4th Conference of Translational Medicine 26-28 October 2015 Baltimore, Maryland, US New technology in CNS rehabilitation Alina Borkowska Chair and Department.

4th Conference of Translational Medicine26-28 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

Agenda

• Diagnosis of brain dysfunction: importancy of right diagnosis for the clinical and functional improvement

• Holistic treatment of brain dysfunction and novel treatment methods onneuronal levelfunctional levelpsychosocial level

• Hyperbaric Oxygen Therapy in brain diseases• NEUROBARY as an complex treatment system of brain disorders

Introduction

• Central Nervous System (CNS) dysfunctions with cognitive decline are considered worldwide major problem o Above 200 subjects per 100 000 EC citizens experience TBIo Increase of prevalence of stroke and TBIo Increase of prevalence of neurodegenerative disorderso 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.

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

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)

• 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

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

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 psychosiso 70-80 % patients after cardiac operationso 50-60% of AD subjectso More frequent in old age depression and bipolar disorderso In reumatoligical diseases (brain phorm of lupus, vasculitis tissue diseases)o In patients with MS and Parkinson diseaseo 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 ?

Misdiagnosis

• In Poland diagnosis of autoimmunological brain disorders are providedin lupus and vasculitis tissue diseaseso P-rib antigeneso SM antigeneso 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

• 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 neurotransmissiono Impairment sensitive sodium and calcium channel functioningo impaired GABA-mediated inhibition and alterations in acid base

balanceo cascade of events leading to neuronal damage and cell death .

Neuroprotection

Holistic treatment of brain disorders

Neuronal levelNeuroprotective therapy

Improvement of brain functioning

Functional levelImprovement of cognitive abilities

Decrease of psychiatric symptoms

Psychosocial levelImprovement 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

Neuronal level therapies

• Therapies focused on elimination or minimalize of brain damaging agentso hypoxiao oxidative stress factorso inflammatory processeso 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

Hiperbaric Oxygen Therapy – history

• HBOT is breathing 100% oxygen at an ambient pressure greater than 1 atmosphere.

• 1662: Henshaw develop first chamber „Domicilium”o Domicilium could create both hyperbaric and hypobaric environments. o Method: increased and decreased air pressure without increasing

oxygen concentration. o Treatmet different diseases: scurvy, arthritis, inflammation, ricketso No significant imrovement because of too litle compression, placebo

effect

Hiperbaric Oxygen Therapy in medicine

• 1861: the first hyperbaric chamber (built by Corning) in New York dedicated to treat ‘nervous and related disorders’

• 1877: french surgeon Fontaine developed the first mobile hyperbaric operating room recommended to facilitate the reduction of hernia, and for patients with asthma, chronic bronchitis, emphysema and anemia.

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)

12 persons chamber in HbOT in Bydgoszcz

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

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

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

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)

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 dayso Control group (traditional treatment)

• The results :o Brain tissue partial pressure of O2 significantly increased in combination NBH/HBOT

compared to controllso Lower intracranial pressure in NBH/HBOT group (and significant imrovement during next

sessions)o Lower microdialysate glycerol in NBH/HBOT groupo Decrease of mycrodialisate lactate/pyruvate ratios in injuted and preinjured brain tissue only

in combination therapy groupo 26% reduction of mortality in NBH/HBOT group and greater improvement on CGS

compared to controlls

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 arresto Treated with 60 sessions of HBOTo Neuropsychological evaluation (computerized test battery, Activity of Daily Living,

Quality of Life scale)o Comparison of the tests results with neuroimaging data (SPECT)

• The resultso 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

Neuroprotective therapies on functional level

• Neuropsychological training (especially based of memory stimulation)o Increase of neurotrophin level in the braino Improvement of synaptic connectivity and neurons synchronizationo Improvement on cognition and emotion

• Phisical activityo Physical activity supports neuroprotection

and patients condition

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

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)

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 patientso High emotional motivation for therapy continuationo Better compliance

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 panelo Rehabilitation panel (diffrent level of exercisses, possibility to programming individual

sets of excercisses) o Televisits panelo Monitoring of therapy process by specialists o Recording and data visualization and transfer them to the statistic programo Patients may use the cognitive therapy programme after finished HBOT treatment

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 panel SRT, GoNoGo

Please klick the button when green circle appears

Press button only if green scuare appears

Single Reaction Time

GoNoGo Test

n TMT A (25 points) n TMT B (1-13, A-L)

1

2

3

4

56

7

8

START

FINISH

1

A

2

B

3C

4D

START

FINISH

Results: time required to complette both part of the testResults: time required to complette both part of the test

Evaluation panel Trail Making Test

In computed version the touch screen is applied

Evaluation panel Stroop Test

GREEN RED BLUE YELLOW BLACKRED BLACK YELLOW BLUE GREENGREEN YELLOW BLACK RED BLUERED BLACK YELLOW BLUE GREEN

GREEN RED BLUE YELLOW BLACKRED BLACK YELLOW BLUE GREENGREEN YELLOW BLACK RED BLUERED 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 testResults: time required to complette both part of the test

Evaluation panel Visual Working Memory Test

Remember the location of each card

The effect of cognitive rehabilitation in patients after TBI

• 42 patients after at least 1 months after TBIo 29 males, 13 femaleso 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

The results – traditional rehabilitationthe level of improvement (% of change vs

baseline)

TMT A

TMT B

Stroop A

Stroop B

Verbal Fluency

Subjective felling of improvement

Depression

0 5 10 15 20 25 30 35

6 months

3 months

2 months

1 month

The results – tele rehabilitationthe level of improvement (% of change vs

baseline)

TMT A

TMT B

Stroop A

Stroop B

Verbal Fluency

Subjective felling of improvement

Depression

0 10 20 30 40 50 60 70 80

6 months

3 months

2 months

1 month

The comparison of the improvement after 6 months follow-up

(% of change vs baseline)

TMT A

TMT B

Stroo

p A

Stroo

p B

Verba

l Flu

ency

Subje

ctiv

e fe

lling

of i

...

Depre

ssio

n0

1020304050607080 traditional re-

habilitation

telerehabilitation

Differences significant on all parameters

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

Marek WiśniewskiKinga GrobelskaAnna Lipińska

Margaret Niznikiewicz

Mariola WnękArtur Jakubowski

Alina BorkowskaMaciej BielińskiKrzysztof SzwedMartyma Gębska

Marta TomaszewskaGosia Piskunowicz

Joanna UlfigIwona Miklasz