Repairing and treating damaged or dysfunctional brains

1. Repairing and treating damaged or dysfunctional brains Professor Keith Kendrick

2. 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 (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

3. 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

4. Progress in the treatment of affective disorders • Depression • Schizophrenia • Social anxiety • Autism

6. Depression highway – “Road to Hell”

7. Increase in prescriptions for anti-depressant drugs Data for Scotland

8. 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

9. Electroconvulsive therapy vs drugs

10. 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

11. 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

12. TMS Treatment of drug-resistant depression

13. Deep brain stimulation

14. 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)

15. Prosocial peptides and their future therapeutic potential • Empathogens and entactogens (Ecstasy/Adam, GHB) • Naturally occurring prosocial peptides – oxytocin and vasopressin

16. 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.]

18. 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)

19. 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

20. Can oxytocin facilitate empathy and socially reinforced learning?

22. Oxytocin facilitates emotional empathy ** *** ** * Placebo n=24 Oxytocin n=24 ** ** Intensity rating/9

23. Emotional empathy Sex Difference ** ** ** ** ** ** Intensity rating / 9 ED ED- ED+ EI EI- EI+ ** P<0.01

24. Oxytocin facilitates learning when social feedback is used S (male) S (female) NS

25. Feedback from female faces is the most effective Hurlemann et al. (2010) Journal of Neuroscience

26. 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?)

27. Oxytocin and autism spectrum disorders

28. Oxytocin receptor SNPs associated with autism and prosocial behaviours rs237887 rs2268490 rs1042778 Lerer et al (2008) Mol Psych Israel et al (2009) PLoS ONE

29. Epigenetic regulation of oxytocin receptor Gregory et al 2009 BMC Medicine

30. Increased methylation and reduced OT receptor expression in autism Gregory et al (2009) BMC Medicine

31. 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

32. 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)

33. 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

34. Progress in treatment of neurodegenerative disorders • Alzheimer’s disease • Parkinson’s disease

35. 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.

36. Parkinson’s disease Stimulation of the Sub-thalamic nucleus

37. 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

38. Parkinson’s disease – gene therapy Phase 2 trials completed

39. Parkinson’s disease – stem cell therapy

40. 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 healthcarePhoto: 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.

41. Alzheimer’s disease

42. Alzheimer’s disease

43. Alzheimer’s disease – drug treatments

44. Other potential cognitive enhancers Provigil (Modafinil), Adderall, Ritalin, Ampakines D- cycloserine?

45. Cycloserine improves learning and enhances brain hippocampal activity Hurlemann et al (2010) Biological Psychiatry

46. 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 community-based cohort. Neurology, 2009

47. 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 perispinaletanercept 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

48. 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, 2010Study 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

49. 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

50. Alzheimer’s disease – lifestyle self help • Use it and delay onset of dementia – The “cognitive reserve” hypothesis Valenzuela et al (2008) PLoS ONE