞋的那一刻 踏进家门直接跪了下去 差点一趔趄连电脑和书一起摔了 把想洗很久的海草鞋拿进厕所浸泡 腰已经酸到不行 头也在痛

直接拧开热水就往身上冲 顾不得多烫手 只想把自己弄暖 

我洗好打算睡下 想去该吃止痛药 就下楼装一点热水 刚好看见面包 烤了两片填肚子

刷好花生酱把刀子拿去洗 突然想象了一下刀子割在腕上的感觉 一激灵手脚都冷了 马上洗好丢回原处

我卷缩在床角 只想靠一靠一不小心就躺了下来 看着墙壁吞下最后的面包

毫不犹豫地拿起一排止痛药挑一颗吃了

床边有面包屑 我只是把它们挥到地上 不想扫地 早上用过的电棒我不想收 连昨天给电脑充电的线我也不想卷

就这么爬上床 拿起手机才发现blogger软件已经旧得打不开 只好下新的 但它一直闪退

今天又忘了买灯泡的插头 不能开小黄灯睡了

躺了就这么一会的功夫身体渐渐发热了 可能是关节感冒发炎之类的

小雪传了什么给我 但我今晚不想理

晚安吧 宝贝 双眼已经酸涩无力

最近常被载 让我有了好多发呆和胡思乱想的时间（笑

又是一个七夕过去了 总觉得时间过得越来越快 上一次七夕写的文好像才刚发出去

一放假惰性就发作 积了不少书要看但至少开始看了 连续剧追了一套另一套追到一半也不追了 慈青活动一个接一个办了不少 想翻修的房间只是整顿了一番

想抛弃的人事倒是很干脆丢了不少 偶尔再看到也觉得无所谓了 但是腹肌先生（哼哼）还是在我空下来的思绪占了一个小角落

好久不太写字了 提笔忘字 不提倒是越来越懒越来越提不起写的劲 该写一写了

看见牟公子最近笔下都写着一种飘飘然的什么 好似什么都放开不在乎了 有一点异曲同工的境界

嗯 无所谓 愿所有遗憾的事都不再惋惜 而所有错过的人都不再回头

该睡了

NAB-Affective Disorders

Depression

• "common cold of mental illness"=most widespread psychological disorder
• 1/10 chance of at least one depressive episode of clinical proportions
• All population groups are vulnerable
• 1/20 visits to doctor due to depression
• >100 depressed patients per doctor's list, but half unrecognised
• 20% develop mild depression
• patients may not mention depression due to embarrassment, stigma avoid lack of sympathy
• Unipolar:
• mixed anxiety and depression
• depressive episode (single)
• recurrent depressive (numerous)
• dysthymia persistent & mild (depressive personality)
• Bipolar:
• bipolar affective disorder with manic episodes
• cyclothymia persistent instability of mood
• associated with creativity:
• Akiskal-50% major depressive illness, 70% manic depressive illness
• Schildkraut & Hirshfeld (1990)->10% cyclothymia, 40% major depressive illness

>Brain areas involved in depression: prefrontal cortex, hippocampus, nucleus accumbens & amygdala

>The longer depression left untreated, the more the hippocampus decrease in volume

>Increased metabolic activity in amygdala and orbitofrontal cortex

Is depression inherited?

>Seligman(1975)-Learned Helplessness Theory

• Dogs were placed in a two-sided box. Dogs that had no prior experience with being unable to escape a shock would jump over the hurdle in the centre of the box to land on the safe side. Dogs that learned that escape was impossible would stay on the original side, not even try to go over the hurdle.
• Animals that learned helpless show biological features of depression: REM sleep alterations, loss of body weight, diminished sexual activity elevated corticosterone.
• Cognitive function is linked to biological function through this observation
• Is it cognitive product or stress induced inactivity? 
• Recovery within 48 hours, which might be due to recovery of hypothalamic noradrenaline levels which is reduced in helpless animals

Chronic Antidepressant Treatment: 

Up-regulation of second messenger pathway

Major Classes of antidepressants & some side effects

Effects of Chronic Antidepressant Treatment on Serotonin Neurons

Neurochemical Hypotheses of Depression

1. Monoamine Theory

>Depression is due to the depletion of monoamines e.g. Noradrenaline, serotonin, dopamine which originated as drugs that depleted such as reserpine neurotransmitters

>Limitations: too simplistic, delayed action of antidepressant drugs

>Modified to include down-regulation of NA receptors

2. Noradrenaline 

>Noradregenic hypothesis-reserpine depression is due to reduced levels of NA

>supported by effects of antidepressants with increased NA metabolism

>problem: time delay of therapeutic effect

>hypothesis expanded to include receptor sensitivity

>by increased exposure of the receptor to NA eventually the sensitivity of the receptor is decreased.

3. Serotonin/5-HT

>Serotonin involved in pain sensitivity, emotionality and response to negative consequences

>Metabolite 5-HIAA (a marker for activity of serotonin) reduced in cerebrospinal fluid

>Low 5-HIAA associated with aggressive hostile and impulsive behaviour as in violent suicide attempts.

>Individuals with different alleles coding for the serotonin transporter have different reactivity to stress

The theory-Monoamine transporters

~Major mechanism controlling extracellular monoamine dynamics is re-uptake.

~This is achieved through presynaptic neurons via plasma membrane transporters

~Dopamine (DAT), Serotonin (SERT), Noradrenaline (NET)

~These remove neurotransmitters from outside cells and recycle back into releasing or neighbouring terminals.

~These transporters are targets of many psychostimulants and antidepressants, which interfere with transporter function.

~Normal function of these transporters can be studied using gene deletion technique.

~Mice lacking both SERT and DAT no place preference for cocaine suggesting SERT involvemnt in cocaine effects on reward.->SERT and DAT play a role in rewarding mechanism, lacking of them can lead to depression.

Drugs used to treat depression:

1. Tricyclics

• Inhibit re-uptake of noradrenaline and serotonin
• effective, cheap, but dose-related anticholinergic side-effects limit compliance
• often fatal in overdose

2. Serotonin selective reuptake inhibitors (SSRI's)

• inhibit reuptake of serotonin, e.g. inhibit reuptake of 5-HT and NA
• lack sedation, free of anticholinergic side effects
• narrow dose range but seem safe in overdose
• diffeent from tricyclics as little action on muscarinic cholinergics and histaminerfic receptors (will cause drowsy side-effect)

How they work

>Inhibiting the enzyme monoamine oxidase MAO that breaks down serotonin

>Blocking the transporter protein for serotonin re-uptake

The theory-Cortico-tropin-releasing factor

>CRF is a major neuropeptide mediator of stress responses in the CNS. It increases with stress level.

>It is expressed in the Paraventricular nucleus of the hypothalamus and coordinates the release of adrenocorticotropin hormone (ACTH) from the anterior pituitary.

>CRF is high in CSF of depressed patients. (up to 6 times)

>HPA axis-Hypothalamic Pituitary Adrenocortical system

• CRF is released in response to environmental stressor (uncertainty arousal).
• ACTH is then released by the pituitary.
• Cortico-steroids are released
• When stressor terminated-negative feedback occurs, shut down of the HPA axis.

>Corticosteroids elevate in times of threat and at times of loss of control

>transcient (short-term) activation does not cause stress

>excessive long-term activation of HPA may induce long-term damage

>Depression is associated with increased activity of the HPA axis, results in enlargement of adrenal gland with elevated levels of cortisol.

>antidepressants lower activity in the HPA axis.

>Early experience (maternal separation) can bias towards later protracted activity of the HPA

>Corticosteroids are given for arthritis and cause depression

>Reuptake inhibitors boost the HPA system. Improvement in mental state associated with normalisation of HPA activity.

>Cushings Disease which involves excessive secretion of corticosteroids is commonly followed by depression.

Neurogenesis:

> Neurogenesis (new neurons generated) occurs throughout life in hippocampus & olfactory bulb.

>In rodent brain studies 9k new cells/day or 250000 new cells/month in adult, 50% became neurons

>Factors affecting neurogenesis:

• increase: exercise, environmental enrichment, antidepressants
• decrease: stress, sleep deprivation, age

NAB-Reward, pleasure and desire

Reward=object/event that elicits approach and is worked for.
It is associated with wanting and liking.
Wanting=feeling of desire and approach behaviours
Liking=feeling of pleasure (explicit liking) and other objective responses (implicit liking)
Alterations in the brain substrates of reward-related processes are likely mechanisms underlying addiction.

Classical techniques to identify brain substrates of reward:

Nucleus accumbens

In rats:

Rewarding stimuli increase dopamine transmission in NAC, animals work to increase dopamine stimulation within NAC, and dopamine antagonists block behavioural effects of rewards.
NAC dopamine causes pleasure and desire.

Similarly, in humans, nucleus accumbens dopamine release during reward anticipation.

>In the Meso-corticolimbic dopamine system:

• rewards increase NAC dopamine
• systemic and intra-NAC dopamine antagonists block responses normally maintained by reward

>Cholinergic projection from PPTg to VTA:

• electrical self-stimulation
• Cholinergic drugs are self-administered into VTA

>Glutamate projections from mPFC to VTA:

• electrical self-stimulation
• stimulate dopamine release in NAC

How much one works for reward may not directly reflect the liking or pleasure induced by the reward, but rather wanting of or desire for the reward.

Overlap between brain substrates of positive and negative emotions:

Brain substrates of emotional states associated with aversive stimuli and appetitive stimuli habe originally been studied seperately, but more recently it has come to the fore that there is an overlap.

• Dopamine and nucleus accumbens play important roles in fear-related processes, in adition to loe in reward-related states and responses.
• Amygdala, apart from playing key role in fear-related responses, ahs also been implicated in responses to appetitive stimuli.

A common currency of emotoion may enable brain to generate adaptive responses baed on integrated assessment of positive and negative stimuli.
Brain substrates such as dopamine, nucleus accumbens and amygdala may not play specific role in emotion per se, but may contribute to fundamental cognitive processes that are associated with both aversive and appettitive stimuli (e.g. salience signalling and attention or associative learning).

NAB-Fear and Anxiety

Fear and anxiety comprise protective/defensive responses normally elicited by aversive stimuli.
Much animal research on brain substrates of emotion over the last 30 years has focused on fear and anxiety.

Fear=phasic escape or avoidance responses to distinct aversive stimuli.
Anxiety=tonic response to diffuse aversive situations and is associated with conflict and uncertainty.

There are many types of fear and anxiety responses, the brain substrates of these different responses may differ.
Fear- and anxiety-related disorders in humans include generalised anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, phobias, and post-traumatic stress disorder(PTSD).

Amygdala

Lesions in amygdala affect the fear conditioning. Lateral and central amygdala having lesions would reduce fear response greatly.

The role of the amygdala in conditioned fear has been very well characterised, however other brain structures e.g. hippocampus, prefrontal cortex may also make important contributions to fear and anxiety, and the substrates of conditioned fear may differ from those of other fear/anxiety-related behaviours.
Amygdala is also involved in other emotional and behavioural processes.

Hippocampus

Hippocampal lesions increase the time rats spent in the open arms of the elevated plus-maze: hippocampal lesions reduce anxiety.

SO...

Is it necessary to refer to subjective feelings if we want to study brain substrates of emotions?
What advantages and disadvantages does it have to study neural mechanisms of emotion without reference to subjective feelings?
How can we study brain substrates relevant to fear/anxiety in rat models?
How can we confirm that similar brain substrates are also important for human fear/anxiety?

Emotional responses can be measured objectively, enabling the scientific study of emotions in animals.
In animal experiments, the measurement of emotional responses can be combined with a variety of techniques to manipulate and monitor brain function in order to reveal brain substrates of emotions and their dysfunctions.
The detailed information from animal experiments can be confirmed by appropriated research on human emotions in healthy subjects and clinical populations.

Of course, human emotions cannot be explained fully through animal studies; but a good understanding of some basic emotional mechanisms that are common to humans and other animals has already been formed.
The interaction between newly evolved functions i.e. language and consciousness, and emotions could be studied.

NAB-Emotion

Emotions are states elicited by rewarding or aversive stimuli (S+ or S-) and their omission(-) or termination(!).

These states comprise thoughts and physiological/behavioural responses to emotional (i.e. rewarding or aversive) stimuli.

The physiological/behavioural responses to emotional stimuli can unambiguously be measured in human and non-human animals.

These physiological/behavioural responses to aversive and positive stimuli have fundamental survival value and, therefore, have been relatively preserved throughout evolution and are very often very similar in different animals including humans.

With the similarities between species, we can study emotions in animals and generalise it.

E.g. using rats as a model system:

>Advantages-easy to breed and keep, well-established behavioural tests, brain large enough to apply selective manipulations to distinct brain structures and brain anatomy very well characterised.

>Disadvantage-difficulty in genetic manipulations->alternative=mouse

Hippocampus, amygdala & hypothalamus:

-Papez theory of emotion (1937)

-Kluver and Bucy's description of temporal lobe lesion effects in monkeys (1939)

-Maclean's limbic system theory (1949)

Prefrontal cortex:

-Case of Phineas Gage described by Harlow (1868)

-Nauta (1971): Frontal lobes and interoception

Meso-corticolimbic dopamine system:

-Olds and Milner (1954): Brain-stimulation induced reward

-Wise et al. (1978): Neuroleptic-induced anhedonia

NAB-Cytoarchitectonics

Cytoarchitecture (Greek κύτος= "cell" + αρχιτεκτονική= "architecture"), also known as cytoarchitectonics: study of the cellular composition of the body's tissue under the microscope.

Microscopic anatomy: Brodmann areas   

• brain segmented according to appearance in microscope (cytoarchitectonics)
• combined with comparative neuroanatomy
• appearance reflects type of cells (e.g. inputs vs outputs)
• type of cells sometimes correlates with function
• studies restricted to small number of brains

Neuroscience methods for physiological psychology

Aim: to study relationship between brain and behaviour

1. Neuroanatomical & Neurochemical methods:

• Cytoarchitectonics (Brodmann areas)-study of cellular composition of the body's tissues under the microscope
• staining, immunocytochemistry & autoradiography

2. Recording & stimulating neural activity:

• non-invasive methods to study living human brain-TMS, EEG, ERPs and fMRI
• micro- and macro-electrodes in animal studies

3. Effects of brain lesions:

• pathology leading to human brain lesions
• virtual lesions induced by TMS
• experimental ablation in animal models with stereotaxic guidance)
• cooling induces reversible lesion

Neuroscience techniques-serving for study of relationship between brain and behaviour
Is there any ideal method that spatial resolution=cellular level, temporal resolution=millisecond scale,  study the whole brain simultaneously and being non-invasive at the same time? NO!
Match existing methods, which all of them come with certain limitations, to the research question.




How to us electrophysiolocial methods for cognitive neuroscience?
>responses to multiple repeated events occurring with fixed latency (time-locked)
>non-time-locked responses to events (oscillations of specific frequency)
>Events are experimentally controlled, e.g. a sensory stimulus or a task instruction occurring at a defined time point

NAB-Transcanial magnetic stimulation (TMS)

TMS:

• Non-invasive, painless, safe stimulation of human brain cortex (through the skull)
• useful in studying behaviour during virtual brain lesions, chronometry and functional connectivity
• could administered as single pulse or repetitive TMS
• stimulater in the shape of 8 placed above the scalp, contains a coil of wire->brief pulse of high electrical current fed through the coil magnetic files in lines of flux formed perpendicular to the plane of the coil, into the skull->magnetic field induces electric filed perpendicular to magnetic filed-> electric field leads to neuronal excitation trans-canially (within the brain)
• effect depends on stimulation site

>>How to measure the effects of TMS:

• Motor cortex stimulation
• activates corticospinal neurons trans-synaptically (occurring or existing across a nerve synapse)
• e.g. TMS coil 5 cm lateral from vertex (highest point)->often contralat' thumb twitches (20 ms post TMS)
• record motor evoke potential (MEPs)* (surface EMG, target muscle relaxed)
• record silent period* in contracted target muscles~150 ms after motor cortex stimulation, cortical mechanisms
• Occipital cortex stimulation:
• excitatory effects: e.g. phosphenes*; inhibitory effects: suppression of motion perception and letter identification
• Somatosensory cortex stimulation
• may elicit tingling, block the detection of peripheral stimuli (tactile, pain)
• can modify somatosensory evoked potentials (SEPs)
• Auditory cortex stimulation: 
• Interpretation of results challenging: loud coil click
•  Frontal cortex stimulation
• Effects on subject's mood? Potential for therapeutic use?

*MEPs=the electromyograph** responses of the peripheral muscles to electrical stimulation to the motor cortex. Changes in the MEP signal have been shown to exhibit significant correlation with neurological deficit and spinal cord injury.
**Electromyograph (EMG)=electrodiagnostic medicine technique for evaluating and recording the electrical activity produced by skeletal muscles, performed with an instrument- electromyograph to produce a record called electromyogram.
*Silent period=MEG silence after MEP
*Phosphenes=a ring or spot of light produced by pressure on the eyeball or direct stimulation the visual system than by light.

TMS application: cross modal plasticity

>Blind people can learn to read Braille, compared to sighted people they have superior tactile perception. Is there any underlying changes in the brain?
>Their visual cortex is known to be activated during Braille reading, is there functional significance of this activation?->TMS
>Chronometry-timing of mental events

• single pulse TMS for mental chronometry
• early blind subjects: blind before 1 year old
• real & nonsensical Braille stimuli presented via tactile stimulator
• interval between tactile stimulus (Braille) and TMS systematically varied
• subjects have to detect stimuli and identify if they are real or nonsensical
• DV: number of correctly detected/identified stimuli
• Conclusion: visual cortex contributes to tactile information processing in early blind subjects=crossmodal plasticity

*Different symbols (square, triangle, circle) representing different subjects.

*Open symbols=detected stimuli; filled=correctly identified stimuli

TMS application: virtual lesions

>Repetitive TMS can create temporary inhibitor of brain areas, fully reversible virtual lesions (for a few minutes, subjects behave as if after a brain lesion)

>errors during Braille reading by early blind and sighted subjects depend on site of virtual lesions

>cross modal plasticity in early blind subjects stated that occipital cortex supports Braille reading

>for sighted controls, max error rate after anterior parietal virtual lesion

>for early blind subjects, max error rate after occipital virtual lesion

TMS Advantages & Disadvantages:

• Advantages:
• temporal resolution in millisecond range
• virtual lesion in subject may be better defined than lesion in patient
• short duration of experiment minimises risk of plasticity
• repeated studies in the same subject
• group studies with standardised experimental setup
• study double dissociations: stimulate or temporal disrupt different cortical regions during one task, one region during different tasks
• Disadvantages:
• spatial undersampling(only one area at a time)
• only cortical area accessible
• auditory cortex stimulation problematic (muscles)
• loud coil click, need 'sham stimulation'

Stats-Questionnaire Design

Types of research/practice:

• Individual differences-psychological traits/characteristics
• Ability-Intelligence tests
• Attitudes-Measure particular beliefs toward something

**Ethics/moral: These tests are now used so widely, it is important to assess that they are reliable and valid that they are measuring what they claim to measure. The test should be ensured to avoid biases, and everyone has an equal opportunity of understanding the tests.

Creating your questionnaire

1. Question formats

• Open format questions
• asks for some written detail, but has no determined set of responses
• Advantages: leads to more qualitative data
• Disadvantages: time consuming to analyse 
• Closed format questions
• short questions or statements followed by a number of options.

2. Theoretical literature

• Theoretical literature: ideas that appear in the theoretical literature should be used as a basis
• Experts: recruit experts in the area to suggest items
• Colleagues: brainstorming to generate more items

3. Clarity of questions

• questions must be clear, short and unambiguous 
• the psychometric test question must not mean different things to different respondents

4. Avoiding leading questions

• the question should not be leading the respondent in particular direction by potentially excusing the behaviour

5. Reverse wording

• how to encourage the participant to read each question, not just get into a pattern of responding to all the questions in the same way.
• reverse wordings allow people to really pay attention

6. Response formats

• dichotomous scales: yes/no true/false
• frequency: always/sometimes/never scale
• attitude scales: strongly agree-strongly disagree
• numerical sales: to what extend the statement describes you

7. Instruction

Classical theory of error in measurement

OBSERVED score=TRUE score+ERROR

-Any score on a test for an individual on any occasion differs from his true score on account of random error.

-If we were to test an individual on many occasions, a distribution of scores would be obtained around his true score. The mean of this distribution, which is assumed to be normal, approximates the true score.

-The true score is the basis of the standard error of measurement. Thus, if we find that there is a large variance of obtained scores for an individual, there is clearly a considerable error of measurement. Since the test-retest reliability is the correlation between the obtained scores on two occasions, it is obvious that the higher the test-retest reliability, the smaller the standard error of measurement, according to this model.

-The classical theory of error assumes that any test consists of a random sample of items from the (hypothetical) universe of items relevant to the trait.

-So the most important point is that in any measurement, there is likely to be some error involved, but in order to make a good questionnaire, we want to minimise error, and to do this we maximise reliability and validity.

Reliability-we are interested in consistency

1. Internal-To what extent do the individual items that make up a test or inventory consistently measure the same underlying characteristic?

• A questionnaire having high internal variability is that all of the questions hand together and measure the same thing.
• The higher the number of resulting coefficient, the more the data are close to each other, the better it is.
• Split-half reliability: split the data into two halves, if the test is reliable, there should be a high correlation between in scores between the two halves of the test.
• Parallel forms: creating a large pool pf items that are measuring the same thing, administer to the same group of participants with interval and counterbalancing. 
• Cronbach's Alpha: mathematically equivalent to the average of all possible split-half estimates, values up to +1.00, usually a figure of +0.70 or greater indicates acceptable internal reliability
• Kuder-Richardson Formula 20(KR-20): measures internal reliability for measures with dichotomous choices (yes/no), values up to +1.00, usually a figure of +0.70 or greater indicate acceptable internal reliability.

2. External-To what degree does a person's measured performance remain consistent across repeated testings?

• test-retest reliability (stability over time): perform the same survey, with the same respondents at different points in time. The closer the results, the greater the test-retest reliability of the survey. The correlation coefficient between the two sets of responses is often used as a measure of the test-retest reliability.

3. Inter-rater reliability (or agreement)

• determines the extent to which two or more raters obtain the same result when coding the same response
• Cohen's Kappa: values up to +1.00, larger numbers indicate better reliability, used when there are two raters
• Fleiss' Kappa: an adaptation which works for any fixed number of raters
• Measures agreement, not accuracy

4. Intra-rater reliability (or agreement)

• The same assessment is completed by the same rater on two or more occasions. These different ratings are then compared, generally by means of correlation.
• Since the same individual is completing both assessments, the rater's subsequent ratings are contaminated by knowledge of earlier ratings.

**Sources of unreliability: guessing, ambiguous items, test length, instructions, temperature, illness, item order effects, response rate, social desirability

Validity-if it measures what it claims to measure

1. Faith

• simply a belief in the validity of an instrument without any objective data to back it up, and the evidence is not wanted.

2. Face

• If something has face validity, it looks like a test that measures the concept it was design to measure. The more a test appears to measure what it claims to measure, the higher its face validity.
• Face validity bears no relation to true validity and it is important only in so far as adults generally will not so-operate on tests that lack face validity, regarding them as silly or insulting. Face validity then, is simply to aid cooperation of subjects.

3. Content

• The extent to which a measure represents all facets of the phenomena being measured

4. Construct

• Seeks to establish a clear relationship between the construct at a theoretical level and the measure that has been developed.
• Convergent validity: That the measure shows associations with measures that is should be related to.
• Discriminnant validity: That the measure is not related to things that it should not be related to.

5. Predictive

• Assesses whether a measure can accurately predict future behaviour.

Stats-Threats to validity

In an experiment, we identify cause-effect relationships:

~we control the cause and observe the effect.

~changes in the DV caused by the manipulation of the IV.

Internal Validity

=>The extent to which the results obtained are a function of the variables that were systematically manipulated. Are changes in the IV responsible for the observed variation in the DV? Might the variation in the DV be attributable to other causes (confounds)?

=>Why is it important?? High internal validity=strong evidence of causality

=>To maximise internal validity:

• must be able to rule out the possibility of other factors producing the change(confounds)
• must control everything and eliminate possible extraneous influences
• easient in highly controlled, laboratory settings

=>Threats to internal validity that compromise our confidence in saying that a relationship exists between the IV and DV:

• History effects-events occurring during the experiment that are not part of the treatment; can be solve by holding experiences constant except for IV/randomlyy assign conditions to time
• Maturation effects-bilogical or psychological processes (e.g. aging, fatique, hunger...) within partcipants that may change due to the passing of time
• Mortality-differential loss of individuals from treatment and/or control groups due to nonrandom reasons (those who drop out of a study could be qualitatively different from those who remain)
• Instrument decay-equipement becomes iaccurate with age/experimenters become more skilled or bored; can be solve by randomisation condition to time, check reliability of instrument and staff.
• Participant selection-different types of participants placed at different levels of the IV; use random assignment or matching method
• Statistical regression to the mean-going back to mean after extreme behaviour
• Participants communicate-diffucion of treatment effects (control group learns about the manipulation), compensatory rivalry (participants in different conditions start competing), compensatory equalisatoin (experimenters know the condition of participants are in and provide enhance services that go beyond the routine), resentful demoralisation (control group leans that they are in the control and not try as hard)

External Validity

=>Does the IV represent the concept we intend? A measure is externally calid if it truly measures the hypothetical construct intended. An experiment is externally valid if it is similarto phenomenon in the real world.

=>Having high external validity often means having a lack of contrl of confounds

=>Population validity: the extent to which the results can be generalised from the experiemntal sample to a defined population

=>Ecological validity: the extent to which the results can be generalised from the set of experimental conditions in the experiment to other conditions.

=>Threts to External Validity compromises our confidence in stating whether the study's result are generalisable:

• reactive effects of testing: when a pre-test increase/decrease the repondents' sensitivity to the treatment (especially in seld-eport measures of attitude and interest)
• reactive effects of experimental setting: when the conditions of the study are such that the results are not likely to be replicated in the non-experimental situation
• selection-treatment interaction: the possibility that some characteristic of the participants selected for the study enteracts with some aspect of the treatment (prior experiences, learning, personality factors...)
• multiple-treatment interference: participants receive more than one treatment, the effects of previous treatment may influence subsequent ones (sequence effects/carry-over effects)

=>Improving External Validity:

• Replication-an additional scientific study conducted in exactly the same manner as the original research project. When we replicate an experimental finding, we are able to place more confidence in that result.
• Replication with extension-seeks to replicate a previous finding but does so in a different setting /with different participants/under different conditions

Statistical Validity

=>Making type 1 error: rejecting the null hypothesis when the null hypothesis is true (false positive)

• possible causes: fishing

=>Making type 2 erroe: failing to reject the null hypothesis when the null hypothesis is false (false negative)

• possible causes: power, reliability of measures/ =treatments, random irrelevance, random heterogeneity of respondents...

Stats-Experiemntal Design

What is an experiment?
Oxford English Dictionary: A scientific procedure undertaken to make a discovery, test a hypothesis or demonstrate a known fact.

Experimental vs. Non-Experimental Research

Experimental Research:
-investigates causality
-manipulate IV to determine if it has an effect on the DV
-hold other variables constant

Non-experimental Research:
-observe and measure only descriptive
-investigates correlation/associations

True vs. Quasi Experiments

-True experiments randomly allocate participants to conditions.\

-Randomization: Each participant has an equal chance of being allocated to any condition.

-Why randomize? To reduce the chance of other variables (confounding oor nuisance variables) changing the outcome. Randomisation worksby spreading any potentially confounding variables evenly accross conditions. It minimizes systematic differences to isolate the causal effects of the treatment on the dependent variable.

-If it is not possible to radomise then a quasi-experiemental approach is used. Quasi-experiments do not use randomization. Also called 'natural experiments'.

-Types of Quasi-experiment:

1. One group pre-post test design: only treatment group, often used in audits to evaluate clinical services but outcomes may be due to other factors.

2. Non-equivalent control group design: A control group is used but randomisation is not. This means conrols are systematically different from the treatment group

3. Interrupted time series design: Do not alys have a control group, good for studying naturally occuring chronological data.

Systematica approaches to control for confounding:

1. Blocking/Randomised Block Design

>Used when a variable might have a particular influence on the outcome.

>Arrage the participants into groups (blocks) according to that variable.

>Randomized the participants within those groups to the treatment group.

>E.g. Gender

2. Matching/Matched-subjects/matched case-control design

>A statistical technique where every participant is compared with another participant who is matched according to a relevant confounding variable.

>E.g. Age, IQ

3. Counterbalancing

>In a within-subjects design the outcome may be affected by the testing order. Counterbalancing can be used to compensate.

>Latin Squares counterbalancing method is used with more than one condition/treatment. Testing is arranged so each condition occupies each rank in the testing order equally often.

Stats-Ethics

Ethics--Moral principles that govern a person's behaviour. (Oxford English Dictionary)

How do you make ethical decisions? Are you a deontologist or consequentialist?
Deontological (duty based): You have a duty to do the right tihing regardless of the consequences.
Consequential (outcome based: Choose the action that maximise good consequences.
     -Utilitarinism: maximise well-being for the most people.
     -Hedonism: maximise pleasure
In practice, people tend to use a mix of deontological and consequential ethics.

The British Psychological Sciety (BPS) Guidelines respects for autonomy and dignity, approving researches according to harm avoided, risk assessed informed consent and debriefing.
In the UK, strct laws require animal researchers uses the three Rs:
1. Refinement: reduce the severity of inhumance procedures
2. Reduction: in numbers of animals used
3. Replacement: of highly sentient animals whenever possible.

NAB-Learning and memory systems

Retrograde and Anterograde Amnesia


Causes of Anterograde Amnesia:

• Alzheimer's disease (also short term memory deficits and confusion)
• Korsakoff's psychosis (RA too, maybe reflecting gradual onset, confabulation)
• Herpes encephalitis
• Anoxia/ ischaemia (can result in very selective AA)*
• Injuries or tumours to limbic system and/or diencephalon (i.e. thalamus & hypothalamus)
• Surgeries for epilepsy involving temporal lobe(s)
• Degenerative brain diseases (e.g. schizophrenia, advanced multiple sclerosis, Huntington's disease)

*Damage to Field CA1 caused by Anoxia:(a) Section through a normal hippocampus. (b) Section through the hippocampus of patient G. D. The pyramidal cells of field CA1 (between the two arrowheads) have degenerated.

>>The case of H.M. (Milner et al., 1968)
-Generalised epileptic seizures
-Bilateral medial temporal lobe resection
-Severe AA
-Above average IQ
-Normal on perceptual tests
-Good memory for events prior to surgery and early life history
-While at the research centre, HM repeatedly asked where he was and how he came to be there.
-Compared with a few other cases with restricted limbic and/or temporal lobe damage: they all have reasonable IQ, intact STM, but very poor LTM for new material, and intact perceptual/motor learning

The Claparede Effect: When Claparede went up to a patient with a pin in his hand when they shook their hands, the pin would hurt her. Everyday Claparede greets the lady and she could not recognise him at all time, however, when he offered to shake, she hesitated, recognising a threat despite her memory has been severely damaged.

The nature of the deficit:

1. Selective effect on LTM, but STM or WM intact.
     >Normal working memory on digit span-usually 7+3 digits
     >Extended digit span-multiple repetitions of same digit string can increase the span, usually up to 20
     >HM could not recall any string in excess of his normal ST span, even after 25 repetitions of the same string
2. Global-impairments across different modalities and materials
     >Various tests conducted on patients to assess their learning and memory (e.g. free recall, cued recall, recognition...)
     >Amnesia seen for information presented in different modalities (e.g. visual, auditory and olfactory)
3. Selective-only impairments in remembering new facts and events
     >HM is unable to report any personal or public events since time of surgery
     >Impaired on list-based tasks (e.g. paired associate learning)
4. Selective-amnesia spares learning and expression of skilled performance
     >Amnesics' performance in repetition priming (e.g. picture fragment completion, word stem completion) improved by experience
     >Amnesics showed savings in mirror tracing task (reproducing outline with only visual information from mirror)
     >Amnesics get fast and accurate with multiple presentations in mirror-image reading task
     **Spared skilled and performance but have little or not memory for learning experience, little recall/recognition of test materials, little or no insight into skills acquired (typically unaware that performance has improved)
5. Information that can be learned is inflexible and can only be expressed in limited contexts
     >Performance has to be measured in exactly the same way to show savings
     >Facilitation does not carry over to other tasks or test contexts

Hypotheses arising from the human clinical literature based on preserved abilities in cases otherwise severely amnesic:
=>Ryle (1949)-A number follow the distinction from philosophy between knowing how and knowing that.
=>Squire (1992)-Procedural vs declarative memory
=>Tulving (1972)-Semantic vs episodic memory

Two(or more) memory systems?
~Wider circuitry, not just hippocampus, involved in declarative or episodic processing
~Relatively pure amnesia also results from damage to mamillary body


Studies of AA confirm the distinction between long-term and working memory & implicit and explicit learning.
Learning and memory affected in amnesia seem to require hippocampus and/or related structures.
But the hippocampus cannot be the storage site for LTM, neocortex?
Intrusions errors evidence suggests material is in memory somewhere but appropriate retrieval is problematic. Lost/reduced encoding specificity?