Ignite Creation Date:
2024-05-06 @ 12:51 AM
Last Modification Date:
2024-10-26 @ 10:56 AM
Study NCT ID:
NCT01677429
Status:
UNKNOWN
Last Update Posted:
2015-06-24
First Post:
2012-08-19
Brief Title:
The Assessment and Treatment of Balance Impairment Using Virtual Reality VR in Panic Disorder Patients
Sponsor:
Sheba Medical Center
Organization:
Sheba Medical Center
Study Overview
Official Title:
None
Status:
UNKNOWN
Status Verified Date:
2015-06
Last Known Status:
NOT_YET_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hypotheses
The investigators hypothesize that among individuals who suffer from panic disorder there is higher incidence of co-morbid balance impairment than in the healthy population
The investigators hypothesize that the treatment of panic disorder through the treatment of co-morbid balance impairment using virtual reality VR exposure therapy environment is more effective than the exposure to still pictures from the same scene in VR without balance challenge or comparing to standard cognitive behavioral therapy CBT for the treatment of panic disorder
Rationale
This research relies on previous studies which have shown mutuality between anxiety and balance impairment even if only sub-clinical The VR-based training environment enables multi-sensorial stimulus in a dynamic interactively changing setting With the addition of a cognitive task dual task distracting the fear the investigators can add cognitive load and therefore challenge the control of balance even more Individuals who suffer from balance impairment avoid their exposure to many balance-challenging situations - a fact that may increase their anxiety The investigators assume that a considerable number of PD individuals also experience balance control impairments - mostly subclinical ones Moreover balance impairment accompanies other psychiatric disorders though not enough literature exists on the subject
The investigators hypothesize that among individuals who suffer from panic disorder there is higher incidence of co-morbid balance impairment than in the healthy population
The investigators hypothesize that the treatment of panic disorder through the treatment of co-morbid balance impairment using virtual reality VR exposure therapy environment is more effective than the exposure to still pictures from the same scene in VR without balance challenge or comparing to standard cognitive behavioral therapy CBT for the treatment of panic disorder
Rationale
This research relies on previous studies which have shown mutuality between anxiety and balance impairment even if only sub-clinical The VR-based training environment enables multi-sensorial stimulus in a dynamic interactively changing setting With the addition of a cognitive task dual task distracting the fear the investigators can add cognitive load and therefore challenge the control of balance even more Individuals who suffer from balance impairment avoid their exposure to many balance-challenging situations - a fact that may increase their anxiety The investigators assume that a considerable number of PD individuals also experience balance control impairments - mostly subclinical ones Moreover balance impairment accompanies other psychiatric disorders though not enough literature exists on the subject
Detailed Description:
Introduction
Anxiety disorders are a group of ailments which are characterized by excessive and abnormal vague senses of apprehension followed by stress and restlessness Berrios 1999 As a group anxiety disorders were found to have the highest lifetime prevalence ie they are the most commonly occurring class of mental disorders Kessler et al 2010 with 177 prevalence in a year Kessler et al 2005 This group of disorders consists of five main mental disorders specific phobia obsessive-compulsive post-traumatic stress generalized anxiety and panic disorder - which the investigators will be focusing on
Panic disorder PD is a chronic ailment characterized by spontaneous unexpected occurrence of panic attacks ie periods of intense fear which vary dramatically in the recurrence of panic attacks between patients and within a patient ranging from a few per day to a few per year American Psychiatric Association 2000 PD often occurs in conjunction with agoraphobia ie the fear and avoidance from situations and settings they perceive they have little control on such as public places and suffocating surroundings Kessler et al 2005 PD can reach a lifetime prevalence of 5 Kessler et al 2010 and above Serretti et al 2011 and women are two to three times more likely to be affected than men Schumacher et al 2011 PD mostly develops in young adulthood 25y mean age however this is not mandatory as onset during childhood or early adolescence most likely remains undiagnosed Schumacher et al 2011 Individuals suffering from PD are also said to have a deregulated autonomic nervous system at rest and during orthostatic challenge ie tilt test displayed by heightened heart rate and diastolic blood pressure compared to those of healthy controls Martinez et al 2010
Many years of research have been invested in seek of an association between anxiety or PD and impaired physical balance Perna et al 2001 Sklare et al 2001 Staab and Ruckenstein 2003 Staab 2006 Redfern et al 2007 Many times the treatment of anxiety disorders in general and PD among them which target limbic areas fail to succeed thus it is recommended to treat the comorbid balance impairment which its treatment alone can ameliorate anxiety Shefer et al 2010 Literature on the subject has indicated high prevalence of comorbid balance disorders and anxiety in general Alvord 1991 Balaban and Jacob 2001 Kalueff et al 2008 as well as anxiety disorders specific ranging from agoraphobia panic attack and generalized anxiety Alvord 1991 Balaban and Jacob 2001 Balaban and Thayer 2001 Jacob and Furman 2001 Anxiety in general and PDs are a common co-morbidity in acute and chronic vestibular disorders Eagger et al 1992 Matheson et al 1999 Jacob and Furman 2001 Pollak et al 2003 evolving from vestibular deficiency or sensorimotor disintegration In spite of abundant literature supporting anxiety-imbalance relationship it is still uncertain whether they are causality related
Further investigation on the subject revealed that individuals who suffer from PD may also display altered cognitive patterns Casey et al 2004 Starcevic and Berle 2006 In addition last decade research in the cognitive field has been dedicated to evaluating cerebellar involvement Andreasen and Pierson 2008 Studies in animal models Brodal et al 1991 Dum and Strick 2003 Kelly and Strick 2003 have shown cerebellar connection to the frontal cortex through the pons and thalamus suggesting its participation in neural circuits mediating higher cognitive functions While cerebellar lesions in animals have indicated motor coordination and motor learning impairments Thach 1996 Bastian et al 1998 studies in humans have assigned the cerebellum a role in time intervals perception Akshoomoff and Courchesne 1992 rhythm sequences imitation Fiez et al 1995 and associative learning Attwell et al 2002 Hence the cerebellum seems to act as a modulator of cognitive processes performed by the cerebral cortex which detects patterns and pattern changes as well as errors in both motor and cognitive functions and feedbacks the cerebrum Andreasen and Pierson 2008
Further support for this association lies in the theory of learning Erez et al Erez et al 2004 present a three-stage of learning theory which includes an acquisition stage and two distinct stages of conditioned response CR the emotional CR driven by the autonomic and hormonal systems is fast and non-specific and the motor CR provides an effective CR and is slow but specific Despite the apparent differences these two stages seem to be highly interrelated as can be explained by a frightening stimulus fear CRs are acquired emotional fear CRs take over and promote motor CRs Contrariwise fear CRs may take over if a subclinical balance disorder exists it could be postulated that intervention of balance may reduce PD
Balance maintenance itself occurs automatically and is involved in the execution of basic motions which enable daily life activities Keshner 1994 Kurtzer et al 2005 as well as high performance skills such as ballet Koutedakis and Jamurtas 2004 and athletics Hrysomallis 2011 Normally once a balance task becomes automatic voluntary or cognitive action are enabled without a trade-off Adi-Japha et al 2008 The success of performing any motor task lies on the ability to conduct task-related voluntary movements on top of constant involuntary postural adjustments Keshner 1994 Kurtzer et al 2005 Thus each task-related maneuver involves the contraction of muscles in the limbs and trunk for the maintenance of body stability Balance maintenance also requires constant integration between sensory input coming from vestibular visual somatosensory mainly proprioceptive channels and the motor system Shefer et al 2010 Converging from different sensory sources this system addresses various balance maintenance aspects Massion and Woollacott 1996 and so the loss of sensory input from either one can result in the alteration of posture Le and Kapoula 2008
Impaired vestibular function causes imbalance nausea vertigo and abnormal eye movements Gilman and Newman 1996 and hinders the acquisition and emission of corrective movements Such occasions are associated with limbic-related anxiety perhaps through the parabrachial circuit Balaban and Thayer 2001 The parabrachial nucleus PBN is reciprocally connected with the spinal cord hypothalamus amygdala and limbic cortex and thus receives vestibular nuclear and visceral afferent information therefore links vestibulo-visceral integrations especially in the adjustment to gravito-inertial challenges In a recent study evaluating vestibular mutation in mice it was found that an elevated plus-maze platform and an open-field test contributed greatly to anxiety levels Shefer et al 2010 While under rotation extra-cellular recordings gave support to vestibulo-recipient areas of the PBN integrate signals from the vestibular nuclei and convey information about whole-bodys orientation to pathways that produce homeostatic and affective responses Balaban et al 2002 giving further support to panic and impaired balance co-morbidity
Individuals who suffer from vestibular or balance disorders many times demonstrate symptoms of anxiety and conversely patients with anxiety disorders often show abnormalities of clinical balance or vestibular function tests Bronstein et al 2004 Furman et al 2005 Perna et al Perna et al 2001 showed that PD patients demonstrate larger velocity and length in body sway in comparison to healthy controls An additional study measured postural sway in anxiety patients as a response to a moving visual environment and found greater sway among the anxiety group comparing to the healthy controls Redfern et al 2007 A Parkinsons disease study has shown that in most cases they did not suffer from a specific vestibular disease but do have subclinical abnormalities of the balance system These patients control their posture relying on non-vestibular cues proprioceptive and mostly visual input Staab 2006 Caldirola et al 2011
Despite some considerable evidence in the literature it is still difficult to isolate and verify balance impairment in PD Thus the investigators propose the implementation of virtual reality exposure therapy The term virtual reality VR refers to the use of an interactive computerized environment software and hardware simulating real world settings which enable the immersion of the individual in trial Weiss et al 2005 With its high sensitivity it is possible to create an environment where the individual is gradually led into a motivating and challenging environment which requires his her alertness and physical attendance rather than imaginational capabilities Within the VR it is possible to design a setting that consists of motivational and challenging elements which indicate for the individual regarding his her own capability and competence in contrast to his her impotence and passiveness and from the amended experience triumph is achieved In addition the therapist has the unique opportunity to be part of that environment in real-time and straightforward
VR exposes the examinee as well as the therapist to salient components of the panic evoking situation and by visual auditory and motor elements the stressing environment is reconstructed and reveals its panic-provoking roots Roy et al 2010 VR exposure enables the identification of intimidating moments as well as confident ones providing the examinee with a competing instrument to deal with the stressing moments while allowing the environment to change and adjust exposure levels and challenge the examinee Wiederhold and Wiederhold 2010 VR exposure is done in laboratory conditions and under full supervision thus it addresses individuals who are physically incapable of outdoors training as well All in all the utilization of the VR method allows the employment of a stepwise exposure approach which is made by computerized and human fine-tuned modifications of the scene Wiederhold and Wiederhold 2010
Furthermore VR exposure therapy in practice for more than twenty years supports the learning and training of neuro-motor tasks such as in flight ski and surgery simulators During the last few years VR exposure method has made its way to clinical utilization in rehabilitation centers and hospitals where balance and motor control are the main focus Roy et al 2010 The exposure to VR may contribute from several aspects which are out of the reach of conventional therapy methods VR exposure therapy provides an innovative and exceptional opportunity to reconstruct the scene and setting which lead to panic behavior and expose the examinee to critical factors consisting of the panic root Altogether VR systems enable the learning of simple and complex skills in a controlled environment due to the endowment of monitored graded and adapted exposure of the various components constructing the therapy in a systematic manner Rizzo et al 1997a Rizzo et al 1997b Schultheis and Rizzo 2001 Merians et al 2002 Deutsch et al 2004 Weiss et al 2005
Using VR balance performance is evaluated precisely and efficiently by measuring body sway during quiet standing and during a few sets of perturbations Nashner 1976 Allum and Carpenter 2005 The measured factor is the displacement of the center of pressure CoP ie a point at which a counter-reaction force vector of the vertical ground is applied This force vector represents a weighted average of the pressure vectors of each foot on the force plates Winter et al 1990 Winter 1995 The CoP is a dynamic factor and displaces a few centimeters within a plane constantly Winter 1995 Winter et al 1996 Body sway is a kinematic term and is often estimated from the CoP displacement in the anterior-posterior and medio-lateral axes which is derived from force plate data and is assumed to be synonymous with the CoP measure Winter et al 1998
Balance maintenance and postural adjustments are modified by repeating experiences and improve with practice Pollock et al 2000 less muscles are recruited and responses refine and become subtle Horak and Nashner 1986 Horak et al 1989 Chong et al 1999 Besides physical conditions balance maintenance depends also on cognitive aspects such as attention memory and dual tasking Plotnik et al Plotnik et al 2011 showed a relationship between dual tasking abilities and fall risk in patients suffering from Parkinsons disease suggesting that Parkinsonian fallers are easily affected by dual tasking with a great likelihood of loss of balance during the execution of daily attention-drawing activities Thus motor skills ranging form very simple to most complex ones can be performed and monitored for the characterization of learning processes and training in virtual environments provides the opportunity to study learning skills and build learning curves Holden 2005 Carelli et al 2009 During VR complete movement sequences are recorded as a pattern allowing full investigation motor skills which is important in accordance with the notion that motor skill learning is task specific Karni et al 1998 Korman et al 2007
Many researches have recognized the potential of using VR in clinical treatment of psychopathologies especially in the anxiety field Some evidence on the application of VR exposure therapy to the treatment of specific phobias and PD can be recently found in the literature Botella et al 2004 Pull and Damsa 2008 de Carvalho et al 2010 Gerardi et al 2010 Meyerbroker and Emmelkamp 2010 Perez-Ara et al 2010 Meyerbroker et al 2011 A Belgian research studying motor vehicle accident trauma examinees showed that the use of VR was the most efficient method in treating phobias and that VR exposure provided a safe controlled therapeutic environment unrelated to treatment circumstances Wiederhold and Wiederhold 2010 Therefore VR exposure is applied interactively since there is more value to an exposure where the examinee is active and the environment is dynamic and challenging as exposure of this nature enhances alertness and emotional excitement which are valuable to the treatments success The investigators will examine prevalence and severity in PD patients taking into consideration that they have higher prevalence of balance impairment
The implementation of the VR method involves research and development costs as well as maintenance ones and sometimes technical impediments may take place due to the relying on advanced and multisensory method VR method calls for the recruitment of a technician beyond the professional therapist which will be thoroughly trained and will operate a large number of software test-runs pilots before introducing it to patients The common belief that multisensory exposure triggering several systems at the same time distract the examinees mind and prevent him her to be fully immersed Roy et al 2010 is refuted In Sheba Rehabilitation Center for Advanced Technologies there is a VR laboratory running for years enabling the rapid and successful rehabilitation of many patients Salient and relevant specification of the VR laboratory can be adjusted to the treatment of balance disorder and panic The investigators intend to implement VR method in the treatment of balance disorder patients and to investigate its role in ameliorating panic behavior The investigators further hypothesize that VR treatment can aid patients with challenging situations and improve neuro-motor functioning and thus better management in their everyday experiences
Objectives
Stage 1 evaluation - to investigate whether there is balance impairment within PD patients in comparison to matched healthy subjects
Stage 2 treatment - to investigate whether balance training using VR exposure therapy is significantly more effective in reducing panic symptoms than the exposure to still pictures from the same scene without balance challenge or from CBT standard protocol for the treatment of PD
Study population
Stage 1 Sixty PD patients men and women at the age of 18-45 will be recruited from Sheba Medical Center psychiatric clinics and an ad PD will be assessed using SCID-1 checklist Patients and 20 healthy controls matched by age sex and BMI will complete the MINI
Stage 2 The same 60 PD patients will be randomized to three treatment groups 1 20 through VR-based balance training 2 20 through exposure to still pictures from the same VR scene but no balance challenge 3 20 through CBT for PD
Ethics
The following study includes a neurological examination which focuses on balance assessment based on questionnaires and a psychiatric examination for PD diagnosis In addition this research exposes the participants to a medical device VR which has been certified by the FDA and has received the Israeli Ministry of Health approval This advanced method is used daily at the Advanced Technologies Department of the Rehabilitation Hospital at Sheba Medical Center Furthermore the identification and contact details of patients and healthy controls will be encoded to follow anonymity
Methods
Stage 1 The investigators will collect demographic data such as age sex and education basic information such as height and weight for BMI calculation for the matching with healthy controls The investigators will also collect medical history and concomitant medicine clinical state as well as general morbidity and sports-related questions
Stage 2 The investigators will ask the participants of this research not to take any part in psychotherapeutic treatment apart from the ones in this study
Panic Disorder Diagnosis
Patients who participate will be diagnosed using the SCID-1 checklist and MINI for PD diagnosis and CGI In addition the participants will go through the following for the assessment of PD severity and functionality under panic attacks
Hamilton Rating Scale for Anxiety HAM-A
Panic Disorder Severity Scale PDSS
Panic and Agoraphobia Scale PAS In addition the investigators will use visual analogue scale VAS for the assessment of the panic severity level from one week to the other will be applied in each visit
Balance Assessment
Participants who are recruited will pass a neurological examination which includes a thorough balance assessment Within this assessment the investigators will implement two self-rating questionnaires Dizziness Handicap Inventory and the The Activities-specific Balance Confidence ABC Scale as well as the functional assessment tools implemented by the neurologist
Berg Balance Scale
Dynamic Gait Index DGI
Functional Gait Assessment FGA Additionally objective balance assessment will be done using VR as given in the detailed description
Physiological measures
The investigators will also collect the following measures blood pressure Galvanic Skin Conductance and Heart Rate
CAREN system
The VR system the investigators will be using is the CAREN Computer Assisted Rehabilitation Environment Integrated Reality System using the CAREN III software This system is designed by MOTEK BV Amsterdam The Netherlands wwwmotekmedicalcom This system works in real-time and enables the creation of a variety of controlled and repeatable simulated environments via dedicated software with 3D visual sound and proprioceptive stimuli It consists of the following components
Motion Platform - CAREN consists of an electro-hydraulic motion 2 meter diameter motion platform Rexroth Hydraudyne MOTEK Micro motion wwwrexroth-hydraudynecom that can be manipulated with 6 degrees of freedom x-y-z translation and pitch-roll-yaw rotation The movement of the platform is either driven by the subjects movements or preprogrammed in synchrony with function curves that define a specific pathway in the virtual environment
Force Plates - Two 51 47 centimeter force plates AMTI - Advanced Mechanical Technology INC Massachusetts USA wwwamtiwebcom are embedded in the motion platform The output of the force plates is three dimensional force and moment data from each platform as well as the CoP displacement
Motion Capture - Up to 41 passive markers are placed on anatomical landmarks and sampled at 120 Hz to record 3D head trunk and limb motion The markers are detected by an optokinetic system which consists of 12 Vicon infra-red cameras having a resolution of 2 megapixels wwwviconcom
Projection The Virtual scene is projected on a large screen 3m 25m Stereo projection may be used
The Road scene In a virtual reality setting standing on a moving platform subjects were required to maintain their balance while advancing along a pre-defined road the road scene The scene was projected onto a large screen in front of the subject The scene consisted of a virtual road bounded on both sides by walls The road itself had flat straight sections vertical bumpy sections movement along the y-axis right and left tilts rotation of z axis - roll and right and left translations movement along the x axis - sway The platforms movement was correlated with the visual stimulus ie when the subject arrived at a bump on the screen the platform elevated When the road tilted the platform tilted accordingly in the same direction The length of the road is 1230m The roads velocity was 30 msec which equals to 18 kmmin or 108 kmh The specific parameters of the platform excursions in the X pitch and Z axis will be determined following a pilot study
The Road scene with an additional task The voluntary secondary task consisted of intercepting 18 moving targets colored ball of 125 cm diameter appearing above the road Each target could be intercepted when appearing no further than 20 cm from the subjects hands which are reflected on the screen as a 45 cm in diameter ball The targets appear one at a time at pre-set points along the road alternately on the right and left sides of the subjects body Each ball is displayed for 5 seconds from its appearance and then disappears unless it has been intercepted After intercepting a target the subject was instructed to return to the home position
On either of the scenes the challenge level may be heightened by increasing the platforms tilt
Study Protocol
Stage 1 A 3-4 hours introductory meeting will take place and will include a couple of hours assessment using the SCID-1 checklist for the diagnosis of PD as well as the implementation of the MINI for psychopathology elimination A general neurological examination for both healthy controls and PD patients will include functional balance assessment and self-rating questionnaires VR-based evaluation of objective measures of balance maintenance described in detail VR exposure will be done in three consecutive exposures a VR road scene movie only - in case the movie itself evokes anxiety and panic symptoms b balance training using VR no movie c movie balance challenge
The evaluation will be done in conditions such as entering a dark closed room assuring the minimum of anxiety is evoked Therefore the investigators will take VAS subjective report and physiological measurements from the participant for cardio-vascular fluent monitoring
Stage 2 The same 60 PD patients will be randomized to three treatment groups 1 20 through VR-based balance training 2 20 through exposure to still pictures from the same VR scene but no balance challenge 3 20 through CBT for PD At this stage too the investigators will use VAS subjective report of the panic levels during the last week as well as objective physiological measurements at each visit
In addition to the neurologist and psychiatrist at the 5th and last visits there will be a CAREN specialist and a physiotherapist from the VR crew in each visit
1 Protocol of imbalance treatment using VR exposure therapy 10 visits 9 visits of VR-training with without parallel task road scene repeating which takes 24 minutes including preparation and the installment of up to 41 sensors 45 minutes per visit The challenge increases if possible and will consist of sharp slopes and bumpy roads and or cognitive load additional task In addition specific balance parameters will be collected HR GSC and a physiological examination and a verbal conversation at the end of each visit will take place and inform the participant on his her improvement
During the 5th visit there will be another psychiatric evaluation using the same questionnaires and assessment tools
Last visit a summary meeting with no VR exposure The investigators will implement all the assessment tools and questionnaires as well as a neurological examination In this visit the investigators will repeat sway and perturbation measurements and will make a summary
2 Protocol of imbalance treatment using VR exposure therapy 10 visits 9 visits of exposure to still pictures from the same VR scene still pictures in a loop which takes 24 minutes including preparation and the installment of up to 41 sensors 45 minutes per visit In addition specific balance parameters will be collected HR GSC and a physiological examination and a verbal conversation at the end of each visit will take place and inform the participant on his her improvement
During the 5th visit there will be another psychiatric evaluation using the same questionnaires and assessment tools
Last visit a summary meeting with no VR exposure The investigators will implement all the assessment tools and questionnaires as well as a neurological examination In this visit the investigators will repeat sway and perturbation measurements and will make a summary
3 CBT standard protocol for the treatment of PD 10 visits A CBT standard protocol for the treatment of PD will be applied in all 10 visits Each visit will last 1 hour except for the 5th and last visits which include a psychiatric assessment using the same evaluation scales and questionnaires as in the evaluation and therefore will last 15 hours CBT will be implemented by a therapist ie a psychologist or psychiatrist trained for the treatment of panic disorder The therapist evokes emotional feelings such as vulnerability disappointment frustration joy etc This supportive therapy helps the individual to normalize his her behavior at the time of a panic-evoking situation and thereafter The therapist tries to lead the individual to self-empowerment by providing him her self-defense mechanisms and inner-strengthening tools
Handling the Data
The investigators will assure anonymity of all data collected and medical discretion
Length of Study
Stage 1 The investigators intend to interview 60 participants in order to recruit 60 PD patients and at the same time the investigators will interview 20 matched healthy controls
Stage 2
The same 60 PD patients from Stage 1 will participate in a 10-12 weeks experiment In addition there will be a follow-up within 6 months and 12 months from end of trial when the participants will be asked to fill assessment questionnaires regarding their PD
Statistical Analysis
The investigators will test for normal distribution of the dependent variables and then will examine the differences between the groups using univariate analyses for continuous independent variables such as scores the investigators will apply t-test and for categorical variables such as sex - chi square All using SPSS software
Any data to be collected during this study will be used for research purposes only and does not have diagnostic significance at the moment However this study may have clinical realizations and application in the future Should the investigators have important findings this research group has intentions to publish them
Anxiety disorders are a group of ailments which are characterized by excessive and abnormal vague senses of apprehension followed by stress and restlessness Berrios 1999 As a group anxiety disorders were found to have the highest lifetime prevalence ie they are the most commonly occurring class of mental disorders Kessler et al 2010 with 177 prevalence in a year Kessler et al 2005 This group of disorders consists of five main mental disorders specific phobia obsessive-compulsive post-traumatic stress generalized anxiety and panic disorder - which the investigators will be focusing on
Panic disorder PD is a chronic ailment characterized by spontaneous unexpected occurrence of panic attacks ie periods of intense fear which vary dramatically in the recurrence of panic attacks between patients and within a patient ranging from a few per day to a few per year American Psychiatric Association 2000 PD often occurs in conjunction with agoraphobia ie the fear and avoidance from situations and settings they perceive they have little control on such as public places and suffocating surroundings Kessler et al 2005 PD can reach a lifetime prevalence of 5 Kessler et al 2010 and above Serretti et al 2011 and women are two to three times more likely to be affected than men Schumacher et al 2011 PD mostly develops in young adulthood 25y mean age however this is not mandatory as onset during childhood or early adolescence most likely remains undiagnosed Schumacher et al 2011 Individuals suffering from PD are also said to have a deregulated autonomic nervous system at rest and during orthostatic challenge ie tilt test displayed by heightened heart rate and diastolic blood pressure compared to those of healthy controls Martinez et al 2010
Many years of research have been invested in seek of an association between anxiety or PD and impaired physical balance Perna et al 2001 Sklare et al 2001 Staab and Ruckenstein 2003 Staab 2006 Redfern et al 2007 Many times the treatment of anxiety disorders in general and PD among them which target limbic areas fail to succeed thus it is recommended to treat the comorbid balance impairment which its treatment alone can ameliorate anxiety Shefer et al 2010 Literature on the subject has indicated high prevalence of comorbid balance disorders and anxiety in general Alvord 1991 Balaban and Jacob 2001 Kalueff et al 2008 as well as anxiety disorders specific ranging from agoraphobia panic attack and generalized anxiety Alvord 1991 Balaban and Jacob 2001 Balaban and Thayer 2001 Jacob and Furman 2001 Anxiety in general and PDs are a common co-morbidity in acute and chronic vestibular disorders Eagger et al 1992 Matheson et al 1999 Jacob and Furman 2001 Pollak et al 2003 evolving from vestibular deficiency or sensorimotor disintegration In spite of abundant literature supporting anxiety-imbalance relationship it is still uncertain whether they are causality related
Further investigation on the subject revealed that individuals who suffer from PD may also display altered cognitive patterns Casey et al 2004 Starcevic and Berle 2006 In addition last decade research in the cognitive field has been dedicated to evaluating cerebellar involvement Andreasen and Pierson 2008 Studies in animal models Brodal et al 1991 Dum and Strick 2003 Kelly and Strick 2003 have shown cerebellar connection to the frontal cortex through the pons and thalamus suggesting its participation in neural circuits mediating higher cognitive functions While cerebellar lesions in animals have indicated motor coordination and motor learning impairments Thach 1996 Bastian et al 1998 studies in humans have assigned the cerebellum a role in time intervals perception Akshoomoff and Courchesne 1992 rhythm sequences imitation Fiez et al 1995 and associative learning Attwell et al 2002 Hence the cerebellum seems to act as a modulator of cognitive processes performed by the cerebral cortex which detects patterns and pattern changes as well as errors in both motor and cognitive functions and feedbacks the cerebrum Andreasen and Pierson 2008
Further support for this association lies in the theory of learning Erez et al Erez et al 2004 present a three-stage of learning theory which includes an acquisition stage and two distinct stages of conditioned response CR the emotional CR driven by the autonomic and hormonal systems is fast and non-specific and the motor CR provides an effective CR and is slow but specific Despite the apparent differences these two stages seem to be highly interrelated as can be explained by a frightening stimulus fear CRs are acquired emotional fear CRs take over and promote motor CRs Contrariwise fear CRs may take over if a subclinical balance disorder exists it could be postulated that intervention of balance may reduce PD
Balance maintenance itself occurs automatically and is involved in the execution of basic motions which enable daily life activities Keshner 1994 Kurtzer et al 2005 as well as high performance skills such as ballet Koutedakis and Jamurtas 2004 and athletics Hrysomallis 2011 Normally once a balance task becomes automatic voluntary or cognitive action are enabled without a trade-off Adi-Japha et al 2008 The success of performing any motor task lies on the ability to conduct task-related voluntary movements on top of constant involuntary postural adjustments Keshner 1994 Kurtzer et al 2005 Thus each task-related maneuver involves the contraction of muscles in the limbs and trunk for the maintenance of body stability Balance maintenance also requires constant integration between sensory input coming from vestibular visual somatosensory mainly proprioceptive channels and the motor system Shefer et al 2010 Converging from different sensory sources this system addresses various balance maintenance aspects Massion and Woollacott 1996 and so the loss of sensory input from either one can result in the alteration of posture Le and Kapoula 2008
Impaired vestibular function causes imbalance nausea vertigo and abnormal eye movements Gilman and Newman 1996 and hinders the acquisition and emission of corrective movements Such occasions are associated with limbic-related anxiety perhaps through the parabrachial circuit Balaban and Thayer 2001 The parabrachial nucleus PBN is reciprocally connected with the spinal cord hypothalamus amygdala and limbic cortex and thus receives vestibular nuclear and visceral afferent information therefore links vestibulo-visceral integrations especially in the adjustment to gravito-inertial challenges In a recent study evaluating vestibular mutation in mice it was found that an elevated plus-maze platform and an open-field test contributed greatly to anxiety levels Shefer et al 2010 While under rotation extra-cellular recordings gave support to vestibulo-recipient areas of the PBN integrate signals from the vestibular nuclei and convey information about whole-bodys orientation to pathways that produce homeostatic and affective responses Balaban et al 2002 giving further support to panic and impaired balance co-morbidity
Individuals who suffer from vestibular or balance disorders many times demonstrate symptoms of anxiety and conversely patients with anxiety disorders often show abnormalities of clinical balance or vestibular function tests Bronstein et al 2004 Furman et al 2005 Perna et al Perna et al 2001 showed that PD patients demonstrate larger velocity and length in body sway in comparison to healthy controls An additional study measured postural sway in anxiety patients as a response to a moving visual environment and found greater sway among the anxiety group comparing to the healthy controls Redfern et al 2007 A Parkinsons disease study has shown that in most cases they did not suffer from a specific vestibular disease but do have subclinical abnormalities of the balance system These patients control their posture relying on non-vestibular cues proprioceptive and mostly visual input Staab 2006 Caldirola et al 2011
Despite some considerable evidence in the literature it is still difficult to isolate and verify balance impairment in PD Thus the investigators propose the implementation of virtual reality exposure therapy The term virtual reality VR refers to the use of an interactive computerized environment software and hardware simulating real world settings which enable the immersion of the individual in trial Weiss et al 2005 With its high sensitivity it is possible to create an environment where the individual is gradually led into a motivating and challenging environment which requires his her alertness and physical attendance rather than imaginational capabilities Within the VR it is possible to design a setting that consists of motivational and challenging elements which indicate for the individual regarding his her own capability and competence in contrast to his her impotence and passiveness and from the amended experience triumph is achieved In addition the therapist has the unique opportunity to be part of that environment in real-time and straightforward
VR exposes the examinee as well as the therapist to salient components of the panic evoking situation and by visual auditory and motor elements the stressing environment is reconstructed and reveals its panic-provoking roots Roy et al 2010 VR exposure enables the identification of intimidating moments as well as confident ones providing the examinee with a competing instrument to deal with the stressing moments while allowing the environment to change and adjust exposure levels and challenge the examinee Wiederhold and Wiederhold 2010 VR exposure is done in laboratory conditions and under full supervision thus it addresses individuals who are physically incapable of outdoors training as well All in all the utilization of the VR method allows the employment of a stepwise exposure approach which is made by computerized and human fine-tuned modifications of the scene Wiederhold and Wiederhold 2010
Furthermore VR exposure therapy in practice for more than twenty years supports the learning and training of neuro-motor tasks such as in flight ski and surgery simulators During the last few years VR exposure method has made its way to clinical utilization in rehabilitation centers and hospitals where balance and motor control are the main focus Roy et al 2010 The exposure to VR may contribute from several aspects which are out of the reach of conventional therapy methods VR exposure therapy provides an innovative and exceptional opportunity to reconstruct the scene and setting which lead to panic behavior and expose the examinee to critical factors consisting of the panic root Altogether VR systems enable the learning of simple and complex skills in a controlled environment due to the endowment of monitored graded and adapted exposure of the various components constructing the therapy in a systematic manner Rizzo et al 1997a Rizzo et al 1997b Schultheis and Rizzo 2001 Merians et al 2002 Deutsch et al 2004 Weiss et al 2005
Using VR balance performance is evaluated precisely and efficiently by measuring body sway during quiet standing and during a few sets of perturbations Nashner 1976 Allum and Carpenter 2005 The measured factor is the displacement of the center of pressure CoP ie a point at which a counter-reaction force vector of the vertical ground is applied This force vector represents a weighted average of the pressure vectors of each foot on the force plates Winter et al 1990 Winter 1995 The CoP is a dynamic factor and displaces a few centimeters within a plane constantly Winter 1995 Winter et al 1996 Body sway is a kinematic term and is often estimated from the CoP displacement in the anterior-posterior and medio-lateral axes which is derived from force plate data and is assumed to be synonymous with the CoP measure Winter et al 1998
Balance maintenance and postural adjustments are modified by repeating experiences and improve with practice Pollock et al 2000 less muscles are recruited and responses refine and become subtle Horak and Nashner 1986 Horak et al 1989 Chong et al 1999 Besides physical conditions balance maintenance depends also on cognitive aspects such as attention memory and dual tasking Plotnik et al Plotnik et al 2011 showed a relationship between dual tasking abilities and fall risk in patients suffering from Parkinsons disease suggesting that Parkinsonian fallers are easily affected by dual tasking with a great likelihood of loss of balance during the execution of daily attention-drawing activities Thus motor skills ranging form very simple to most complex ones can be performed and monitored for the characterization of learning processes and training in virtual environments provides the opportunity to study learning skills and build learning curves Holden 2005 Carelli et al 2009 During VR complete movement sequences are recorded as a pattern allowing full investigation motor skills which is important in accordance with the notion that motor skill learning is task specific Karni et al 1998 Korman et al 2007
Many researches have recognized the potential of using VR in clinical treatment of psychopathologies especially in the anxiety field Some evidence on the application of VR exposure therapy to the treatment of specific phobias and PD can be recently found in the literature Botella et al 2004 Pull and Damsa 2008 de Carvalho et al 2010 Gerardi et al 2010 Meyerbroker and Emmelkamp 2010 Perez-Ara et al 2010 Meyerbroker et al 2011 A Belgian research studying motor vehicle accident trauma examinees showed that the use of VR was the most efficient method in treating phobias and that VR exposure provided a safe controlled therapeutic environment unrelated to treatment circumstances Wiederhold and Wiederhold 2010 Therefore VR exposure is applied interactively since there is more value to an exposure where the examinee is active and the environment is dynamic and challenging as exposure of this nature enhances alertness and emotional excitement which are valuable to the treatments success The investigators will examine prevalence and severity in PD patients taking into consideration that they have higher prevalence of balance impairment
The implementation of the VR method involves research and development costs as well as maintenance ones and sometimes technical impediments may take place due to the relying on advanced and multisensory method VR method calls for the recruitment of a technician beyond the professional therapist which will be thoroughly trained and will operate a large number of software test-runs pilots before introducing it to patients The common belief that multisensory exposure triggering several systems at the same time distract the examinees mind and prevent him her to be fully immersed Roy et al 2010 is refuted In Sheba Rehabilitation Center for Advanced Technologies there is a VR laboratory running for years enabling the rapid and successful rehabilitation of many patients Salient and relevant specification of the VR laboratory can be adjusted to the treatment of balance disorder and panic The investigators intend to implement VR method in the treatment of balance disorder patients and to investigate its role in ameliorating panic behavior The investigators further hypothesize that VR treatment can aid patients with challenging situations and improve neuro-motor functioning and thus better management in their everyday experiences
Objectives
Stage 1 evaluation - to investigate whether there is balance impairment within PD patients in comparison to matched healthy subjects
Stage 2 treatment - to investigate whether balance training using VR exposure therapy is significantly more effective in reducing panic symptoms than the exposure to still pictures from the same scene without balance challenge or from CBT standard protocol for the treatment of PD
Study population
Stage 1 Sixty PD patients men and women at the age of 18-45 will be recruited from Sheba Medical Center psychiatric clinics and an ad PD will be assessed using SCID-1 checklist Patients and 20 healthy controls matched by age sex and BMI will complete the MINI
Stage 2 The same 60 PD patients will be randomized to three treatment groups 1 20 through VR-based balance training 2 20 through exposure to still pictures from the same VR scene but no balance challenge 3 20 through CBT for PD
Ethics
The following study includes a neurological examination which focuses on balance assessment based on questionnaires and a psychiatric examination for PD diagnosis In addition this research exposes the participants to a medical device VR which has been certified by the FDA and has received the Israeli Ministry of Health approval This advanced method is used daily at the Advanced Technologies Department of the Rehabilitation Hospital at Sheba Medical Center Furthermore the identification and contact details of patients and healthy controls will be encoded to follow anonymity
Methods
Stage 1 The investigators will collect demographic data such as age sex and education basic information such as height and weight for BMI calculation for the matching with healthy controls The investigators will also collect medical history and concomitant medicine clinical state as well as general morbidity and sports-related questions
Stage 2 The investigators will ask the participants of this research not to take any part in psychotherapeutic treatment apart from the ones in this study
Panic Disorder Diagnosis
Patients who participate will be diagnosed using the SCID-1 checklist and MINI for PD diagnosis and CGI In addition the participants will go through the following for the assessment of PD severity and functionality under panic attacks
Hamilton Rating Scale for Anxiety HAM-A
Panic Disorder Severity Scale PDSS
Panic and Agoraphobia Scale PAS In addition the investigators will use visual analogue scale VAS for the assessment of the panic severity level from one week to the other will be applied in each visit
Balance Assessment
Participants who are recruited will pass a neurological examination which includes a thorough balance assessment Within this assessment the investigators will implement two self-rating questionnaires Dizziness Handicap Inventory and the The Activities-specific Balance Confidence ABC Scale as well as the functional assessment tools implemented by the neurologist
Berg Balance Scale
Dynamic Gait Index DGI
Functional Gait Assessment FGA Additionally objective balance assessment will be done using VR as given in the detailed description
Physiological measures
The investigators will also collect the following measures blood pressure Galvanic Skin Conductance and Heart Rate
CAREN system
The VR system the investigators will be using is the CAREN Computer Assisted Rehabilitation Environment Integrated Reality System using the CAREN III software This system is designed by MOTEK BV Amsterdam The Netherlands wwwmotekmedicalcom This system works in real-time and enables the creation of a variety of controlled and repeatable simulated environments via dedicated software with 3D visual sound and proprioceptive stimuli It consists of the following components
Motion Platform - CAREN consists of an electro-hydraulic motion 2 meter diameter motion platform Rexroth Hydraudyne MOTEK Micro motion wwwrexroth-hydraudynecom that can be manipulated with 6 degrees of freedom x-y-z translation and pitch-roll-yaw rotation The movement of the platform is either driven by the subjects movements or preprogrammed in synchrony with function curves that define a specific pathway in the virtual environment
Force Plates - Two 51 47 centimeter force plates AMTI - Advanced Mechanical Technology INC Massachusetts USA wwwamtiwebcom are embedded in the motion platform The output of the force plates is three dimensional force and moment data from each platform as well as the CoP displacement
Motion Capture - Up to 41 passive markers are placed on anatomical landmarks and sampled at 120 Hz to record 3D head trunk and limb motion The markers are detected by an optokinetic system which consists of 12 Vicon infra-red cameras having a resolution of 2 megapixels wwwviconcom
Projection The Virtual scene is projected on a large screen 3m 25m Stereo projection may be used
The Road scene In a virtual reality setting standing on a moving platform subjects were required to maintain their balance while advancing along a pre-defined road the road scene The scene was projected onto a large screen in front of the subject The scene consisted of a virtual road bounded on both sides by walls The road itself had flat straight sections vertical bumpy sections movement along the y-axis right and left tilts rotation of z axis - roll and right and left translations movement along the x axis - sway The platforms movement was correlated with the visual stimulus ie when the subject arrived at a bump on the screen the platform elevated When the road tilted the platform tilted accordingly in the same direction The length of the road is 1230m The roads velocity was 30 msec which equals to 18 kmmin or 108 kmh The specific parameters of the platform excursions in the X pitch and Z axis will be determined following a pilot study
The Road scene with an additional task The voluntary secondary task consisted of intercepting 18 moving targets colored ball of 125 cm diameter appearing above the road Each target could be intercepted when appearing no further than 20 cm from the subjects hands which are reflected on the screen as a 45 cm in diameter ball The targets appear one at a time at pre-set points along the road alternately on the right and left sides of the subjects body Each ball is displayed for 5 seconds from its appearance and then disappears unless it has been intercepted After intercepting a target the subject was instructed to return to the home position
On either of the scenes the challenge level may be heightened by increasing the platforms tilt
Study Protocol
Stage 1 A 3-4 hours introductory meeting will take place and will include a couple of hours assessment using the SCID-1 checklist for the diagnosis of PD as well as the implementation of the MINI for psychopathology elimination A general neurological examination for both healthy controls and PD patients will include functional balance assessment and self-rating questionnaires VR-based evaluation of objective measures of balance maintenance described in detail VR exposure will be done in three consecutive exposures a VR road scene movie only - in case the movie itself evokes anxiety and panic symptoms b balance training using VR no movie c movie balance challenge
The evaluation will be done in conditions such as entering a dark closed room assuring the minimum of anxiety is evoked Therefore the investigators will take VAS subjective report and physiological measurements from the participant for cardio-vascular fluent monitoring
Stage 2 The same 60 PD patients will be randomized to three treatment groups 1 20 through VR-based balance training 2 20 through exposure to still pictures from the same VR scene but no balance challenge 3 20 through CBT for PD At this stage too the investigators will use VAS subjective report of the panic levels during the last week as well as objective physiological measurements at each visit
In addition to the neurologist and psychiatrist at the 5th and last visits there will be a CAREN specialist and a physiotherapist from the VR crew in each visit
1 Protocol of imbalance treatment using VR exposure therapy 10 visits 9 visits of VR-training with without parallel task road scene repeating which takes 24 minutes including preparation and the installment of up to 41 sensors 45 minutes per visit The challenge increases if possible and will consist of sharp slopes and bumpy roads and or cognitive load additional task In addition specific balance parameters will be collected HR GSC and a physiological examination and a verbal conversation at the end of each visit will take place and inform the participant on his her improvement
During the 5th visit there will be another psychiatric evaluation using the same questionnaires and assessment tools
Last visit a summary meeting with no VR exposure The investigators will implement all the assessment tools and questionnaires as well as a neurological examination In this visit the investigators will repeat sway and perturbation measurements and will make a summary
2 Protocol of imbalance treatment using VR exposure therapy 10 visits 9 visits of exposure to still pictures from the same VR scene still pictures in a loop which takes 24 minutes including preparation and the installment of up to 41 sensors 45 minutes per visit In addition specific balance parameters will be collected HR GSC and a physiological examination and a verbal conversation at the end of each visit will take place and inform the participant on his her improvement
During the 5th visit there will be another psychiatric evaluation using the same questionnaires and assessment tools
Last visit a summary meeting with no VR exposure The investigators will implement all the assessment tools and questionnaires as well as a neurological examination In this visit the investigators will repeat sway and perturbation measurements and will make a summary
3 CBT standard protocol for the treatment of PD 10 visits A CBT standard protocol for the treatment of PD will be applied in all 10 visits Each visit will last 1 hour except for the 5th and last visits which include a psychiatric assessment using the same evaluation scales and questionnaires as in the evaluation and therefore will last 15 hours CBT will be implemented by a therapist ie a psychologist or psychiatrist trained for the treatment of panic disorder The therapist evokes emotional feelings such as vulnerability disappointment frustration joy etc This supportive therapy helps the individual to normalize his her behavior at the time of a panic-evoking situation and thereafter The therapist tries to lead the individual to self-empowerment by providing him her self-defense mechanisms and inner-strengthening tools
Handling the Data
The investigators will assure anonymity of all data collected and medical discretion
Length of Study
Stage 1 The investigators intend to interview 60 participants in order to recruit 60 PD patients and at the same time the investigators will interview 20 matched healthy controls
Stage 2
The same 60 PD patients from Stage 1 will participate in a 10-12 weeks experiment In addition there will be a follow-up within 6 months and 12 months from end of trial when the participants will be asked to fill assessment questionnaires regarding their PD
Statistical Analysis
The investigators will test for normal distribution of the dependent variables and then will examine the differences between the groups using univariate analyses for continuous independent variables such as scores the investigators will apply t-test and for categorical variables such as sex - chi square All using SPSS software
Any data to be collected during this study will be used for research purposes only and does not have diagnostic significance at the moment However this study may have clinical realizations and application in the future Should the investigators have important findings this research group has intentions to publish them
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None