Lecture 6: Neuroanatomy of White Matter

Question 1

What is white matter?

Answer 1

• It is not a uniform structure within the brain
• White matter is the anatomical connections between the neurons: (the axons) and it is organized in bundles of fasciculi.
• There are no anatomical differences in white matter so we represent it with colour coded maps.

Question 2

What are the three types of white mater fibres (AKA the three main white matter tracts)?

Answer 2

1. Commissural fibres: fibres that connect the two hemispheres together, they go from the left to the right.
2. Association fibres: short and long distance.
   - Together these two fibres make cortical-cortical connections
   - Commissural fibres connect the brain areas from one area toanother (interhemispheric connection)
   - Association fibres are intrahemispheric connections.
   - anterior to posterior orientations!!
3. Projection fibres: connect the cortex to subcortical areas and then down to the spinal cord.
   - Superior to inferior orientation (up down orientation).

Question 3

White matter fasiculi

Answer 3

• Each fasciculi has a name and associated function depending on which cortical area they
  connect –> not random.
• As the brain develops, connections are formed and some are eliminated between specific brain areas to form networks between the brain.
• At birth there is more connections in the brain than in the adult brain –> more synapse and connection in a newborn brain
• Then there is some elimination that is done, some of this is done by genes, some of this is by cell proliferation, and some of the elimination is from the environment. White matter becomes networks.

Question 4

Brain development

Answer 4

Birth:
- more neurons and connections than in the adult brain.

Preschool age: 4 times volume - more gray matter than in the adult brain.

6 years old: 90% of adult volume.

Growth:
- Proliferation
- Myelinisation
- Synapse formation; new synapse are formed.
- Internal signals (genes)
- Elimination: by process of competition influenced by experience (external signals). External signals can reinforce new developements and also eliminate unused connections.
- Better efficiency

Question 5

Commisural fibres

Answer 5

Main one is The Corpus Callosum
- This is the largest commissural bundle (a lot of white matter)
- Connects the two hemispheres together
- Fibres within the corpus callosum do not cross each other, they really just go from left to right –> Connect the homologous regions from one hemisphere to the other.
- Can be divided into multiple sections
- the CC is crucial for many brain functions

Question 6

Division of the corpus callosum

Answer 6

Genu and rostrum: connect the Orbitofrontal and Prefrontal areas (more frontal part - “knee”).

Rostral Body: connects the Premotor and Supplementary motor areas (central part - motor areas)

Anterior midbody: Connects the Sensori-motor areas (sensory area).

Posterior midbody: connects parietal areas

Isthmus: connects the Posterior Parietal and Superior Temporal areas

Splenium: connects Inferior Temporal area and the left and right Occipital areas (connects maily the occipital areas).

Question 7

Other commissural fibres

Answer 7

• Corpus callosum is NOT the only one.
• There is also the anterior commissure, the hippocampal commissure (connects the two hippocampi), and the posterior commissure.

Question 8

Anterior Commissure (AC)

Answer 8

• Connects areas of the temporal cortex as well as subcortical structures (amygdala) and olfactory bulbs.
  Connects the anterior part of the temporal lobe
• Very small, and to be able to see it in a slice you have to cut a very specific section the green bean on the image

Question 9

Association fibres

Answer 9

Intra-hemispheric fibres: involved in information transfer from one brain area to another
1. Superior longitudinal fasciculus (SLF): connect frontal to parietal areas (3 branches)
2. Arcuate fasciculus (AF): connects frontal to posterior temporal areas (connects brocas region to wernickes region)
3. Middle longitudinal fasciculus (MLF): connects temporal to parietal areas
4. Temporo-Frontal Extreme Capsule fasciculus (TFexcF): connects frontal to intermediate temporal areas (more anterior region of the temporal lobe).
5. Uncinate fasciculus: connect orbitofrontal and anterior temporal areas (connects the amygdala).
6. Inferior longitudinal fasciculus: occipito-temporal connections (very longitudinal: occipital to temporal connections).
7. Inferior Fronto-Occipital Fasciculus (IFOF): involved in occipito-frontal connections,
but not everyone believes this pathway is real (hard to study this pathway, lots of debate).

Question 10

Projection fibres

Answer 10

• Ascending and descending fiber tracts from and to the cortex (go in the up-down direction)
• Connect cortext to the subcortical areas and to the spinal cord and vice versa.
• Within the brain, there are two different white matter areas that include projection fibres: on each side of the putamen and the globus pallidus
  1. Internal capsule
  2. External capsule
• Once they enter the hemispheres and start to fan out they are called the corona radiata

Question 11

External capsule

Answer 11

External capsule: motor cortex, primarily to putamen (uni-directional/one way tract)

Question 12

Internal Capsule

Answer 12

Internal capsule: a massive white matter highway connecting cortex with subcortical structures, the brainstem, and the spinal cord and vice versa (bi-directional)
- Basically just the name of the narrow space where the axons pass.

So within this white matter internal capsule you have two tracts:
- Descending tract: motor pathway
- Ascending tract: sensory pathways

Question 13

Methods to study white matter: Dissections

Answer 13

• Oldest method
• Had to be done post-mortem
• Hard to see where the axons start and where they terminated in the brain

Dejerine in 1895 –>Arcuate fasciculus example
- Identified a white matter tract arching (hence the name arcuate
fasciculus) around the end of the Sylvian fissure
- Described this tract anatomically as “temporo-occipito-frontal” connections. They did not know exaclty where the tracts went in what areas.

Question 14

Diffusion Imaging Tractography (dMRI)

Answer 14

• Measures water diffusion along the axons –> movement of water molecules in brain follows axons.
• Allows one to reconstruct or virtually dissect white matter tracts in vivo
• Tractography is not an exact method to find out where fibres go or which brain areas are anatomically connected
• Useful to have anatomical priors (knowledge from dissections and monkey studies to better identify white matter tracts in the brain)

dMRI = same scanner as fMRI and MRI

Question 15

What are the limitations/challenges of tractography?

Answer 15

Limitations/challenges:
- Where there are crossing fibres (hard to dissect white matter tracts that cross)
- When several fibre tracts run in parallel within the same white matter
area there is no way to know where the connect
- Cannot detect if there is a synapse

Question 16

Studying anatomical connections - gold standard macaque monkey studies

Answer 16

• Inject a tracer in a specific cortical area and see the exact termination
  and course of the axons.
• Two types of tracers: anterograde (forward -> away from cell body) and retrograde (backwards -> towards cell body)
• Indicates direct connectivity

Question 17

What type of brain “connectivity” does diffusion imaging look at?

Answer 17

Structural connectivity (or anatomical connectivity)
* Virtual reconstruction/dissection of white matter tracts
* Index of the white matter
microstructure (axon diameter, myelination,directionality….) –> see how well info travels in these white matter areas.

Question 18

What type of brain “connectivity” does resting-state fMRI look at?

Answer 18

Functional connectivity
* Correlated brain activation (if brain regions become activated at the same time).
* Does not indicate direct anatomical connectivity –> when you see functional connectivity it does not mean there is an anatomical connectivity between these two areas.

Question 19

Research example: Dissociating the white matter tracts connecting the temporo-parietal cortical region with frontal cortex using diffusion tractography (Prof Barbeau’s study)

Answer 19

The language tract:
* The Arcuate Fasciculus (AF) is a white matter tract connecting the posterior temporal region (Wernicke’s area) involved in the comprehension of language with the inferior frontal gyrus (IFG; Broca’s region) involved in the production of language
- Several studies have used diffusion imaging tractography to reconstruct and study it

Mixing with other tracts:
- Because of the limitations of dMRI technique –> can lead to some error in reconstruction

Examples of errors that could occur:
- Mixing the AF and Superior Longitudinal Fasciculus (SLF). There is no way of disinguishing them because they run in parallel.
- Reconstructing the AF and Middle Longitudinal Fasciculus (MLF) as one continuous tract

• The SLF connects the IFG (inferior frontal gyrus) to IPL (inferior parietal lobule) and courses parallel to the AF which connects the IFG to the posterior temporal cortex.
• The posterior temporal lobe is responsible for language comprehension.

*the monkey brain is anatomically like the human brain.

Question 20

Previous reconstruction of the AF using diffusion Magnetic Resonance Imaging (MRI) tractography
Problems with this!!

Answer 20

Terminology –> saying posterior and anterior segment vs. their actual name is
confusing for people

Not everyone agrees where the tracts are supposed to end
ie: Error in red tract = AF does not really go to the anterior temporal areas.

Question 21

Using prior knowledge (Prof Barbeau’s study)

Answer 21

How they divided the SLF into 3 branches:
- Gold standard macaque monkey studies: able to inject the tracer in a specific cortical area and see the exact termination and course of the axons
- Using the cytoarchitectonic homologues of BA 44 and BA 45 Petrides and
Pandya, identified the two retrospective distinct connection profiles of those two
IFG areas using tracers in the monkey and divided the SLF into distinct branches
*neurons in 44 were only going to supramarginal gyrus
*neurons in 45 only going to angular gyrus.

Question 22

Goal of the study (Prof Barbeau’s study)

Answer 22

• To use dMRI tractography to dissect separately the AF from the SLF using specific anatomical landmarks and prior knowledge from gold standard monkey research
• To separate the SLF into SLF II and SLF III. To understand the function of these tracts (use lesions to study these).
• Provide methods to the research community → Better understand and define the functional role of each of those
  tracts in human cognition
• Overall goal is to better understand and define the functional role of each of those tracts in human cognition.

Question 23

Using anatomical landmarks (Prof Barbeau’s study)

Answer 23

Goal was to restrict white matter connections that came from the frontal lobe to the:
1. Supramarginal gyrus
2. Angular gyrus
3. Posterior temporal lobe
Program to get only tracts which end in specific regions of interest

• Also wanted to support their research using resting state connectivity as evidence
• When you put a seed in the supramarginal gyrus we can see that area 44 is strongly correlated with the supramarginal gyrus (SFL III)
• But when we put the seed in the angular gyrus there is no correlated activity in
  area 44 at all, only area 45 was active (SFL II)
• When you put the seed in the posterior temporal area you can see very well how
  the IFG was active (area 44 and 45 are active) (AF).
• Also wanted to provide MNI coordinates:
  Sulci and MNI coordinates:
  Look at the sulci anf gyri to place the seeds at the correct place. Use MNI brain as coordinates to locate white matter tracts.

Question 24

More questions to be answered about the anatomy of white matter tracts?

Answer 24

There are many more questions about the anatomy of the white matter tracts to be answered!
- Is the IFOF a real fasciculus?
- Some people do not see why the brain would have a direct connection between
the primary visual area and the high order inferior-frontal cortex
- May not be a direct axonal connection, but could be a combination of the
inferior longitudinal fasciculus (ILF) that runs along the occipital and temporal
area and the Fronto-temporal extreme fasciculus (FtexcF)

• Is it a combination of the ILF and the FtexcF?
• Maybe!

Question 25

What do you require to be accurate with dMRI reconstruction?

Answer 25

To be accurate with dMRI reconstruction you REALLY need prior anatomical knowledge.

Question 26

Impairments and recovery of lesions depend on?

Answer 26

▪ Where the stroke happens (location), and which brain areas are affected
▪ The extent of the lesion also affects the symptom severity
▪ The patient

Severity depends on
* Individual
* Size
* Location

Question 27

Common impairments in stroke patients include?

Answer 27

• motor deficits: upper or lower limb weakness
• dysphagia: difficulty swallowing
• visual impairments: e.g. neglect
• language deficits: aphasia (losing language, main depression symptom)

Depends on where the stroke happens, and which brain areas are affected
- The location and extent of the lesion affects the symptom severity
- Why are language deficits studied so much?
Patients would like to be able to predict their outcome after a lesion

Question 28

White matter vs Gray Matter

Answer 28

• Different outcomes and post-stroke symptom severity

Study: 44 patients who had experienced a left hemisphere ischemic stroke
Result: Less severe aphasia if more cortical areas are still integrated into the network (less severe if more cortical areas are intact).

Importance of studying not only the cortical areas affected but also the whitematter integrity in stroke to add valuable information to the analysis of possibleoutcomes (e.g. language)

*remember language is localized in left hemisphere for right handed individuals.

Question 29

Aphasia

Answer 29

• A disorder caused by damage to the areas of the brain that support our ability to comprehend and produce speech.
• Usually caused by stroke, tumor, traumatic brain injury or degenerative brain disease
• Leads to difficulties in speaking, understanding, reading and writing. Depending where in the network the lesion is, it will affect different ones.

There is a relationship between lesion site and language outcome.
* Different location = different language deficits
* Different patient = different language deficits

After a lesion a specialist will come examine the patient and try to determine which
disorder or deficit they have
- Speech, writing, and comprehension of speech may all be evaluated
- One or more aspects of language can be affected depending on location of lesion
- Aphasia is likely to result from many different lesion sites and the association of damage
to one region does NOT exclude the involvement of other regions –> speech production involves many cognitive processing steps

Question 30

From functional imaging and lesion studies, we know that…

Answer 30

many brain regions support both speech comprehension and production.

Language involves a lot of different brain areas. Different individuals may rely on different regions more than others for language.

Question 31

Speech production and its many cognitive processing steps

Answer 31

• Aphasia is likely to result from many different lesion sites and the association of damage to one region does not exclude the involvement of other regions.

fMRI studies have shown that the main sources of between subject variability in task-dependent brain activity reflect different ways of doing the same task.
→ If alternative neural systems are available to support speech production, then selective disruption to one area (e.g. Broca’s area) may only have a transient effect (on speech production).

Question 32

Schematic and hypothetical
illustration of the effects of
lesions (grey hatched areas) when
there are two alternative
pathways (orange and pink) to
the same output (red).

Answer 32

**The effect of the lesion depends on whether one of the pathways remains intact.
Although this is more likely after a small lesion, it is not so much the size of the lesion that matters but
where the lesion occurs.
For example:
- the middle configuration has a small lesion that knocks out one area that is critical to both pathways
- the left configuration has a large lesion that leaves one pathway intact.
- the right configuration illustrates how damage to two pathways can have a much more devastating
effect than damage to one pathway

Lesions in each of the regions may cause their own functional
impairment but the combination of multiple regions of damage may have a much greater effect on behavior than the sum of the effect of each region alone.
The effect of the lesion on recovery will influence the most appropriate type of therapy.

Question 33

Lesion to Disorder

Answer 33

• Each lesion is different
• They can affect gray mater or white matter
• Effects can be different in different individuals (lesions in similar location in two patients can have different effects and recovery patterns - this is why it is important to always test the patient)
  →Factors that might underlie the inconsistency across patients with similar lesions include: co-morbidity, age, handedness, gender, hearing, vision, education, premorbid learning ability, motivation to relearn, attention, working memory, multilingual experience, ethnicity, social and cultural background (Price et al. 2010) do not need to know these by heart
• We can try to predict from what we know about the brain and which brain region does what, but it’s just theory, there is no one to one correspondence that is always true.