CLINICAL
NEUROSCIENCE
Claire Snel
Master Biomedical Sciences –
Specialization Neurobiology – Year
2024/2025
78
,Inhoudsopgave
Week 1 – Introduction ................................................................................................................... 3
Lecture 1 – Brain development ......................................................................................................... 3
Week 2 – Leukodystrophies ........................................................................................................... 9
Lecture 1 – Leukodystrophies: an introduction of concepts ................................................................ 9
Lecture 2 – Leukodystrophies: to study disease mechanisms ............................................................18
Lecture 3 – Leukodystrophies: to develop outcome measures, clinical trials and clinimetry ................24
Lecture 4 – Leukodystrophies: what has water homeostasis to do with them? ....................................32
Lecture 5 – Leukodystrophies: current treatment(s) ..........................................................................41
Lecture 6 – Leukodystrophies: envision gene therapy ........................................................................49
Week 3 – Multiple Sclerosis .......................................................................................................... 56
Lecture 1 – Clinical features of MS ...................................................................................................56
Part 1 – Background.................................................................................................................... 56
Part 2 – Clinical symptoms ......................................................................................................... 57
Part 3 – Disease course and subtypes ......................................................................................... 59
Part 4 – Case description ............................................................................................................ 60
Lecture 2 – Imaging methods ...........................................................................................................61
Lecture 3 – Pathophysiology/ Etiological mechanisms and neuropathology .......................................66
Lecture 4 – Current therapy for MS ...................................................................................................72
Part 5 – Prognosis ....................................................................................................................... 72
Part 6 – Treatment ...................................................................................................................... 72
Lecture 5 – Cognitive dysfunction in MS ...........................................................................................77
Lecture 6 – Networks in MS .............................................................................................................87
Week 4 – Student presentations ................................................................................................... 94
Week 5 – Parkinson’s disease ....................................................................................................... 95
Lecture 1 – Clinical features of PD ...................................................................................................95
Part 1 – Introduction ................................................................................................................... 95
Part 2 – Diagnosis ....................................................................................................................... 95
Part 3 – Disease course .............................................................................................................. 99
Part 4 – Conclusion .................................................................................................................. 101
Lecture 2 – Brain imaging and PD part I .......................................................................................... 102
Lecture 3 – Brain imaging and PD part II ......................................................................................... 107
Lecture 4 – Disease mechanisms of PD part I ................................................................................. 111
Lecture 5 – Disease mechanisms of PD part II ................................................................................ 120
Lecture 6 – Current therapy for PD ................................................................................................. 125
Week 6 – Neuropsychiatry .......................................................................................................... 132
1
, Lecture 1 – Brain circuits in OCD ................................................................................................... 132
Part 1 – OCD & disease model................................................................................................... 132
Lecture 2 – Circuit-based neuromodulation rTMS ........................................................................... 137
Part 2 – From disease model to personalized targeting ............................................................... 137
Lecture 3 – The depression paradox ............................................................................................... 144
Lecture 4 – Ins & outs of depression research ................................................................................. 148
Lecture 5 – Biological pathways of MDD ......................................................................................... 151
Part 1 – Hypothalamic-pituitary-adrenal (HPA) axis .................................................................... 152
Part 2 – Autonomic Nervous System (ANS)................................................................................. 153
Part 3 – Immune system (inflammation) .................................................................................... 154
Week 7 – Glioma ........................................................................................................................ 157
Lecture 1 – Clinics of neuro-oncology ............................................................................................ 157
Lecture 2 – Current therapy for glioma ........................................................................................... 161
2
,Week 1 – Introduction
Lecture 1 – Brain development
Learning objectives
- Able to describe landmarks in brain development
- Have knowledge about neurological disease resulting from failure in this process
- Have basic knowledge about what we can see clinically from pediatrically neurological
development
Timeline
Ø The figure provides a summary of some key cellular processes in
the developing prefrontal cortex and functional milestones
Ø Illustrations in the top panel show the gross anatomical features
of the developing and adult CNS, with prenatal brain features
magnified
Ø The second panel, which is duplicated at the bottom of the figure,
provides a timeline of human development and the associated periods (designed by
Kang et al., 2011), and age in postconceptional days (pcd), post- conceptional weeks
(pcw), and postnatal years (y)
Ø The schematic below details the approximate timing and sequence of key cellular
processes and devel- opmental milestones
Ø Bars indicate the peak developmental period in which each feature is acquired; dotted
lines indicate that feature acquisition occurs at these ages, though to a relatively minor
degree; and arrows indicate that the feature is present thereafter
Development and milestones
- Psychiatric and Neurological disorders have discrete ages of onset
- Indicative of the biological challenge of precisely regulating diverse
molecular and cellular processes over a protracted period of time
and across myriad cell types and regions, the CNS exhibits
regionally and temporally distinct patterns of vulnerability to
various diseases and insults
- Intellectual disabilities, ASD, ADD: before age of 10
- Anxiety disorders, schizophrenia, substance abuse, mood
disorders start in adolescence
- Huntington’s, Parkinson’s and aAlzheimer’s disease later on in life
Main processes in brain development
Ø Neurogenesis in ventricular zone Ø Synaptogenesis
Ø Neuronal migration Ø Synaptic pruning
Ø Formation of astroglia/ Ø Myelination
oligodendrocytes
- One important mechanism of development is growth of the brain, can be followed by
measuring the head size
- Head size is determined by the volume inside of the skull: brain and CSF
o Microcephaly: small head
3
, o Macrocephaly: big head, either by:
§ Brain is too big
§ Tumors
§ Hydrocephalus (= abnormal built up of CSF deep within the brain))
o Growth of the brain happens during first 2 years of life, continuous into adult
hood
o But especially in first months of life, neurogenesis (formation of neurons) and
myelination cause the brain to grow
Development and milestones
Ø Milestones = a set of goals or markers that a child is expected to achieve during
maturation, divided into:
o Sensory motor development: crawling (7 months), sitting up (8 months) >
examples of gross motor skills, which are the result of myelination of motor
neurons
o Communication: smiling (age of 3 months) (expression of social-emotional
development), understanding words and sentences of father and mom, using 25
words (age of 2), putting words together to start making sentences (age of 3)
o Social-emotional skills: enjoying social play with caregiver, feeling they don’t
want to be left alone
o Cognitive development: imitation and smiles, symbolic play (feeding a dole)
Motor development (I)
Ø Muscle tone:
Ø Asymmetry in movement in children: permeative reflex (scherm reflex), asymmetric tonic
neck reflex, child moves with head towards one side to get more extension of legs and
arms towards that side
o In child on video: asymmetry in movement of leg and arm: more stretched on left
side, more flexed on right side > example of permeative reflex
Ø Permeative reflex = reflexes resulting from brain stem during first 6 months of life, they
are present for survival and development in the early months of life, they disappears
after 6 months: examples: sucking reflex, grabbing reflex
o These permeative reflexes reappear in neurodegenerative disease (dementia)
§ If you lose the cortical functions, permeative reflexes of the CNS appear
again
§ If these reflexes are persisting, indicating for CNS developmental disease
Ø First steps in gross motor development: head balance (lifting the head and turning
around at age of 3 months)
Motor development (II)
- First steps in gross motor development in first year of life: head-balance, lifting the head,
turning around (= at age of 3 months)
- Motor development (12 months): standing/ walking with support
o Fine motor development: grabbing something
>> Lot of variation between children, but there are limits for what is
normal and what is not
Planes on MRI à see image
4
, Psychiatric and Neurological disorders have discrete ages of onset
Ø Development of the brain are the result of all kinds of molecular processes that have to
be switched on and switched oa at the right time and at diaerent anatomical places in
the brain à this is a very complex process, so not surprising that sometimes this goes
wrong
Ø Regulation of these processes is the basis for the onset of diseases
o Intellectual disabilities (diagnosed in first year of life)
o ADHD, Autism spectrum disorder (ASD) later on
o Psychiatric disorders: adolescence
o Neurodegenerative diseases: end of life
Neuronal development (youtube)
- Before neurulation, week 3: gastrulation > during gastrulation cells
migrate to the interior of embryo, forming three germ layers
(endoderm, mesoderm, ectoderm)
o Endoderm: gut
o Mesoderm: rest of organs
o Ectoderm: skin and nervous system
1. First 4 weeks after conception: neural tissue known as the neural
plate forms in the outermost layer of embryonic cells (ectoderm) > in 3th week:
neurectoderm appears and forms the neural plate, neural plate folds to form neural
groove, then curls into neural tube (week 4)
o After gastrulation, notochord has been formed from mesoderm
o During week 3: notochord sends signals to the overlying ectoderm, inducing it to
become neurectoderm > results in the neural plate, which folds into neural tube
§ Basal plate = ventral (front) part of neural tube
§ Alar plate = dorsal part of neural tube
§ Neural canal = hollow interior of neural tube
o By the end of the fourth week of gestation, the open ends of the neural tube
(neuropores) close oa
o Neural plate is the source of majority of neurons and glial cells
o Because this neural tube later gives rise to the brain and spinal cord any
mutations at this stage in development can lead to lethal deformities like
anencephaly or lifelong disabilities like spina bifida
o Neurulation = formation of neural tube from the ectoderm of the embryo
2. The neural tube diaerentiates into the forebrain, midbrain, hindbrain and spinal cord
o Forebrain: cerebral cortex (translates sensory stimulation, also controls complex
behaviors, thoughts, memories and problem solving)
o Midbrain: neural relay station for sending information from the body to various
sites in the brain
o Hindbrain: control basic physiological processes (breathing, heartrate)
o Spinal cord: pathway for conveying information between the brain and the rest of
the body
3. Between weeks 4-8: embryo grows, face becomes recognizably human, two
hemispheres of cerebral cortex arise
4. Between weeks 8-26: cerebral cortex grows to cover the midbrain
5. Week 28: major structural change, cortex expands greatly in surface area and becomes
wrinkled and folded inside the skull > continuing to week 40: the brain surface fills with
hills and valleys called gyri and sulci
5
NEUROSCIENCE
Claire Snel
Master Biomedical Sciences –
Specialization Neurobiology – Year
2024/2025
78
,Inhoudsopgave
Week 1 – Introduction ................................................................................................................... 3
Lecture 1 – Brain development ......................................................................................................... 3
Week 2 – Leukodystrophies ........................................................................................................... 9
Lecture 1 – Leukodystrophies: an introduction of concepts ................................................................ 9
Lecture 2 – Leukodystrophies: to study disease mechanisms ............................................................18
Lecture 3 – Leukodystrophies: to develop outcome measures, clinical trials and clinimetry ................24
Lecture 4 – Leukodystrophies: what has water homeostasis to do with them? ....................................32
Lecture 5 – Leukodystrophies: current treatment(s) ..........................................................................41
Lecture 6 – Leukodystrophies: envision gene therapy ........................................................................49
Week 3 – Multiple Sclerosis .......................................................................................................... 56
Lecture 1 – Clinical features of MS ...................................................................................................56
Part 1 – Background.................................................................................................................... 56
Part 2 – Clinical symptoms ......................................................................................................... 57
Part 3 – Disease course and subtypes ......................................................................................... 59
Part 4 – Case description ............................................................................................................ 60
Lecture 2 – Imaging methods ...........................................................................................................61
Lecture 3 – Pathophysiology/ Etiological mechanisms and neuropathology .......................................66
Lecture 4 – Current therapy for MS ...................................................................................................72
Part 5 – Prognosis ....................................................................................................................... 72
Part 6 – Treatment ...................................................................................................................... 72
Lecture 5 – Cognitive dysfunction in MS ...........................................................................................77
Lecture 6 – Networks in MS .............................................................................................................87
Week 4 – Student presentations ................................................................................................... 94
Week 5 – Parkinson’s disease ....................................................................................................... 95
Lecture 1 – Clinical features of PD ...................................................................................................95
Part 1 – Introduction ................................................................................................................... 95
Part 2 – Diagnosis ....................................................................................................................... 95
Part 3 – Disease course .............................................................................................................. 99
Part 4 – Conclusion .................................................................................................................. 101
Lecture 2 – Brain imaging and PD part I .......................................................................................... 102
Lecture 3 – Brain imaging and PD part II ......................................................................................... 107
Lecture 4 – Disease mechanisms of PD part I ................................................................................. 111
Lecture 5 – Disease mechanisms of PD part II ................................................................................ 120
Lecture 6 – Current therapy for PD ................................................................................................. 125
Week 6 – Neuropsychiatry .......................................................................................................... 132
1
, Lecture 1 – Brain circuits in OCD ................................................................................................... 132
Part 1 – OCD & disease model................................................................................................... 132
Lecture 2 – Circuit-based neuromodulation rTMS ........................................................................... 137
Part 2 – From disease model to personalized targeting ............................................................... 137
Lecture 3 – The depression paradox ............................................................................................... 144
Lecture 4 – Ins & outs of depression research ................................................................................. 148
Lecture 5 – Biological pathways of MDD ......................................................................................... 151
Part 1 – Hypothalamic-pituitary-adrenal (HPA) axis .................................................................... 152
Part 2 – Autonomic Nervous System (ANS)................................................................................. 153
Part 3 – Immune system (inflammation) .................................................................................... 154
Week 7 – Glioma ........................................................................................................................ 157
Lecture 1 – Clinics of neuro-oncology ............................................................................................ 157
Lecture 2 – Current therapy for glioma ........................................................................................... 161
2
,Week 1 – Introduction
Lecture 1 – Brain development
Learning objectives
- Able to describe landmarks in brain development
- Have knowledge about neurological disease resulting from failure in this process
- Have basic knowledge about what we can see clinically from pediatrically neurological
development
Timeline
Ø The figure provides a summary of some key cellular processes in
the developing prefrontal cortex and functional milestones
Ø Illustrations in the top panel show the gross anatomical features
of the developing and adult CNS, with prenatal brain features
magnified
Ø The second panel, which is duplicated at the bottom of the figure,
provides a timeline of human development and the associated periods (designed by
Kang et al., 2011), and age in postconceptional days (pcd), post- conceptional weeks
(pcw), and postnatal years (y)
Ø The schematic below details the approximate timing and sequence of key cellular
processes and devel- opmental milestones
Ø Bars indicate the peak developmental period in which each feature is acquired; dotted
lines indicate that feature acquisition occurs at these ages, though to a relatively minor
degree; and arrows indicate that the feature is present thereafter
Development and milestones
- Psychiatric and Neurological disorders have discrete ages of onset
- Indicative of the biological challenge of precisely regulating diverse
molecular and cellular processes over a protracted period of time
and across myriad cell types and regions, the CNS exhibits
regionally and temporally distinct patterns of vulnerability to
various diseases and insults
- Intellectual disabilities, ASD, ADD: before age of 10
- Anxiety disorders, schizophrenia, substance abuse, mood
disorders start in adolescence
- Huntington’s, Parkinson’s and aAlzheimer’s disease later on in life
Main processes in brain development
Ø Neurogenesis in ventricular zone Ø Synaptogenesis
Ø Neuronal migration Ø Synaptic pruning
Ø Formation of astroglia/ Ø Myelination
oligodendrocytes
- One important mechanism of development is growth of the brain, can be followed by
measuring the head size
- Head size is determined by the volume inside of the skull: brain and CSF
o Microcephaly: small head
3
, o Macrocephaly: big head, either by:
§ Brain is too big
§ Tumors
§ Hydrocephalus (= abnormal built up of CSF deep within the brain))
o Growth of the brain happens during first 2 years of life, continuous into adult
hood
o But especially in first months of life, neurogenesis (formation of neurons) and
myelination cause the brain to grow
Development and milestones
Ø Milestones = a set of goals or markers that a child is expected to achieve during
maturation, divided into:
o Sensory motor development: crawling (7 months), sitting up (8 months) >
examples of gross motor skills, which are the result of myelination of motor
neurons
o Communication: smiling (age of 3 months) (expression of social-emotional
development), understanding words and sentences of father and mom, using 25
words (age of 2), putting words together to start making sentences (age of 3)
o Social-emotional skills: enjoying social play with caregiver, feeling they don’t
want to be left alone
o Cognitive development: imitation and smiles, symbolic play (feeding a dole)
Motor development (I)
Ø Muscle tone:
Ø Asymmetry in movement in children: permeative reflex (scherm reflex), asymmetric tonic
neck reflex, child moves with head towards one side to get more extension of legs and
arms towards that side
o In child on video: asymmetry in movement of leg and arm: more stretched on left
side, more flexed on right side > example of permeative reflex
Ø Permeative reflex = reflexes resulting from brain stem during first 6 months of life, they
are present for survival and development in the early months of life, they disappears
after 6 months: examples: sucking reflex, grabbing reflex
o These permeative reflexes reappear in neurodegenerative disease (dementia)
§ If you lose the cortical functions, permeative reflexes of the CNS appear
again
§ If these reflexes are persisting, indicating for CNS developmental disease
Ø First steps in gross motor development: head balance (lifting the head and turning
around at age of 3 months)
Motor development (II)
- First steps in gross motor development in first year of life: head-balance, lifting the head,
turning around (= at age of 3 months)
- Motor development (12 months): standing/ walking with support
o Fine motor development: grabbing something
>> Lot of variation between children, but there are limits for what is
normal and what is not
Planes on MRI à see image
4
, Psychiatric and Neurological disorders have discrete ages of onset
Ø Development of the brain are the result of all kinds of molecular processes that have to
be switched on and switched oa at the right time and at diaerent anatomical places in
the brain à this is a very complex process, so not surprising that sometimes this goes
wrong
Ø Regulation of these processes is the basis for the onset of diseases
o Intellectual disabilities (diagnosed in first year of life)
o ADHD, Autism spectrum disorder (ASD) later on
o Psychiatric disorders: adolescence
o Neurodegenerative diseases: end of life
Neuronal development (youtube)
- Before neurulation, week 3: gastrulation > during gastrulation cells
migrate to the interior of embryo, forming three germ layers
(endoderm, mesoderm, ectoderm)
o Endoderm: gut
o Mesoderm: rest of organs
o Ectoderm: skin and nervous system
1. First 4 weeks after conception: neural tissue known as the neural
plate forms in the outermost layer of embryonic cells (ectoderm) > in 3th week:
neurectoderm appears and forms the neural plate, neural plate folds to form neural
groove, then curls into neural tube (week 4)
o After gastrulation, notochord has been formed from mesoderm
o During week 3: notochord sends signals to the overlying ectoderm, inducing it to
become neurectoderm > results in the neural plate, which folds into neural tube
§ Basal plate = ventral (front) part of neural tube
§ Alar plate = dorsal part of neural tube
§ Neural canal = hollow interior of neural tube
o By the end of the fourth week of gestation, the open ends of the neural tube
(neuropores) close oa
o Neural plate is the source of majority of neurons and glial cells
o Because this neural tube later gives rise to the brain and spinal cord any
mutations at this stage in development can lead to lethal deformities like
anencephaly or lifelong disabilities like spina bifida
o Neurulation = formation of neural tube from the ectoderm of the embryo
2. The neural tube diaerentiates into the forebrain, midbrain, hindbrain and spinal cord
o Forebrain: cerebral cortex (translates sensory stimulation, also controls complex
behaviors, thoughts, memories and problem solving)
o Midbrain: neural relay station for sending information from the body to various
sites in the brain
o Hindbrain: control basic physiological processes (breathing, heartrate)
o Spinal cord: pathway for conveying information between the brain and the rest of
the body
3. Between weeks 4-8: embryo grows, face becomes recognizably human, two
hemispheres of cerebral cortex arise
4. Between weeks 8-26: cerebral cortex grows to cover the midbrain
5. Week 28: major structural change, cortex expands greatly in surface area and becomes
wrinkled and folded inside the skull > continuing to week 40: the brain surface fills with
hills and valleys called gyri and sulci
5
