1. 4th Conference of Translational Medicine 26-28 October 2015 Baltimore, Maryland, US New technology in CNS rehabilitation Alina Borkowska Chair and Department of Clinical Neuropsychology, Nicolaus Copernicus University Toruń, Collegium Medicum in Bydgoszcz, Poland Center of Hyperbaric Oxygen Therapy and Wound Treatment in Bydgoszcz, Poland Alina Borkowska Chair and Department of Clinical Neuropsychology, Nicolaus Copernicus University Toruń, Collegium Medicum in Bydgoszcz, Poland Center of Hyperbaric Oxygen Therapy and Wound Treatment in Bydgoszcz, Poland

2. Agenda Diagnosis of brain dysfunction: importancy of right diagnosis for the clinical and functional improvement Holistic treatment of brain dysfunction and novel treatment methods on neuronal level functional level psychosocial level Hyperbaric Oxygen Therapy in brain diseases NEUROBARY as an complex treatment system of brain disorders Diagnosis of brain dysfunction: importancy of right diagnosis for the clinical and functional improvement Holistic treatment of brain dysfunction and novel treatment methods on neuronal level functional level psychosocial level Hyperbaric Oxygen Therapy in brain diseases NEUROBARY as an complex treatment system of brain disorders

3. Introduction Central Nervous System (CNS) dysfunctions with cognitive decline are considered worldwide major problem o Above 200 subjects per 100 000 EC citizens experience TBI o Increase of prevalence of stroke and TBI o Increase of prevalence of neurodegenerative disorders o Highh medical and social costs associated with the diseases Despite advances in medicine and rehabilitation there is still no effective treatment to improve neural and functional recovery Strategies focused on increase the effectiveness of neuroprotection may be considered as a most promising methods in CNS therapy. Central Nervous System (CNS) dysfunctions with cognitive decline are considered worldwide major problem o Above 200 subjects per 100 000 EC citizens experience TBI o Increase of prevalence of stroke and TBI o Increase of prevalence of neurodegenerative disorders o Highh medical and social costs associated with the diseases Despite advances in medicine and rehabilitation there is still no effective treatment to improve neural and functional recovery Strategies focused on increase the effectiveness of neuroprotection may be considered as a most promising methods in CNS therapy.

4. Etiology of brain dysfunctions: Traumatic Brain Injury (TBI) Stroke Neurodegerative disorders (AD, FTD, DLB) Vascular diseases Inflammatory porocesses Autoimmunological diseases Psychiatrics disorders Hipoxia, oxidative stress (e.g. stage after cardiac operations) Brain tumors and disorders after neurosurgery operations Neurodevelopmental disorders Somatic illnesses (methabolic syndromes) Influence of pharmeceutical treatment Stress Traumatic Brain Injury (TBI) Stroke Neurodegerative disorders (AD, FTD, DLB) Vascular diseases Inflammatory porocesses Autoimmunological diseases Psychiatrics disorders Hipoxia, oxidative stress (e.g. stage after cardiac operations) Brain tumors and disorders after neurosurgery operations Neurodevelopmental disorders Somatic illnesses (methabolic syndromes) Influence of pharmeceutical treatment Stress

5. Cognitive functions Information processing Psychomotor speed Attention Memory Visuospatial skills Working memory and executive functions Language Are related to: The brain regional activity Neurotransmitters activity Polymorphism of genes associated with cognition and emotional processess Enviromental factors (e.g brain stimulations, diet) Pharmacological treatment (e.g. benzodiazepines) Information processing Psychomotor speed Attention Memory Visuospatial skills Working memory and executive functions Language Are related to: The brain regional activity Neurotransmitters activity Polymorphism of genes associated with cognition and emotional processess Enviromental factors (e.g brain stimulations, diet) Pharmacological treatment (e.g. benzodiazepines)

6. Working memory – ability to keep information in short-term memory and to manipulate them Association with consciousness Basic process of executive functions: Planning Problem solving Orientation in complex situations Mental flexibility Adaptation Working memory – ability to keep information in short-term memory and to manipulate them Association with consciousness Basic process of executive functions: Planning Problem solving Orientation in complex situations Mental flexibility Adaptation Declarative memory Procedural memory Working memory Executive functions main processess in adaptation and functioning

7. Effective treatment- right diagnosis Diagnosis of etiology of brain damage Diagnosis of specificity of brain damage (localization, severity) Neuropsychological evaluation o performing individual patient profile o Searching for cognitive, clinical, biochemical and genetics endophenotypic markers associated with vulnerability to the illness illness progression treatment response Diagnosis of etiology of brain damage Diagnosis of specificity of brain damage (localization, severity) Neuropsychological evaluation o performing individual patient profile o Searching for cognitive, clinical, biochemical and genetics endophenotypic markers associated with vulnerability to the illness illness progression treatment response

8. Misdiagnosis Psychosis and cognitive dysfunctions: set of symptoms or disodrers ? Psychotic symptoms are related to the level of brain destabilisation in patients with genetics vulnerabilty to develop of psychosis o 70-80 % patients after cardiac operations o 50-60% of AD subjects o More frequent in old age depression and bipolar disorders o In reumatoligical diseases (brain phorm of lupus, vasculitis tissue diseases) o In patients with MS and Parkinson disease o In autoimmunological brain inflammatory disorders (e.g. with anty NMDA receptors antibodies) How many patients with atypical course of schizophrenia, bipolar disorders or autism obtained misdiagnosis ? How many patients with atypical course of schizophrenia, bipolar disorders or autism obtained misdiagnosis ? Psychosis and cognitive dysfunctions: set of symptoms or disodrers ? Psychotic symptoms are related to the level of brain destabilisation in patients with genetics vulnerabilty to develop of psychosis o 70-80 % patients after cardiac operations o 50-60% of AD subjects o More frequent in old age depression and bipolar disorders o In reumatoligical diseases (brain phorm of lupus, vasculitis tissue diseases) o In patients with MS and Parkinson disease o In autoimmunological brain inflammatory disorders (e.g. with anty NMDA receptors antibodies) How many patients with atypical course of schizophrenia, bipolar disorders or autism obtained misdiagnosis ? How many patients with atypical course of schizophrenia, bipolar disorders or autism obtained misdiagnosis ?

9. Misdiagnosis In Poland diagnosis of autoimmunological brain disorders are provided in lupus and vasculitis tissue diseases o P-rib antigenes o SM antigenes o DS DNA antigenes Patients with atypical psychosis are not diagnosed for autoimmunological brain inflammatory disease with antyNMDA receptors antibodies Probably this is the reason of partial response for treatment or ineffective brain disorders therapy In Poland diagnosis of autoimmunological brain disorders are provided in lupus and vasculitis tissue diseases o P-rib antigenes o SM antigenes o DS DNA antigenes Patients with atypical psychosis are not diagnosed for autoimmunological brain inflammatory disease with antyNMDA receptors antibodies Probably this is the reason of partial response for treatment or ineffective brain disorders therapy

10. Neuroprotection is an effect that may result in salvage, recovery or regeneration of the nervous system, cells, structure and function. Associated with neurochemical modulators of nervous system damage o excessive glutamate-mediated neurotransmission o Impairment sensitive sodium and calcium channel functioning o impaired GABA-mediated inhibition and alterations in acid base balance o cascade of events leading to neuronal damage and cell death. Neuroprotection is an effect that may result in salvage, recovery or regeneration of the nervous system, cells, structure and function. Associated with neurochemical modulators of nervous system damage o excessive glutamate-mediated neurotransmission o Impairment sensitive sodium and calcium channel functioning o impaired GABA-mediated inhibition and alterations in acid base balance o cascade of events leading to neuronal damage and cell death.Neuroprotection

11. Holistic treatment of brain disorders Neuronal level Neuroprotective therapy Improvement of brain functioning Functional level Improvement of cognitive abilities Decrease of psychiatric symptoms Psychosocial level Improvement of patients quality of life, functioning in family, society, work Eliminate bariers to acces to fast and right diagnosis and treatment Increse the level of knowledge in society

12. Neuronal level therapies Therapies focused on elimination or minimalize of brain damaging agents o hypoxia o oxidative stress factors o inflammatory processes o edema o Improving of neural synchronization Such as…. Operative methods (e.g „no touch” vs traditional OPCABG) Novel pharmaceutical pro-cognitive therapies Blood cells therapies (e.g. in MS, Parkinson disease) Hyperbaric oxygen therapy – HBOT Transcranial brain stimulation Therapies focused on elimination or minimalize of brain damaging agents o hypoxia o oxidative stress factors o inflammatory processes o edema o Improving of neural synchronization Such as…. Operative methods (e.g „no touch” vs traditional OPCABG) Novel pharmaceutical pro-cognitive therapies Blood cells therapies (e.g. in MS, Parkinson disease) Hyperbaric oxygen therapy – HBOT Transcranial brain stimulation

13. Hiperbaric Oxygen Therapy – history

14. Hiperbaric Oxygen Therapy in medicine

15. Hiperbaric Oxygen Therapy in brain dysfunctions Traumatic brain injury, CNS dysfunctions after neurosurgery interventions Stroke Mild Cognitive Impairment on different etiology Cognitive decline in old subjects Neurodegenerative disorders (Alheimer’s Disease, vascular dementia) Neurodevelopmental disorders in children (autism, cerebral palsy) Traumatic brain injury, CNS dysfunctions after neurosurgery interventions Stroke Mild Cognitive Impairment on different etiology Cognitive decline in old subjects Neurodegenerative disorders (Alheimer’s Disease, vascular dementia) Neurodevelopmental disorders in children (autism, cerebral palsy) 12 persons chamber in HbOT in Bydgoszcz

16. HBOT: contradications Tension Pneumothorax o All patients get screening CXR Chemotherapeutic drugs – Bleomycin, Doxoribicin, Cisplatin, Disulfiram History of spontaneous pneumothorax History of throacic surgery Chronic obstructvie pulmonary diseases Acute infections, hyperthermia Acute psychosis, anxiety (claustrophobia, panic disorder) Seizure disorders Malignant tumors higher risk of barotrauma, lung impairment Tension Pneumothorax o All patients get screening CXR Chemotherapeutic drugs – Bleomycin, Doxoribicin, Cisplatin, Disulfiram History of spontaneous pneumothorax History of throacic surgery Chronic obstructvie pulmonary diseases Acute infections, hyperthermia Acute psychosis, anxiety (claustrophobia, panic disorder) Seizure disorders Malignant tumors higher risk of barotrauma, lung impairment

17. Treatment procedure Lack of big, randomized multicenters studies to establish more effective treatment procedure At the denegerative stage (acute stroke, TBI): HBOT must be administred carefuly to avoid toxicity At the regenerative stage (more than 1 month of acute brain injury) HBOT is administred between 1.5- 2.0 ATA Time of treatment: o 20-60 of 1-1.5 hour’s sessions Lack of big, randomized multicenters studies to establish more effective treatment procedure At the denegerative stage (acute stroke, TBI): HBOT must be administred carefuly to avoid toxicity At the regenerative stage (more than 1 month of acute brain injury) HBOT is administred between 1.5- 2.0 ATA Time of treatment: o 20-60 of 1-1.5 hour’s sessions

18. Underlying brain repair mechanisms of HBOT Improvement of cerebral blood flow Improvement of brain metabolism Initiate vascular repair, improvement of angiogenesis Recovery of synaptic plasticity and connectivity Regeneration of axonal white matter Stimulation of axonal growth Promote blod-brain barier integrity Reduction of inflammatory reactions and brain edema Improvement of cerebral blood flow Improvement of brain metabolism Initiate vascular repair, improvement of angiogenesis Recovery of synaptic plasticity and connectivity Regeneration of axonal white matter Stimulation of axonal growth Promote blod-brain barier integrity Reduction of inflammatory reactions and brain edema

19. Underlying brain repair mechanisms of HBOT on cellural level Improvement of cellural matabolism Reduction of apoptosis Alleviate of oxidative stress Increase the neurotophins level (e.g. BDNF, kinases) and nitric oxide through enhancement of mitochondrial functions in neurons and glial cells Inhibition of mitochondrial premability transition (Efrati et al., 2014; Hadanny et al., 2015) Improvement of cellural matabolism Reduction of apoptosis Alleviate of oxidative stress Increase the neurotophins level (e.g. BDNF, kinases) and nitric oxide through enhancement of mitochondrial functions in neurons and glial cells Inhibition of mitochondrial premability transition (Efrati et al., 2014; Hadanny et al., 2015)

20. HBOT in severe TBI treatment A prospective randomised II phase clinical trial to evaluate of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity and clinical outcome in severe TBI (Rockswold et al., 2013 – University of Minnesota) Forthy two patients with severe TBI (Coma Glasgow Scale 5.7) within 24 hours of injury were allocated to the o combination normobaric treatment – NBH (1.0ATA 3 hours) with HBOT (1.5 ATA 1 hour) for three consecutive days o Control group (traditional treatment) The results : o Brain tissue partial pressure of O2 significantly increased in combination NBH/HBOT compared to controlls o Lower intracranial pressure in NBH/HBOT group (and significant imrovement during next sessions) o Lower microdialysate glycerol in NBH/HBOT group o Decrease of mycrodialisate lactate/pyruvate ratios in injuted and preinjured brain tissue only in combination therapy group o 26% reduction of mortality in NBH/HBOT group and greater improvement on CGS compared to controlls A prospective randomised II phase clinical trial to evaluate of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity and clinical outcome in severe TBI (Rockswold et al., 2013 – University of Minnesota) Forthy two patients with severe TBI (Coma Glasgow Scale 5.7) within 24 hours of injury were allocated to the o combination normobaric treatment – NBH (1.0ATA 3 hours) with HBOT (1.5 ATA 1 hour) for three consecutive days o Control group (traditional treatment) The results : o Brain tissue partial pressure of O2 significantly increased in combination NBH/HBOT compared to controlls o Lower intracranial pressure in NBH/HBOT group (and significant imrovement during next sessions) o Lower microdialysate glycerol in NBH/HBOT group o Decrease of mycrodialisate lactate/pyruvate ratios in injuted and preinjured brain tissue only in combination therapy group o 26% reduction of mortality in NBH/HBOT group and greater improvement on CGS compared to controlls

21. HBOT in brain damage after cardiac arrest HBOT can induce neuroplasticity and improve cognition of patients with anoxic brain damage (Hadanny et al., 2015, Tel-Aviv University) o 11 patients with chronic cognitive impairments (CCI) after cardiac arrest o Treated with 60 sessions of HBOT o Neuropsychological evaluation (computerized test battery, Activity of Daily Living, Quality of Life scale) o Comparison of the tests results with neuroimaging data (SPECT) The results o Improvement on neuropsychological functions (memory, attention, executive functions 12-20-24% respectively) o Correlation of clinical improvement with the level of brain activity improvement in SPECT HBOT can induce neuroplasticity and improve cognition of patients with anoxic brain damage (Hadanny et al., 2015, Tel-Aviv University) o 11 patients with chronic cognitive impairments (CCI) after cardiac arrest o Treated with 60 sessions of HBOT o Neuropsychological evaluation (computerized test battery, Activity of Daily Living, Quality of Life scale) o Comparison of the tests results with neuroimaging data (SPECT) The results o Improvement on neuropsychological functions (memory, attention, executive functions 12-20-24% respectively) o Correlation of clinical improvement with the level of brain activity improvement in SPECT

22. Neuroprotective therapies on functional level Neuropsychological training (especially based of memory stimulation) o Increase of neurotrophin level in the brain o Improvement of synaptic connectivity and neurons synchronization o Improvement on cognition and emotion Phisical activity o Physical activity supports neuroprotection and patients condition Neuropsychological training (especially based of memory stimulation) o Increase of neurotrophin level in the brain o Improvement of synaptic connectivity and neurons synchronization o Improvement on cognition and emotion Phisical activity o Physical activity supports neuroprotection and patients condition

23. Eric Kandel Nobel Prise 2000 Eric Kandel, Center for Neurobiology and Behavior, Columbia University, New York. Neuropsychological training especially based on memory may results in morphological changes in the brain Improved synaptic plasticity Support neuroprotection Influence gene expression This is the basis of cognitive and behavioral therapy The only winner - sea snail Aplysia

24. Physical exercise and neurons protection Regular and moderate exercise initiated in middle age prevents age-related amyloidogenesis and preserves synaptic and neuroprotective signaling in mouse brain cortex (Di Loretto et al., 2014) Aerobic fitness (walking) interventions improve cognition (Stothart et al., 2014) Acute exercise increases oxygenated hemoglobin in the prefrontal cortex – association with working memory improvement (Giles et al., 2014) Significant improvement of cognition, movement and decrease of depressed symptoms in patients with preclinical AD (Hagner-Derengowska et al., 2015) Regular and moderate exercise initiated in middle age prevents age-related amyloidogenesis and preserves synaptic and neuroprotective signaling in mouse brain cortex (Di Loretto et al., 2014) Aerobic fitness (walking) interventions improve cognition (Stothart et al., 2014) Acute exercise increases oxygenated hemoglobin in the prefrontal cortex – association with working memory improvement (Giles et al., 2014) Significant improvement of cognition, movement and decrease of depressed symptoms in patients with preclinical AD (Hagner-Derengowska et al., 2015)

25. Telemedicine in cognitive therapy About 30% patients trained with traditional (face to face) methods lost to the rehabilitation 1% of drop-out in patients treated with telemedicine methods The time and place of training is convinient to the patient No geographical barriers with therapy access Interesting tasks based on computer games – important especially for young patients o High emotional motivation for therapy continuation o Better compliance About 30% patients trained with traditional (face to face) methods lost to the rehabilitation 1% of drop-out in patients treated with telemedicine methods The time and place of training is convinient to the patient No geographical barriers with therapy access Interesting tasks based on computer games – important especially for young patients o High emotional motivation for therapy continuation o Better compliance

26. NEUROBARY system Complex system for brain dysfunctions treatment involved HBOT and neuropsychological therapy using telemedicine methods 30 sessions of HBOT, each 1.5 hours Neuropsychological training using COGTEL platform o Eveluation panel o Rehabilitation panel (diffrent level of exercisses, possibility to programming individual sets of excercisses) o Televisits panel o Monitoring of therapy process by specialists o Recording and data visualization and transfer them to the statistic program o Patients may use the cognitive therapy programme after finished HBOT treatment Complex system for brain dysfunctions treatment involved HBOT and neuropsychological therapy using telemedicine methods 30 sessions of HBOT, each 1.5 hours Neuropsychological training using COGTEL platform o Eveluation panel o Rehabilitation panel (diffrent level of exercisses, possibility to programming individual sets of excercisses) o Televisits panel o Monitoring of therapy process by specialists o Recording and data visualization and transfer them to the statistic program o Patients may use the cognitive therapy programme after finished HBOT treatment

27. Evaluation panel of COGTEL Evaluation of basic cognitive abilities: Single Reaction Time: attention, psychomotor abilities GoNoGo : divided attention, decision making Visual Working Memory Test: working memory and executive functions Verbal Memory Test: short term and delayed recall Trail Making Test : set shifting, visuaospatial working memory, executive functions Stroop Test: verbal working memory, executive functions Evaluation of basic cognitive abilities: Single Reaction Time: attention, psychomotor abilities GoNoGo : divided attention, decision making Visual Working Memory Test: working memory and executive functions Verbal Memory Test: short term and delayed recall Trail Making Test : set shifting, visuaospatial working memory, executive functions Stroop Test: verbal working memory, executive functions

28. Evaluation panel SRT, GoNoGo Please klick the button when green circle appears Press button only if green scuare appears Single Reaction Time GoNoGo Test

29. TMT A (25 points) TMT B (1-13, A-L) 1 2 3 4 56 7 8 START FINISH 1 A 2 B 3 C 4 D START FINISH Results: time required to complette both part of the test Evaluation panel Trail Making Test In computed version the touch screen is applied

30. Evaluation panel Stroop Test GREEN RED BLUE YELLOW BLACK RED BLACK YELLOW BLUE GREEN GREEN YELLOW BLACK RED BLUE RED BLACK YELLOW BLUE GREEN GREEN RED BLUE YELLOW BLACK RED BLACK YELLOW BLUE GREEN GREEN YELLOW BLACK RED BLUE RED BLACK YELLOW BLUE GREEN Read as soon as possible the color names Name as soon as possible the colors of words Results: time required to complette both part of the test

31. Evaluation panel Visual Working Memory Test Remember the location of each card

32. The effect of cognitive rehabilitation in patients after TBI 42 patients after at least 1 months after TBI o 29 males, 13 females o Aged 18-45 (mean 36.2+4.2) years 22 patients treated with telemedicine 20 patients treated with traditional methods Evaluation of cognition, intensity of depression, subjective feeling of cognitive improvement Assessment were performed before, after 1, 2 and 3 months of training and 6 months follow-up Observation finished 22 patients received tele-rehabilitation and 16 patients received traditional rehabilitation 42 patients after at least 1 months after TBI o 29 males, 13 females o Aged 18-45 (mean 36.2+4.2) years 22 patients treated with telemedicine 20 patients treated with traditional methods Evaluation of cognition, intensity of depression, subjective feeling of cognitive improvement Assessment were performed before, after 1, 2 and 3 months of training and 6 months follow-up Observation finished 22 patients received tele-rehabilitation and 16 patients received traditional rehabilitation

33. The results – traditional rehabilitation the level of improvement (% of change vs baseline)

34. The results – tele rehabilitation the level of improvement (% of change vs baseline)

35. The comparison of the improvement after 6 months follow-up (% of change vs baseline) Differences significant on all parameters

36. Conclusions Effective treatment of patients with CNS dyfunctions Holistic perception of patient with brain problem Right diagnosis based on current knowledge within a reasonable time Immplementation of novel effective therapies focusing on neuroprotection on neuronal, functional and psychosocial level Effective treatment of patients with CNS dyfunctions Holistic perception of patient with brain problem Right diagnosis based on current knowledge within a reasonable time Immplementation of novel effective therapies focusing on neuroprotection on neuronal, functional and psychosocial level

37. Marek Wiśniewski Kinga Grobelska Anna Lipińska Margaret Niznikiewicz Mariola Wnęk Artur Jakubowski Alina Borkowska Maciej Bieliński Krzysztof Szwed Martyma Gębska Marta Tomaszewska Gosia Piskunowicz Joanna Ulfig Iwona Miklasz Marek Wiśniewski Kinga Grobelska Anna Lipińska Margaret Niznikiewicz Mariola Wnęk Artur Jakubowski Alina Borkowska Maciej Bieliński Krzysztof Szwed Martyma Gębska Marta Tomaszewska Gosia Piskunowicz Joanna Ulfig Iwona Miklasz