Combining Robotic-Assisted Therapy and Pharmacotherapy in Post-Stroke Rehabilitation
| Status: | Recruiting |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 18 - 85 |
| Updated: | 12/23/2016 |
| Start Date: | March 2015 |
| End Date: | March 2017 |
| Contact: | Catherine Adans-Dester |
| Email: | cadans-dester@partners.org |
| Phone: | 6179526321 |
The Effect of Combining Robotic-Assisted Therapy With Levodopa/Carbidopa in Chronic Post-Stroke Upper-Limb Hemiparesis
Stroke is the leading cause of acquired long-term disability in adults in developed
countries. Despite aggressive rehabilitation, lasting upper extremity impairment remains in
the majority of stroke survivors. It is hypothesized that enhancing neuroplasticity through
the combination of drug therapy and physical therapy could enhance outcomes for stroke
survivors. The combination of levodopa and intensive physical therapy shows promise in
enhancing the functional motor recovery of stroke patients during the sub-acute and chronic
period without reported significant side effects. Robotic-aided training is a promising tool
that has the potential to deliver high-intensity, task-oriented, reproducible therapy that
can decrease the burden on a therapist. Since the evidence behind dopaminergic potentiation
of neuroplasticity and stroke recovery is promising, it is the investigators aim to combine
dopaminergic drug therapy with highly intensive robotic-assisted therapy to provide superior
upper extremity functional recovery over traditional stroke rehabilitation.
countries. Despite aggressive rehabilitation, lasting upper extremity impairment remains in
the majority of stroke survivors. It is hypothesized that enhancing neuroplasticity through
the combination of drug therapy and physical therapy could enhance outcomes for stroke
survivors. The combination of levodopa and intensive physical therapy shows promise in
enhancing the functional motor recovery of stroke patients during the sub-acute and chronic
period without reported significant side effects. Robotic-aided training is a promising tool
that has the potential to deliver high-intensity, task-oriented, reproducible therapy that
can decrease the burden on a therapist. Since the evidence behind dopaminergic potentiation
of neuroplasticity and stroke recovery is promising, it is the investigators aim to combine
dopaminergic drug therapy with highly intensive robotic-assisted therapy to provide superior
upper extremity functional recovery over traditional stroke rehabilitation.
Every year, approximately 795,000 people suffer a new or recurrent stroke in the United
States, meaning that every 40 seconds someone has a stroke. In the United States, stroke is
the third most frequent cause of death and the leading cause of lasting hemiparesis and
adult disability. Since the prevalence of stroke increases with age, and since the world
population is aging, the incidence of stroke is expected to rise in the coming years. This
will become a significant societal burden since the care of stroke survivors is costly, to
the individual and to society.
Post-stroke upper extremity (UE) impairment usually implies initial weakness, with
subsequent diminished dexterity and limitation or incapacity for reaching, transport and
grasping movements since the onset. Survivors may regain partial or, less often, complete
muscle strength in the affected UE during the recovery process. However, a persistent degree
of weakness and evolution to secondary complications as spasticity (characterized by
increased flexor hypertonia), shoulder pain and contractures is frequent. These additional
issues are associated with greater impairment, worse function and lower health-related
quality of life. Treatment interventions for hemiparesis after stroke usually include
stretching, strengthening of antagonist muscles, splinting, oral medications, and focal
injections (phenol or botulinum toxin) and intrathecal baclofen. However, the amount,
intensity and length of therapies still need further investigation. Despite adequate
traditional treatment, a high number of patients are still permanently limited as a
consequence of stroke. Based on motor learning theories, recent studies have demonstrated
that intensive, repetitive, task-oriented therapies can help the paretic extremity "relearn"
how to perform movements that were lost after brain damage.
ROBOTIC-ASSISTED UPPER-LIMB TRAINING WITH ARMEO®
Current evidence has shown that rehabilitation without specific training will not result in
measurable outcomes. Factors such as intensity and specificity of motor training are
important to achieve recovery of motor function, especially in the chronic phase of the
stroke. There is robust evidence that highly-repetitive movement rehabilitation could
improve motor and functional ability, based on its role in motor learning processes.Robotic
devices have become a very important area of research because of their capacity to achieve
high-intensity and specificity therapies.
In this proposed project, we plan to use the Armeo robotic system to deliver motor training
therapy. The Armeo system is an adjustable arm orthosis that has received FDA 510k
exemption. It passively counterbalances the weight of the arm, thereby reducing the effort
required by the paretic arm to overcome gravity. The device is able to augment feedback
through a virtual environment (i.e. computer games). The tasks presented in the virtual
environment are designed to achieve functional movements, i.e. the subject has to perform
tasks such as reaching for objects as part of the game. Gravity compensation, which can
reduce the level of difficulty of performing an activity, facilitates active arm movement,
especially when it involves training in grasping and reaching. By using the Armeo system, we
hope to achieve repetitive training of reach, grasp, and release in an engaging environment
that can be adapted to individual capabilities. We also expect to enable stroke survivors
whose motor weakness may have excluded them from performing repetitive therapy tasks to
participate in this study.
LEVODOPA Several agents have widely proved their influence on neuronal plasticity. Among
these agents, pharmacological drugs increasing the availability of Central Nervous System
(CNS) neurotransmitters (dopamine, norepinephrine, serotonin, acetylcholine and hista mine)
have shown the ability to modulate excitability in cortical neurons and exert a subsequent
facilitator effect in neuroplasticity. In this regard, several studies have been conducted
in the past two decades investigating, among other agents, the effects of amphetamines,
selective serotonin reuptake inhibitors, donepezil, psychostimulants as methylphenidate and
dopaminergic agents. Levodopa (LD) is a desirable drug to evaluate because of its safe
action profile. This oral medication is a precursor of dopamine (DA) that is actively
transported across the blood-brain barrier and is converted to DA in the CNS and peripheral
tissues. Approximately 95% of LD is converted to DA, stimulating dopaminergic
neurotransmission, and the remaining 5% is converted to norepinephrine and affects
adrenergic neurotransmission. DA plays a role in the formation of motor memories and thereby
facilitates neuroplasticity, through the strengthening (long term potentiation, LTP) or
weakening (long term depression, LTD) of the neuronal synapses, thereby generating
neuroplasticity. DA has an inverted U-shape concentration curve effect to facilitate LTP. In
previous studies doses of 100mg generated a facilitator effect, and 25 mg and 200 mg exerted
an inhibitor effect on human cortex. This pharmacological agent has shown promising results
in the treatment of stroke by enhancing functional motor recovery in the sub-acute and
chronic period, in combination with intensive physical therapy, without reported significant
side effects. In the acute and sub-acute phases, LD was demonstrated to improve functional
motor skills that were maintained at three weeks follow up. LD also showed an additional
benefit on the activities of daily living and in the severity of the stroke. In the chronic
period, a single dose of LD combined with physical therapy for five weeks enhanced the
formation of training-dependent elementary motor memory while improving UE dexterity.
COMBINING LEVODOPA/CARBIDOPA WITH THE ARMEO SYSTEM
It is our hypothesis that the intake of levodopa/carbidopa LD/CD in combination with
intensive robotic-assisted therapy will provide better outcomes in functional recovery tests
than the same training alone. We also hypothesize that these improvements could be
correlated with changes in motor cortex excitability. Current strategies to improve motor
recovery after stroke focus on neuroplasticity and neuromodulation. There is growing
interest in the combination of therapies and strategies to enhance plasticity and thereby
functional recovery through the rehabilitation process. It is frequently hypothesized that
the combination of drug therapy and physical rehabilitation could provide better outcomes by
enhancing neuroplasticity phenomenon
We propose a randomized, double-blind, placebo-controlled study of LD/CD in combination with
repetitive upper-extremity functional task-oriented and robotic-aided training.
States, meaning that every 40 seconds someone has a stroke. In the United States, stroke is
the third most frequent cause of death and the leading cause of lasting hemiparesis and
adult disability. Since the prevalence of stroke increases with age, and since the world
population is aging, the incidence of stroke is expected to rise in the coming years. This
will become a significant societal burden since the care of stroke survivors is costly, to
the individual and to society.
Post-stroke upper extremity (UE) impairment usually implies initial weakness, with
subsequent diminished dexterity and limitation or incapacity for reaching, transport and
grasping movements since the onset. Survivors may regain partial or, less often, complete
muscle strength in the affected UE during the recovery process. However, a persistent degree
of weakness and evolution to secondary complications as spasticity (characterized by
increased flexor hypertonia), shoulder pain and contractures is frequent. These additional
issues are associated with greater impairment, worse function and lower health-related
quality of life. Treatment interventions for hemiparesis after stroke usually include
stretching, strengthening of antagonist muscles, splinting, oral medications, and focal
injections (phenol or botulinum toxin) and intrathecal baclofen. However, the amount,
intensity and length of therapies still need further investigation. Despite adequate
traditional treatment, a high number of patients are still permanently limited as a
consequence of stroke. Based on motor learning theories, recent studies have demonstrated
that intensive, repetitive, task-oriented therapies can help the paretic extremity "relearn"
how to perform movements that were lost after brain damage.
ROBOTIC-ASSISTED UPPER-LIMB TRAINING WITH ARMEO®
Current evidence has shown that rehabilitation without specific training will not result in
measurable outcomes. Factors such as intensity and specificity of motor training are
important to achieve recovery of motor function, especially in the chronic phase of the
stroke. There is robust evidence that highly-repetitive movement rehabilitation could
improve motor and functional ability, based on its role in motor learning processes.Robotic
devices have become a very important area of research because of their capacity to achieve
high-intensity and specificity therapies.
In this proposed project, we plan to use the Armeo robotic system to deliver motor training
therapy. The Armeo system is an adjustable arm orthosis that has received FDA 510k
exemption. It passively counterbalances the weight of the arm, thereby reducing the effort
required by the paretic arm to overcome gravity. The device is able to augment feedback
through a virtual environment (i.e. computer games). The tasks presented in the virtual
environment are designed to achieve functional movements, i.e. the subject has to perform
tasks such as reaching for objects as part of the game. Gravity compensation, which can
reduce the level of difficulty of performing an activity, facilitates active arm movement,
especially when it involves training in grasping and reaching. By using the Armeo system, we
hope to achieve repetitive training of reach, grasp, and release in an engaging environment
that can be adapted to individual capabilities. We also expect to enable stroke survivors
whose motor weakness may have excluded them from performing repetitive therapy tasks to
participate in this study.
LEVODOPA Several agents have widely proved their influence on neuronal plasticity. Among
these agents, pharmacological drugs increasing the availability of Central Nervous System
(CNS) neurotransmitters (dopamine, norepinephrine, serotonin, acetylcholine and hista mine)
have shown the ability to modulate excitability in cortical neurons and exert a subsequent
facilitator effect in neuroplasticity. In this regard, several studies have been conducted
in the past two decades investigating, among other agents, the effects of amphetamines,
selective serotonin reuptake inhibitors, donepezil, psychostimulants as methylphenidate and
dopaminergic agents. Levodopa (LD) is a desirable drug to evaluate because of its safe
action profile. This oral medication is a precursor of dopamine (DA) that is actively
transported across the blood-brain barrier and is converted to DA in the CNS and peripheral
tissues. Approximately 95% of LD is converted to DA, stimulating dopaminergic
neurotransmission, and the remaining 5% is converted to norepinephrine and affects
adrenergic neurotransmission. DA plays a role in the formation of motor memories and thereby
facilitates neuroplasticity, through the strengthening (long term potentiation, LTP) or
weakening (long term depression, LTD) of the neuronal synapses, thereby generating
neuroplasticity. DA has an inverted U-shape concentration curve effect to facilitate LTP. In
previous studies doses of 100mg generated a facilitator effect, and 25 mg and 200 mg exerted
an inhibitor effect on human cortex. This pharmacological agent has shown promising results
in the treatment of stroke by enhancing functional motor recovery in the sub-acute and
chronic period, in combination with intensive physical therapy, without reported significant
side effects. In the acute and sub-acute phases, LD was demonstrated to improve functional
motor skills that were maintained at three weeks follow up. LD also showed an additional
benefit on the activities of daily living and in the severity of the stroke. In the chronic
period, a single dose of LD combined with physical therapy for five weeks enhanced the
formation of training-dependent elementary motor memory while improving UE dexterity.
COMBINING LEVODOPA/CARBIDOPA WITH THE ARMEO SYSTEM
It is our hypothesis that the intake of levodopa/carbidopa LD/CD in combination with
intensive robotic-assisted therapy will provide better outcomes in functional recovery tests
than the same training alone. We also hypothesize that these improvements could be
correlated with changes in motor cortex excitability. Current strategies to improve motor
recovery after stroke focus on neuroplasticity and neuromodulation. There is growing
interest in the combination of therapies and strategies to enhance plasticity and thereby
functional recovery through the rehabilitation process. It is frequently hypothesized that
the combination of drug therapy and physical rehabilitation could provide better outcomes by
enhancing neuroplasticity phenomenon
We propose a randomized, double-blind, placebo-controlled study of LD/CD in combination with
repetitive upper-extremity functional task-oriented and robotic-aided training.
Inclusion Criteria:
- Male and female, community dwelling, age 18-85.
- First episode of stroke.
- Diagnosis of chronic ischemic stroke at least six months before study enrollment
resulting in objective motor upper-extremity impairment as demonstrated during
physical/neurological examination.
- Score of 15-55 out of 66 on the arm motor Fugl-Meyer scale.
- The ability to extend ≥ 10 degrees at metacarpophalangeal and interphalangeal joint
of all digits.
- Signed written informed consent.
Exclusion Criteria:
- Intracranial hemorrhages.
- Pregnancy, planning to become pregnant or breast-feeding.
- History of seizures within the previous six months.
- Previous residual motor deficit in the affected side.
- Treatment with Botox injections in the affected arm in the previous 6 months.
- Cognitive impairment that may interfere with understanding instructions for motor
tasks and assessment tools.
- Other major neurologic disorder (Parkinson's disease).
- Major depression defined by the Patient Health Questionnaire, other major psychiatric
pathology, dementia, agitation (defined as a score of >21 on the Agitated Behavior
Scale) or another uncooperative behavior.
- Inability to operate the Armeo system (which will be assessed during the calibration
process). Subjects must have sufficient range of movement to enable calibration of
the virtual workspace.
- Contraindications for Levodopa/ Carbidopa:
- Hypersensitivity to levodopa, carbidopa or any component of the formulation.
- Use of monoamine oxidase inhibitors (MAOIs) within prior 14 days. Treatment with
tricyclic antidepressants, antipsychotics, sapropterin, selective serotonin
reuptake inhibitors (SSRIs), pimozide, benzodiazepines, amantadine,
methylphenidate, dopamine-agonists or neuroleptic drugs when inclusion or the
month before.
- Narrow-angle glaucoma.
- Suspicious, undiagnosed skin lesions or a history of melanoma.
- Presence of metallic hardware in close contact to the discharging coil (cochlear
implants, aneurism clips, brain implants, internal pulse generator, medication
pumps).
- Contemporary participation in another interventional trial focused on the impaired
arm recovery.
- Drug or alcohol abuse in the last 3 years.
- A terminal medical diagnosis with survival < 1 year.
- End-stage or uncompensated hepatic, cardiovascular, cerebrovascular, endocrine,
renal, digestive, hematologic or pulmonary disease. Active ulcer disease.
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