Techniques in Systems Neuroscience

Question 1

What is systems neuroscience?

Answer 1

Systems neuroscience seeks to understand how groups of neurons are organised into circuits, how neural circuits mediate brain function and how this understanding can be used to improve function

Question 2

What are the different levels of descriptions that need to be considered in systems neuroscience?

Answer 2

Psychological
Systems
Microcircuit
Neuronal
Intracellular
Molecular

Question 3

How do we consider multiple levels of description in research?

Answer 3

Use several different methods to explore different levels of description

A single method will usually only provide information at one level of description

Question 4

How do you decide which methods you should use to test a hypothesis in research?

Answer 4

There are many different methods to choose from
Need to consider the spatial scale and the temporal scale of methods which suits your research
Also need to consider the constraints

Question 5

What are the constraints of research which you need to consider?

Answer 5

Expertise - are you trained to use certain methods

Facilities - what equipment is available to you, can you collaborate with other departments to use their equipment

Time - e.g., are you funded on a 3 year grant? Do you have deadlines to work towards?

Money - do you have funding? Do you have the money to use certain methods?

Ethics - have you received ethics approval for the use of certain methods

Question 6

How do we know which data will enable us to most easily test the hypothesis?

Answer 6

This requires consideration of the question being asked
For example:
Which bits of the brain is responsible for behaviour X?
Which bits of the brain does structure Y connect to?
How does structure Y enable us to perform behaviour X?

Each question can be answered using a range of techniques
In modern neuroscience, it is often the case that the best research brings multiple techniques together in a single study.

Question 7

What is MRI, how does it work?

Answer 7

Magnetic resonance imaging
- Put energy in via radiofrequency waves
- The energy is absorbed and then emitted in a way that gives information about the chemical properties of the tissues
- So MRI allows you to build up a detailed picture of brain structure that is sensitive to the differing tissue types
- Very high spatial resolution but it is just brain structure

Question 8

What is fMRI?

Answer 8

Same principles as MRI, the only difference is that you ‘tune’ your scanner to be sensitive to something that disturbs the way the energy is absorbed and the emitted

This something is blood, because blood contains haemoglobin, which contains iron

The scanner can be made very sensitive to the effect of the iron in the blood on the way the energy given to tissue by the radiofrequency pulse is re-emitted

When haemoglobin is carrying oxygen, it ‘hides’ the iron, so actually fMRI is really picking up on the oxygenation of blood in the tissue

Activated brain cells can call up more oxygenated blood, so fMRI tells us about brain activity

So fMRI blood acts as a contrast agent

Question 9

What is PET?

Answer 9

Positron emission tomography

• Make a contrast agent that is specifically targeted to the biological process we want to image
• Get a chemical that binds to the target e.g., oxygen, glucose etc
• Attach a radioisotope (radiation emitting molecule) to that chemical (specifically a positron emitter)
• Inject this tracer (contrast agent) into the subject
• Detect the emitted radiation and use a computer to work our where it is coming from (tomography)

Question 10

What are the uses of PET?

Answer 10

Excellent for informing on specific biological processes (fMRI very limited in this respect)

PET may also be used to evaluate the function of organs, such as the heart or brain. The most common use of PET is in the detection of cancer and the evaluation of cancer treatment

Question 11

What are the limitations of PET?

Answer 11

Spatial and temporal resolution poor compared to fMRI
Uses radiation, so much more limited in research applications

Question 12

How do we reduce the limitations of PET and MRI?

Answer 12

Combine the advantages of PET and MRI/fMRI in a MRI-PET scanner

Question 13

What is EEG?

Answer 13

Electroencephalography
EEG gives indication of regional brain activity underlying electrodes

Question 14

What is EEG used for?

Answer 14

Good for detecting signs of epilepsy

As well as monitoring ongoing activity, EEG can be used to look at brain responses to a specific stimulus - event related potentials

Question 15

What are the constraints of EEG?

Answer 15

Helps to have subject in an electrically shielded environment to minimise electrical noise

Analysis is complex and takes a lot of time

Good temporal resolution

Poor spatial resolution

Question 16

How is EEG data analysed?

Answer 16

Signals are often separated into different frequency bands (slow wavesfast waves)

Different frequency bands appear to relate to distinct neurophysiological processes

Question 17

What is MEG?

Answer 17

Magnetoencephalography

The electrical current of large numbers of cells and white matter tracts (bundles of axons, think wires) induces a magnetic field that can be detected with a very large machine

MEG signals are very small and hard to detect

But, a little less interference by scalp & skull than electrical signals so can offer better spatial resolution than EEG

Question 18

What techniques can be used to stimulate the brain?

Answer 18

Transcranial magnetic stimulation (TMS)
Transcranial direct current stimulation (TDCS)

Question 19

How does TMS work?

Answer 19

TMS uses an alternating magnetic field to produce a secondary electrical current in brain tissue which disrupts the ongoing activity

Used in research to ‘turn off’ parts of the brain so that their role in a cognitive function can be assessed

Question 20

What are the uses of TMS?

Answer 20

It is hard to target precisely but there is some evidence of clinical potential e.g., in treating depression

Question 21

How does TDCS work?

Answer 21

Pass (mild) current through the brain, between the positively charged anode and the negatively charged cathode

Can excite or inhibit underlying brain tissue, which may be useful experimentally

Question 22

What are the uses of TDCS?

Answer 22

Early evidence for cognitive enhancement effects and possible clinical benefits, but simplicity of device may risk mis/over-use

Question 23

What psychophysiological measures can be used to infer brain function?

Answer 23

External or internal stimuli that are of survival significance will act through the brain to trigger the sympathetic nervous system

It is probably a uniquely human phenomenon that ‘thoughts’ can also achieve this

Through this, aspects of brain function can be inferred by measuring systemic (non-CNS) factors
- Skin conductance (sweating)
- Heart Rate
- Blood Pressure
- Pupil Dilation
- Muscle Tension
- Body Language?

Question 24

What is considered when choosing whether to use invasive methods in animal models?

Answer 24

Requires a careful justification of how likely benefits of the research for either other animals or humans outweigh the costs

Strictly regulated by the Home Office in the UK

Question 25

What are the three guiding principles for all research involving animals?

Answer 25

1. Replacement (can another method be used?
2. Refinement (can it be done in a better way that further maximises the cost/benefit equation)
3. Reduction (can it be done with a smaller number of animals)

Question 26

What is possible with the use of invasive methods?

Answer 26

1. Make direct measurements of the activity of brain cells

• Direct measurement of activity of human brain cells is possible but only in rare circumstances - although EEG measures electrical activity of neurons the spatial resolution is poor

2. Determine connectivity between structures, flow of information
3. Disrupt connectivity between structures to determine effects upon circuit function
   - Measure effects on activity in downstream structures
   - Measure effects on behaviour
4. Lesion specific structures to inform us about what function that structure performs

Question 27

What methods can be used to directly measure the activity of brain cells?

Answer 27

There are several different methods of recording activity of brain cells, some target single cells (intracellular recoding, also termed unicellular recording)

Some record from larger numbers of cells (extracellular recording)

The intra vs extra –cellular terminology just refers to whether the tip of the electrode is inside the cell itself (intra), where it is relatively insulated from the activity of surrounding cells

Question 28

How do we determine connectivity between structures?

Answer 28

Stimulating electrodes can be inserted into one part of the brain (including into single cells) [A] and recording electrodes inserted into another region (or single cell) [B]

The effect of stimulating the first region (or cell) [A] on the second [B] can then be determined

Alternately (or as well), we can inject tracers into a structure and map out their connection to other structures by examining post-mortem brain tissue
Anterograde tracers
Retrograde tracers

Question 29

How do anterograde tracers work?

Answer 29

Tracer injected into region A
Tracer travels forward along axon towards next synapses in regions B and C
This would identify region A as connecting to B and C

Question 30

How do retrograde tracers work?

Answer 30

Tracer injected into region C
Tracer travels backwards along axon towards cell body in region
This would identify regions A as connecting to C

Question 31

What is psychopharmacology?

Answer 31

A field that investigates the effect of drugs on thoughts or behaviour

Psychoactive drugs such as coffee and alcohol and other (illegal) compounds often have complex actions on many brain regions, acting on different types of receptor on different cell types

From a research perspective, is it often necessary to use specially designed compounds that have much more targeted (and known) actions

Question 32

How do pharmacological research methods work?

Answer 32

Different drugs will act at different points in the process of neurotransmission, e.g.
Some will mimic the neurotransmitter to act on the receptor
Some will block the receptor
Some will prevent manufacture of the neurotransmitter
Some will block re-uptake

Pharmacological manipulations can be combined with other methods:
- Stimulate region A, record region B (hypothesised pathway)
- Administer drug (block receptor thought to be involved here) and see if the resulting effects on region B or behaviour are similar to effects of a lesion of structure A