Repairing and treating damaged or dysfunctional brains

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Repairing and treating damaged or dysfunctional
brains
Professor Keith Kendrick
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Some big Neuroscience challenges

• A prosocial, happy brain
• 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 (90years)
• Parkinsons Disease 1 in 500
• Traumatic brain injury 1 in 50
• Blind 1 in 300
• 2 billion people on the planet have a mental
  disorder

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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

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Progress in the treatment of affective disorders

• Depression
• Schizophrenia
• Social anxiety
• Autism

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Depression highway Road to Hell
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Increase in prescriptions for
anti-depressant drugs
Data for Scotland
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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
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Electroconvulsive therapy vs drugs
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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
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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
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TMS Treatment of drug-resistant depression
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Deep brain stimulation
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The Dalai Lama of Tibet on Wireheading
"If it was possible to become free of negative
emotions by a risklessimplementation of an
electrode - without impairing intelligence and
the critical mind - I would be the first
patient."Dalai Lama (Society for Neuroscience
Congress, Nov. 2005)
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Prosocial peptides and their future therapeutic
potential

• Empathogens and entactogens (Ecstasy/Adam, GHB)
• Naturally occurring prosocial peptides oxytocin
  and vasopressin

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Oxytocin 104 years of discovery

• 1906 (J. Phys) Uterine contraction (oxytocic)
  effects discovered by Sir Henry Dale New Latin,
  from Late Greek oxutokia, sudden delivery, from
  Greek okutokios, oxytocic okus, swift tokos,
  birth.

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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
non-social 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)
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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
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Can oxytocin facilitate empathy and socially
reinforced learning?
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Oxytocin facilitates emotional empathy


Placebo n24 Oxytocin n24




Intensity rating/9
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Emotional empathy Sex Difference






Intensity rating / 9
ED ED- ED
EI EI- EI
Plt0.01
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Oxytocin facilitates learning when social
feedback is used
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Feedback from female faces is the most effective
Hurlemann et al. (2010) Journal of Neuroscience
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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?)

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Oxytocin and autism spectrum disorders
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Oxytocin receptor SNPs associated with autism and
prosocial behaviours
rs237887
rs2268490
rs1042778
Lerer et al (2008) Mol Psych Israel et al (2009)
PLoS ONE
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Epigenetic regulation of oxytocin receptor
Gregory et al 2009 BMC Medicine
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Increased methylation and reduced OT receptor
expression in autism
Gregory et al (2009) BMC Medicine
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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

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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)

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Other disorders

• 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

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Progress in treatment of neurodegenerative
disorders

• Alzheimers disease
• Parkinsons disease

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Parkinsons 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.
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Parkinsons disease
Stimulation of the Sub-thalamic nucleus
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Parkinsons disease fetal transplants
Fetal transplants Freed et al New Eng J Med
2001 20 patients
Transplanted Cells still healthy 4-12 years
later
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Parkinsons disease gene therapy
Phase 2 trials completed
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Parkinsons disease stem cell therapy
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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 745AM 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.
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Alzheimers disease
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Alzheimers disease
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Alzheimers disease drug treatments
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Other potential cognitive enhancers
Provigil (Modafinil), Adderall, Ritalin,
Ampakines D- cycloserine?
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Cycloserine improves learning and enhances brain
hippocampal activity Hurlemann et al
(2010) Biological Psychiatry
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Alzheimers disease reducing inflammatory
effects

• Anti-inflamatory drugs (NSAIDs) despite early
  claims of beneficial effects in Alzheimers
  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 community-based
  cohort. Neurology, 2009

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Alzheimers disease tumour necrosis factor

• Some genes associated with inflammatory disease
  such as
• rheumatism appear to be associated with
  Alzheimers

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
Alzheimers Risk Released 11/1/2010 800 AM EDT
Source American College of Rheumatology
(ACR) Chou et al 2010
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Alzheimers 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
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Alzheimers 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
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Alzheimers disease lifestyle self help

• Use it and delay onset of dementia The
  cognitive reserve hypothesis

Valenzuela et al (2008) PLoS ONE
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Alzheimers 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(gtjezh45b3
  s0df2amh5emvf3))/leq.aspx

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Sensory and motor impairments

• Hearing for the deaf
• Vision for the blind
• Artificial limbs for amputees

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Hearing for the deaf
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Restoring sight to the blind
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Restoring sight to the blind
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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

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Neural prosthesis
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Neural prosthetic arm
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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

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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.