Repairing and treating damaged or
dysfunctional brains
Professor Keith Kendrick
Some big Neuroscience challenges
• A prosocial, “happy” brain
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1 in 4 will suffer clinical depression
1 in 10 social anxiety disorder (social phobia)
1 in 100 schizophrenia
1 in 200 autism spectrum disorder
• Repairing damaged brains
 Dementia - 1 in 60 (60 years); 1 in 20 (70 years); 1 in 10 (80 years); 1 in 3
(90+years)
 Parkinson’s Disease – 1 in 500
 Traumatic brain injury – 1 in 50
 Blind – 1 in 300
• 2 billion people on the planet have a mental disorder
Focus of talk
Treatment of:
• Affective disorders
• Neurodegenerative disorders
• Restoration of sight, hearing and damaged
limbs
Focus on current strategies and likely
developments in next 5-10 years
Progress in the treatment of affective
disorders
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Depression
Schizophrenia
Social anxiety
Autism
Depression highway – “Road to Hell”
Increase in prescriptions for anti-depressant drugs
Data for Scotland
Around 50% of individuals with severe chronic depression do not
respond to current drugs
Side Effects Of
Antidepressants:
-Dry mouth
-Constipation
-Weight gain
-Bladder problems
-Sexual problems
-Blurred vision
-Dizziness
-Drowsiness
-Increased heart rate
-Headaches
-Heart palpitations
-Nausea
-Nervousness and
insomnia
-Agitation (feeling jittery)
-Nightmares
Electroconvulsive therapy vs drugs
ECT is more effective than anti-depressant drugs for severe depression
UK – UK ECT Review Group (2003)
Lancet
USA – Pagnin et al (2004) J ECT
Other approaches to treatment of depression
Cognitive behaviour therapy (CBT) - Identifies distorted
perceptions patients have of the world and themselves,
helps change them and discover new patterns of actions
and behaviour (12-14 weeks)
Brain stimulation – Aims to relieve depression by
targeting brain regions promoting positive affect
TMS Treatment of drug-resistant depression
Deep brain stimulation
The Dalai Lama of Tibet on “Wireheading”
"If it was possible to become free of negative emotions by a riskless
implementation of an electrode - without impairing intelligence and
the critical mind - I would be the first patient."
Dalai Lama (Society for Neuroscience Congress, Nov. 2005)
Prosocial peptides and their future therapeutic
potential
• Empathogens and entactogens (Ecstasy/Adam,
GHB)
• Naturally occurring prosocial peptides –
oxytocin and vasopressin
Oxytocin – 104 years of discovery
• 1906 (J. Phys) Uterine contraction (oxytocic)
effects discovered by Sir Henry Dale [New Latin,
from Late Greek *oxutokiā, sudden delivery, from Greek ōkutokios,
oxytocic : ōkus, swift + tokos, birth.]
Oxytocin: Animal-based research
Released in brain during birth and suckling (1986)
Stimulates maternal care and mother-infant bonds (1987)
Facilitates social recognition (1987)
Improves tolerance to heroin withdrawal (1980s)
Reduces food intake (1990s)
Released in brain during sex
Promotes monogamous pair bonds
Different receptor distribution in nonsocial species (1991, 1992)
Is an anxiolytic; reduces aggression (increases maternal aggression)
Important for social but not non-social recognition (2000)
Social recognition actions via brain amygdala (2001)
Effects of oxytocin treatments on human social
behaviours
•Social bonds
•Trust
•Generosity
•Responses to face expressions
•Memory for faces
•Enhances positive social memories
•Reduces psychosocial stress
syntocinon
Can oxytocin facilitate empathy and socially
reinforced learning?
Oxytocin facilitates emotional empathy
Intensity rating/9
**
*
***
**
**
**
Placebo n=24
Oxytocin n=24
Emotional empathy Sex Difference
7
**
**
**
**
**
**
Intensity rating / 9
6
5
4
Females n=12
Males n=24
3
2
1
0
ED
ED-
ED+
EI
EI-
EI+
** P<0.01
Oxytocin facilitates learning when social feedback is used
S (female)
S (male)
NS
Feedback from female faces is the most effective
Hurlemann et al. (2010) Journal of Neuroscience
Putative roles for oxytocin
• Promote feelings of attachment, trust and
empathy in both sexes (dopamine?)
• Reduce anxiety in social contexts
(serotonin/GABA?)
• Help focus attention on and attraction to
social cues and increases protective behaviors
(noradrenaline?)
Oxytocin and autism spectrum disorders
Oxytocin receptor SNPs associated with autism and prosocial
behaviours
rs237887
rs2268490
rs1042778
Lerer et al (2008) Mol Psych
Israel et al (2009) PLoS ONE
Epigenetic regulation of oxytocin receptor
Gregory et al 2009 BMC Medicine
Increased methylation and reduced OT receptor expression in autism
Gregory et al (2009) BMC
Medicine
Effects of oxytocin treatment
• Bartz and Hollander (2006) The neuroscience
of affiliation…. Hormones and Behavior (reduces
repetitive behaviours in autistic individuals –
need to know, repeating, ordering, need to
tell/ask, self-injury and touching)
• Hollander et al (2007) Biol Psych. Improves
retention of emotional speech intonation
recognition in autistic individuals
• Andari et al (2010) Promoting social behavior
with oxytocin in high-functioning autism
spectrum disorders. PNAS
Oxytocin and affective disorders - Schizophrenia
• OT first suggested to have antipsychotic
properties by Bujanow in 1974
• Some abnormalities in OT levels and
responses to trust
• Intranasal OT further improves symptoms in
patients already being treated with
antipsychotics (Feifel et al 2010 Biol Psych)
Other disorders
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Social anxiety disorder
Depression
Borderline personality disorder
Post-traumatic stress disorder
Drug-addiction
Likely to be a useful adjunct treatment in a
number of disorders
Progress in treatment of neurodegenerative
disorders
• Alzheimer’s disease
• Parkinson’s disease
Parkinson’s disease
Drug Treatments:
Dopamine – levodopa
Dopaminergic agonists
Bromocriptine (Parlodel),
pergolide (Permax),
pramipexole (Mirapex) and
ropinirole (Requip).
MAO-B inhibitors selegiline
(Eldepryl) and rasagiline
(Azilect), prevent and COMT
inhibitors are tolcapone
(Tasmar) and entacapone
(Comtan) reduce break down
of dopamine in the brain.
Parkinson’s disease
Stimulation of the
Sub-thalamic nucleus
Parkinson’s disease – fetal transplants
Fetal transplants:
Freed et al New Eng J Med 2001
20 patients
Transplanted
Cells still healthy 4-12
years later
Parkinson’s disease – gene therapy
Phase 2 trials
completed
Parkinson’s disease – stem cell therapy
Availability of stem cell therapies before successful clinical trials
Stem cell law loopholes allow XCell-Center to operate in Germany
The XCell-Center, which would be banned in the UK, has been able to thrive in Germany due to a legal
loophole about to be closed under new European legislation
.
Stem cells have promised to provide a revolution in healthcare Photo: AP
By Robert Mendick, Chief Reporter 7:45AM BST 24 Oct 2010
Article from
“The Telegraph”
The law governing stem cell clinics is extremely complex.
The UK classifies stem cell treatments as medicines. This means that before
procedures can be licensed, the therapies must undergo the same kind of
rigorous trials as those used for other medicines.
Alzheimer’s disease
Alzheimer’s disease
Alzheimer’s disease – drug treatments
Other potential cognitive enhancers
Provigil (Modafinil), Adderall, Ritalin,
Ampakines
D- cycloserine?
Cycloserine improves
learning and enhances
brain hippocampal
activity
Hurlemann et al (2010)
Biological Psychiatry
Alzheimer’s disease – reducing inflammatory effects
•Anti-inflamatory drugs (NSAIDs) despite early claims of
beneficial effects in Alzheimer’s patients may only at best
delay the onset of dementia
J. C.S. Breitner, S. J.P.A. Haneuse, R. Walker, S. Dublin, P. K.
Crane, S. L. Gray, and E. B. Larson. Risk of dementia and AD
with prior exposure to NSAIDs in an elderly communitybased cohort. Neurology, 2009
Alzheimer’s disease – tumour necrosis factor
• Some genes associated with inflammatory disease such as
rheumatism appear to be associated with Alzheimer’s
Rapid cognitive improvement in Alzheimer's disease following perispinal
etanercept administration
Edward L Tobinick* and Hyman Gross
Journal of Neuroinflammation (2008)
Anti-TNF Therapies for Rheumatoid Arthritis Could Reduce Alzheimer’s Risk
Released: 11/1/2010 8:00 AM EDT
Source: American College of Rheumatology (ACR)
Chou et al 2010
Alzheimer’s disease – gene therapy
• Clinical trials underway targeting increased production
of nerve growth factor in damaged parts of the brain
Historic Gene Therapy Trial for
Alzheimer's Disease Underway
at Georgetown
October 22, 2010 Study First to
Test Gene Therapy Injected into
the Brain
Randomized, Controlled Study
Evaluating CERE-110 in Subjects
With Mild to Moderate
Alzheimer's Disease
This study is currently recruiting
participants.
ClinicalTrials.gov Identifier:
NCT00876863
Phase 2 trials
underway
Alzheimer’s disease – lifestyle self help
•Diet and exercise
Exercise and Alzheimer's disease biomarkers in
cognitively normal older adults
Kelvin Y. Liang et al, Annals of Neurology 2010
Mediterranean diet
Number of different types of exercises
performed inversely associated with
onset of cognitive impairment (P = .002)
Number of exercise sessions lasting at
least 20 minutes (P = .007).
Jedrziewski et al (2010) Alzheimers &
Dementia
Alzheimer’s disease – lifestyle self help
• Use it and delay onset of dementia –
The “cognitive reserve” hypothesis
Valenzuela et al (2008) PLoS ONE
Alzheimer’s disease
The Lifetime of Experiences Questionnaire (LEQ)
What is the LEQ?
•The LEQ is a questionnaire to determine both your current mental activity
levels and how active you have been over your lifetime. It was designed for
individuals over 65 years of age or now retired.
Dr Michael Valenzuela and Professor Perminder Sachdev
http://train.headstrongcognitive.com/(S(gtjezh45b3s0df2amh5emvf3))/leq.
aspx
Sensory and motor impairments
•Hearing for the deaf
•Vision for the blind
•Artificial limbs for amputees
Hearing for the deaf
Restoring sight to the blind
Restoring sight to the blind
Stem cell therapy for retinal degeneration
•Age-related macular degeneration
•Diabetic retinopathy
Pfizer to produce stem cells for AMD therapy
British scientists have developed the world's first
stem cell therapy for age-related macular
degeneration (AMD). Surgeons predict it will become
a routine, one-hour procedure that will be generally
available in six or seven years' time.
Apr 19, 2009
Patient from X-Cell Centre
AstraZeneca joins UCL to find stem cell cure for diabetic blindness
AstraZeneca and UCL researchers look to use stem cells to repair eyesight in
rising number of diabetic retinopathy patients
•Sunday 12 September 2010 20.02 BST
Neural prosthesis
Neural prosthetic arm
Summary
• Considerable progress is being made in
identifying molecular targets for potential
treatment of brain disorders.
• Therapeutic advances have been made using
electrical brain stimulation approaches
• Gene therapy approaches have potential promise
although require use of viral vectors
• Stem cell therapies also have potential promise
although unregulated treatment centers may
impede confidence and progress
Summary
• Embryonic vs adult stem cells?
• Neural prosthethic approaches are developing
rapidly
• New treatments in Clinical trials now may still
need another 5-10 years before they are
approved for general use
• Life-style choices are still of great importance in
helping to avoid or reduce problems.