The following lecture has been approved for University Undergraduate Students

1. The following lecture has been approved for University Undergraduate Students This lecture may contain information, ideas, concepts and discursive anecdotes that may be thought provoking and challenging It is not intended for the content or delivery to cause offence Any issues raised in the lecture may require the viewer to engage in further thought, insight, reflection or critical evaluation

2. Neurobehavioural performances associated with occupational hazards The poor state of Neurobehavioural testing Dr. Craig Jackson Professor of Occupational Health Psychology Birmingham City University Hon Senior Lecturer in Occupational PsychologyInstitute of Occ & Env Medicine University of Birmingham

3. Brain Training

4. Brain Training

5. The Exposed Brain Structural Changes Functional Changes Behavioural Changes Susceptibility to other neurotoxins Possibly largest contributor to: Learning disability Attentional Disorders Development Disabilities

6. Head Injuries Severity depends on amount of Primary and Secondary brain injury Main cause of Secondary injury = hypoxia Categories: Open or Closed Forces: Shearing and Compression

7. Multiple Toxic Substances Industrial Chemicals Pesticides Therapeutic Drugs Drugs of Abuse Food Additives Brain is highly vulnerable to toxic effects In utero Post-natal Ingestion Inhalation Absorption Multiple toxic exposures: Alter cell migration, synaptic connections, cell death

8. Principles of Neurobehavioural Testing Damage to CNS due to exposure to Neurotoxic substances Neurotoxic medicines Metabolic disorders Neurotoxic diseases in top ten work-related diseases in USA Occupational exposures to toxins such as Lead Manganese Solvents Pesticides Herbicides Insecticides Contributors to the development of neurobehavioral dysfunction

9. Neurobehavioural Testing Standard tests Evaluate different aspects of functioning of the CNS including Cognition Motor Skills Memory Reaction Time Coordination Attention Visuospatial Reasoning General Affect Non-invasive Portable Cheap Range of behavioural functions affected is extremely wide Investigators typically use sets (batteries) of tests.

10. Speed / Accuracy Trade-off slow and accurate Accuracy optimum fast but sloppy Reaction Time (sec)

11. Example of Neurobehavioural Tests Trail-making 1) Worker presented diagram 2) Worker must join dots 1 – A – 2 – B etc Outcomes: a) Time to complete b) No. of errors made error

12. Example of Neurobehavioural Tests Complex Reaction Time Worker presented with 4 stimuli Worker must click button on cue (4 possible responses) Outcomes: a) Time taken to react (milliseconds) b) No. correct responses c) No. errors

13. Pencil and Paper Tests - Line Tracing

14. Digit Span Subject presented with numbers Subject must recall numbers Number string gets longer each time Outcome: Length of longest correct recall

15. Digit Symbol Subject presented with number and symbol code Subject must fill in blanks, working left to right Outcome: Number of correct cells completed Time taken to get to bottom of list

16. Benton Visual Retention Subject presented with stimulus Subject must find target Outcome: Time taken to react Correct responses Errors

17. Pattern Memory Test Subject presented with stimulus Subject must decide which is target after rotation Outcome: Time taken to react Correct responses Errors

18. Continuous Performance Test Focused attention Divided attention Sustained attention Sustained & Focused attention Efficiency = Accuracy / Speed F F F F E F F F F F F E F F E F F F F F F F E V V V V W W W V W W W W W V W W V W F F F F E F F F F F F E F F E F F F F F F F E X X X X X Y Y Y Y Y Y X Y Y Y Y Y Y Y Y Y Y Y Y Y X Y Y Y Y Y Y Y Y Y Y Y X Y Y Y Y X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y X Y Y Y Y Y Y Y Y Y Y X Y Y Y Y Y

19. Colour Word Vigilance REDGREEN YELLOW BLUE BLACK RED YELLOWBLUEGREEN Subject presented with stimulus Subject must find target word which matches colour Outcome: Time taken to react Correct responses Errors

20. Pre-Test Procedures Pre-test questionnaire Determine subjects’ general state at time of test Exclude subjects with: Seizures Functional visual impairment Language problems Drug effects Temporary physical impairment Mental impairment Illiteracy

22. Speed / Accuracy Trade-off slow and accurate Accuracy optimum fast but sloppy Reaction Time (sec)

23. n Numbers recalled Rationale of Neurobehavioural Testing Evaluate functioning in individuals exposed to pathogens Normal population exhibits a range of performance function Exposure places individuals outside of that normal range Some factors affect performance: age sex education

24. History Behavioural testing began in 1960s Hanninen (1979) developed first behavioural test battery Assess effects of chemicals and neurotoxins 1980 - 60 unique tests 1990 - 250 unique tests 1983 – WHO wanted battery to screen / identify nervous system effects

25. Neurobehavioural Core Test Battery (NCTB) 1983 WHO & NIOSH Seven behavioural tests: Digit Span Santa Ana Dexterity Digit Symbol Pursuit Aiming II Benton Visual Retention Profile of Mood States Simple Reaction Time Johnson et al. 1987

28. Minnesota Manual Dexterity Test

29. Tower of Hanoi

30. Finger Tapper

31. Testing Must Be Cross-Cultural, Valid, & Reliable Higher proportion of: Minorities Foreign born > exposures to neurotoxins Poor status & pathogens May not speak English May be “developmentally delayed” Test batteries must be suitable for people of all abilities & backgrounds

32. Testing Conditions All subjects tested under same conditions Standardized testing Not always possible in the field Furniture Lighting Visual distraction Ambient sound Temperature

33. Factors to be Aware of in Testing STABLE FACTORSSITUATIONAL FACTORS Age Alcohol (recent use) Education Caffeine (recent use) Sex Nicotine (recent use) Socioeconomics Medication (recent use) Language Paints, glues, pesticides (recent) Handedness Near visual acuity Computer experience Restricted movement (injury) Caffeine (habitual use) Cold / flu Alcohol (habitual use) Stress Nicotine (habitual use) Arousal / Fatigue Medication (habitual use) Sleep Paint, glue, pesticide (habitual use) Screen luminance Diabetes Time of day Epilepsy Time of year Other CNS / PNS disease Alcohol / drug addiction Head injury (out >1 hr) Physical activity

34. Problems of Neurobehavioural Testing Used since the 1960s in occ and env health toxicology Interpretation of different test scores is not straightforward Less straightforward role in the regulation of chemicals Difficulties neurobehavioural studies encountered by regulators (1) Studies lack scientific rigor (2) Interpretation of results of scientific studies e.g. clinically meaningful? which domains effected? smallest level of exposure associated with impairment? Stephens & Barker 1998

35. Landmark Occupational Neurobehavioural Papers Stollery & Flindt 1988 Memory sequelae of solvent intoxication Stephens et al. 1995 Neuropsychological effects of long-term exposure to organophosphates in sheep dip Lucchini et al.1995 Neurobehavioral effects of manganese in workers from a ferroalloy plant after temporary cessation of exposure Kishi et al. 1994 Residual neurobehavioural effects associated with chronic exposure to mercury vapour Sjögren et al. 1996 Effects on the nervous system among welders exposed to aluminium and manganese Gamberale 1985 Use of behavioral performance tests in the assessment of solvent toxicity

36. Landmark Occupational Neurobehavioural Papers Rosenstock et al. 1991 Chronic central nervous system effects of acute organophosphate pesticide intoxication. The Pesticide Health Effects Study Group Verberk et al. 1990 Health effects of pesticides in the flower-bulb culture in Holland Mackay et al. 1987 Behavioral changes during exposure to 1,1,1-trichloroethane: time-course and relationship to blood solvent levels.  Chia et al. 1994 Impairment of color vision among workers exposed to low concentrations of styrene Echeverria et al. 1995 A behavioral evaluation of PCE exposure in patients and dry cleaners: a possible relationship between clinical and preclinical effects

37. Neurobehavioural testing Welding & Parkinson’s Disease Is there evidence of a link? Prof. Craig Jackson Head of Psychology BCU

38. “Careless” Neurobehavioural Testing and the Manganese Problem Current Problem in USA Steel Welding Parkinson’s Disease Neurobehavioural Testing Systematic Review Conclusion

39. Litigation October 1st 2004 Larry Elam versus A.O. Smith Elam, former welder, aged 65 Developed PD Lifetime welder Wins £1M from Welding Rod Manufacturers

40. Parkinson’s Disease Neurological Condition James Parkinson Cell atrophy in substantia nigra Cardinal Symptoms Tremor (initial symptom in 70% cases) Slowness Stiffness of movement (bradykineasia) Postural instability Usual onset in mid-late 50s ( 1 in 20 diagnosed <40 years) Mostly male 1 case per 500 in UK

41. Introduction Parkinson's disease (also known as Parkinson disease or PD) Degenerative disorder of the CNS Impairs the sufferer's motor skills and speech. Belongs to a group of conditions called movement disorders. Primary Symptoms Muscle rigidity Tremor Slowing of physical movement (bradykinesia) Loss of physical movement (akinesia)

42. Dopamine Symptoms result from decreased stimulation of the motor cortex by the basal ganglia caused by insufficient formation and action of dopamine produced in the dopaminergic neurons Secondary symptoms may include: high level cognitive dysfunction subtle language problems. PD is both chronic and progressive.

43. Dopaminergic Pathways

44. Dopamine Symptoms result from the loss of dopamine-secreting (dopaminergic) cells Subsequent loss of melanin (secreted by the same cells) in the substantia nigra These neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement Essentially an inhibition of the direct pathway and excitation of the indirect pathway

45. Dopamine Pathways Four major dopamine pathways; nigrostriatal pathway mesocortical volition and emotional responsiveness mesolimbic desire, initiative, and reward Tuberoinfundibular sensory processes and maternal behaviour Disruption of dopamine along the non-striatal pathways explains much of the neuropsychiatric pathology sometimes associated with Parkinson's Disease.

46. Head Injury Previous episodes of head injury are reported more frequently by PD sufferers than by non PD sufferers in the population Those with head injury 4 times more likely to develop PD than those who have never suffered a head injury - Bower et al. 2003 Risk of developing PD increases X 8 head trauma requiring hospitalization Increases X 11severe head injury. However, since head trauma is rare, the contribution to PD incidence in the general population is minimal. T Recall Bias? ? ?

47. Drug Inducement Antipsychotic medication, used to treat / manage psychoses and schizophrenia can induce PD symptoms Lowering dopaminergic activity Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson's disease that it initially relieves Dopamine agonists can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.

48. Pallidotomy Surgery was common Liq Nit 80 Celcius for 6 sec Immediate benefits Limited duration? Declined since LevoDopa Surgery more popular again for drug-resistant PD Deep Brain Stimulation

49. LevoDopa The most widely used form of treatment is L-dopa Various formats. L-dopa is transformed into dopamine in the dopaminergic neurons Done by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). Only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is metabolised to dopamine elsewhere, Causes a wide variety of side effects.

50. LevoDopa Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive Carbidopa and Benserazide are dopa decarboxylase inhibitors They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations e.g. Carbidopa / Levodopa (co-careldopa) (e.g. Sinemet, Parcopa) Benserazide / Levodopa (co-beneldopa) (e.g. Madopar). Stalevo