**3. Interhemispheric inhibition imbalance after brain injury**

Interhemispheric inhibition refers to the phenomenon in which activation of one side of the cerebrum inhibits the activity of neurons in the opposite side of the brain [9]. In humans, sensory information from the right half of the body is normally conveyed to the neocortex of the left hemisphere, while sensory information from the left half of the body is conveyed to the neocortex of the right hemisphere. The left and right neocortices are connected via the corpus callosum. The inhibition of information exchange between the left and right hemispheres allows humans to move the bilateral upper and lower limbs dexterously. Recent research has revealed the mechanism of this neural network of interhemispheric inhibition. Palmer et al.

**303**

between the cerebral hemispheres.

*Rehabilitation Strategies and Key Related Mechanisms Involved in Stroke Recovery*

within layer V of the neocortex, thereby inhibiting nerve activity.

believed to influence the balance of the left and right cerebrum.

How does the disuse of the paretic limbs and overuse of the non-paretic limbs influence the left and right cerebrum in reality? Avanzino et al. [13] established an environment resembling that of a hemiplegic patient to explore the effect of restraining one-sided upper limb use in healthy individuals on interhemispheric balance using transcranial magnetic stimulation (TMS). To examine cortical changes due to abnormal unequal use of the hands, two experimental groups were compared: a group in which one hand (right) was fixed in place but the loose hand (left) could be moved freely and a group in which use of the left hand was also restricted. Note that the upper limbs were restrained for a period of 10 min. Despite the short restraint period, disuse of the right upper limb was found to decrease excitation in the left primary motor cortex and reduce interhemispheric inhibition from the left hemisphere to the right for both groups. Further, the group that not only disused the right upper limb but also overused the left upper limb showed increased excitatory activity in the primary motor cortex of the right hemisphere and increased interhemispheric inhibition from the right hemisphere to the left. Thus, it was revealed that disuse of one upper limb and overuse of the other—that is, imbalance in usage frequency between both upper limbs—causes imbalance

The hypothesis regarding the imbalance in interhemispheric inhibition post-brain injury is called the abnormal interhemispheric inhibition hypothesis [14, 15]. It states that in cases of subcortical brain injury, an abnormal inhibitory effect arises from the non-injured hemisphere, in which there is increased excitation, to the injured hemisphere. There are two conceivable strategies for

[10] explored neuronal activity in the left and right brain of conscious rats with foot stimulation in order to observe nerve activity in a more natural setting. This study revealed the following series of events: when information is conveyed to one side of the neocortex, excitatory information is conveyed to the other side via the corpus callosum, activating the inhibitory nerve cells that exist on its surface and releasing gamma aminobutyric acid (GABA)—an inhibitory neurotransmitter—within the brain. GABA binds to GABAB receptors on the dendrites of pyramidal neurons

However, this interhemispheric inhibition between the left and right brain becomes imbalanced after a brain injury, leading to various dysfunctions. Grefkes et al. [11] investigated the functional intrahemispheric and interhemispheric connections of motor-related areas during voluntary hand movement in healthy individuals and stroke patients using fMRI. Interhemispheric inhibition functioned normally as described above for healthy individuals; it was found that in the resting condition, the left and right brain inhibited one another, while motor-related areas within each hemisphere stimulated one another (**Figure 2A**). It was further found that when healthy individuals moved the right hand, inhibition from the right hemisphere to the left hemisphere ceased, and inhibition from the left hemisphere to the right hemisphere was activated (**Figure 2B**). However, in contrast to healthy individuals, when stroke patients moved the paretic right hand, the right hemisphere (non-injured primary motor cortex) was found to inhibit the left hemisphere (injured primary motor cortex) (**Figure 2C**), such that the stronger the inhibition, the lower the motor performance in the paretic hand (**Figure 2D**). Use-dependent plasticity (use-dependent reorganization) is involved in this imbalance in interhemispheric inhibition in stroke patients [12]. Stroke causes paresis of the upper and lower limbs resulting in reduced motor function. As such, stroke patients commonly disuse the paretic limbs while overusing the non-paretic limbs. This poststroke disuse of the paretic and overuse of the non-paretic limbs—in other words, imbalance in the frequency of use for paretic vs. non-paretic limbs—is

*DOI: http://dx.doi.org/10.5772/intechopen.91025*

#### *Rehabilitation Strategies and Key Related Mechanisms Involved in Stroke Recovery DOI: http://dx.doi.org/10.5772/intechopen.91025*

[10] explored neuronal activity in the left and right brain of conscious rats with foot stimulation in order to observe nerve activity in a more natural setting. This study revealed the following series of events: when information is conveyed to one side of the neocortex, excitatory information is conveyed to the other side via the corpus callosum, activating the inhibitory nerve cells that exist on its surface and releasing gamma aminobutyric acid (GABA)—an inhibitory neurotransmitter—within the brain. GABA binds to GABAB receptors on the dendrites of pyramidal neurons within layer V of the neocortex, thereby inhibiting nerve activity.

However, this interhemispheric inhibition between the left and right brain becomes imbalanced after a brain injury, leading to various dysfunctions. Grefkes et al. [11] investigated the functional intrahemispheric and interhemispheric connections of motor-related areas during voluntary hand movement in healthy individuals and stroke patients using fMRI. Interhemispheric inhibition functioned normally as described above for healthy individuals; it was found that in the resting condition, the left and right brain inhibited one another, while motor-related areas within each hemisphere stimulated one another (**Figure 2A**). It was further found that when healthy individuals moved the right hand, inhibition from the right hemisphere to the left hemisphere ceased, and inhibition from the left hemisphere to the right hemisphere was activated (**Figure 2B**). However, in contrast to healthy individuals, when stroke patients moved the paretic right hand, the right hemisphere (non-injured primary motor cortex) was found to inhibit the left hemisphere (injured primary motor cortex) (**Figure 2C**), such that the stronger the inhibition, the lower the motor performance in the paretic hand (**Figure 2D**). Use-dependent plasticity (use-dependent reorganization) is involved in this imbalance in interhemispheric inhibition in stroke patients [12]. Stroke causes paresis of the upper and lower limbs resulting in reduced motor function. As such, stroke patients commonly disuse the paretic limbs while overusing the non-paretic limbs. This poststroke disuse of the paretic and overuse of the non-paretic limbs—in other words, imbalance in the frequency of use for paretic vs. non-paretic limbs—is believed to influence the balance of the left and right cerebrum.

How does the disuse of the paretic limbs and overuse of the non-paretic limbs influence the left and right cerebrum in reality? Avanzino et al. [13] established an environment resembling that of a hemiplegic patient to explore the effect of restraining one-sided upper limb use in healthy individuals on interhemispheric balance using transcranial magnetic stimulation (TMS). To examine cortical changes due to abnormal unequal use of the hands, two experimental groups were compared: a group in which one hand (right) was fixed in place but the loose hand (left) could be moved freely and a group in which use of the left hand was also restricted. Note that the upper limbs were restrained for a period of 10 min. Despite the short restraint period, disuse of the right upper limb was found to decrease excitation in the left primary motor cortex and reduce interhemispheric inhibition from the left hemisphere to the right for both groups. Further, the group that not only disused the right upper limb but also overused the left upper limb showed increased excitatory activity in the primary motor cortex of the right hemisphere and increased interhemispheric inhibition from the right hemisphere to the left. Thus, it was revealed that disuse of one upper limb and overuse of the other—that is, imbalance in usage frequency between both upper limbs—causes imbalance between the cerebral hemispheres.

The hypothesis regarding the imbalance in interhemispheric inhibition post-brain injury is called the abnormal interhemispheric inhibition hypothesis [14, 15]. It states that in cases of subcortical brain injury, an abnormal inhibitory effect arises from the non-injured hemisphere, in which there is increased excitation, to the injured hemisphere. There are two conceivable strategies for

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

**3. Interhemispheric inhibition imbalance after brain injury**

Interhemispheric inhibition refers to the phenomenon in which activation of one side of the cerebrum inhibits the activity of neurons in the opposite side of the brain [9]. In humans, sensory information from the right half of the body is normally conveyed to the neocortex of the left hemisphere, while sensory information from the left half of the body is conveyed to the neocortex of the right hemisphere. The left and right neocortices are connected via the corpus callosum. The inhibition of information exchange between the left and right hemispheres allows humans to move the bilateral upper and lower limbs dexterously. Recent research has revealed the mechanism of this neural network of interhemispheric inhibition. Palmer et al.

*Longitudinal changes in motor network activity in the initial phase after stroke onset [8]. (A) Brain activity during right/left hand movement in healthy adults. (B) Brain activity during non-paretic/paretic hand movement in stroke patients (2, 5, and 10 days after onset). Bilateral activation is expanded for the paretic hand. (C) Brain activity during paretic hand movement for mild and severe stroke patients (2, 5, and 10 days after onset). In patients with mild functional impairment, only the contralateral hemisphere is active, whereas the activity in both hemispheres expands for severe patients. (D) Map of brain regions involved in favorable* 

**302**

**Figure 1.**

*motor function recovery.*

#### **Figure 2.**

*Differences in cortical connectivity between healthy adults and stroke patients [11]. Green arrows represent excitation and red arrows represent inhibition. (A) Intra-/interhemispheric functional connectivity in healthy adults at rest. (B) Intra-/interhemispheric functional connectivity in healthy adults during voluntary movement of the right hand. (C) Intra-/interhemispheric functional connectivity in stroke patients during voluntary movement of the paretic hand (right hand). (D) Correlation between interhemispheric inhibition of the primary motor cortex and motor performance for the paretic hand (right hand) in stroke patients. The stronger the inhibition from the non-injured hemisphere to the injured hemisphere, the more the paretic hand motor performance was reduced.*

treatment interventions corresponding to this hypothesis: increasing corticomotor excitation in the injured hemisphere or decreasing excitation in the non-injured hemisphere. Approaches for these strategies are known as hypothesis-driven approaches (**Figure 3**) [16]. Specifically, proposed methods include (1) reducing non-paretic limb somatosensory input in order to decrease excitation of the non-injured hemisphere, (2) increasing paretic limb somatosensory input in order to increase excitation of the injured hemisphere, (3) increasing excitation in the injured hemisphere through a combination of movement training of the paretic hand and anesthesia of the paretic upper arm, (4) directly increasing excitation in the injured hemisphere, or (5) directly reducing excitation in the non-injured hemisphere. With regard to procedures to directly manipulate excitation in one hemisphere, as in methods (4) and (5), effects can be exerted through the use of noninvasive brain stimulation methods such as transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS). These methods of stimulation bring about changes that are similar to long-term potentiation or long-term depression, resulting in increased or reduced excitation,

**305**

**Figure 3.**

*Rehabilitation Strategies and Key Related Mechanisms Involved in Stroke Recovery*

respectively, at the stimulation site. Regarding the efficacy of these methods, Hsu et al. [17] performed a meta-analysis that showed that rTMS was effective in motor function recovery in stroke patients. It was also reported in the 2011 Cochrane Review [18] that tDCS improved ADL function poststroke. At present, it has been established that the effects of rTMS and tDCS work on cortical neuromodulation and do not cause direct recovery from paresis. In other words, these methods are used for preconditioning to create a more plastic state in the brain or to stabilize the activity of the cerebral cortex. It is thought that these effects can be demonstrated with a combination of motor therapy, which is based on the process of motor learning. Constraint-induced movement therapy (CI therapy), established by Wolf et al. [19] and Taub et al. [20], is representative methods (1) and (2). In CI therapy, the non-paretic upper limb is first restrained in a sling or with a mitten to create a situation in which the patient is forced to use the paretic upper limb. Voluntary movement is then induced on the paretic side with intensive tasks of incremental difficulty levels leading to improvement in motor function. Regarding the results of this method, the 2009 Cochrane Review [21] confirmed the shortterm effects on the recovery of motor function in stroke patients directly after CI therapy intervention. A meta-analysis by Langhorne et al. [22] about the effects of various rehabilitation methods on upper limb paresis in stroke patients also found that CI therapy had better intervention effects than other methods and that there was little variation among such effects. In addition, recent studies have used randomized comparative experiments to study the effects of behavioral strategies for the utilization of function acquired through CI therapy in daily life (transfer

*Approach based on the abnormal interhemispheric inhibition hypothesis (hypothesis-driven approach) [16]. (1) Reducing non-paretic limb somatosensory input in order to decrease excitation in the non-injured hemisphere. (2) Increasing paretic limb somatosensory input in order to increase excitation in the injured hemisphere. (3) Increasing excitation in the injured hemisphere through a combination of movement training of the paretic hand and anesthesia of the paretic upper arm. (4) Directly increasing excitation in the injured* 

*hemisphere. (5) Directly reducing excitation in the non-injured hemisphere.*

*DOI: http://dx.doi.org/10.5772/intechopen.91025*

*Rehabilitation Strategies and Key Related Mechanisms Involved in Stroke Recovery DOI: http://dx.doi.org/10.5772/intechopen.91025*

#### **Figure 3.**

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

treatment interventions corresponding to this hypothesis: increasing corticomotor excitation in the injured hemisphere or decreasing excitation in the non-injured hemisphere. Approaches for these strategies are known as hypothesis-driven approaches (**Figure 3**) [16]. Specifically, proposed methods include (1) reducing non-paretic limb somatosensory input in order to decrease excitation of the non-injured hemisphere, (2) increasing paretic limb somatosensory input in order to increase excitation of the injured hemisphere, (3) increasing excitation in the injured hemisphere through a combination of movement training of the paretic hand and anesthesia of the paretic upper arm, (4) directly increasing excitation in the injured hemisphere, or (5) directly reducing excitation in the non-injured hemisphere. With regard to procedures to directly manipulate excitation in one hemisphere, as in methods (4) and (5), effects can be exerted through the use of noninvasive brain stimulation methods such as transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS). These methods of stimulation bring about changes that are similar to long-term potentiation or long-term depression, resulting in increased or reduced excitation,

*Differences in cortical connectivity between healthy adults and stroke patients [11]. Green arrows represent excitation and red arrows represent inhibition. (A) Intra-/interhemispheric functional connectivity in healthy adults at rest. (B) Intra-/interhemispheric functional connectivity in healthy adults during voluntary movement of the right hand. (C) Intra-/interhemispheric functional connectivity in stroke patients during voluntary movement of the paretic hand (right hand). (D) Correlation between interhemispheric inhibition of the primary motor cortex and motor performance for the paretic hand (right hand) in stroke patients. The stronger the inhibition from the non-injured hemisphere to the injured hemisphere, the more the paretic hand* 

**304**

**Figure 2.**

*motor performance was reduced.*

*Approach based on the abnormal interhemispheric inhibition hypothesis (hypothesis-driven approach) [16]. (1) Reducing non-paretic limb somatosensory input in order to decrease excitation in the non-injured hemisphere. (2) Increasing paretic limb somatosensory input in order to increase excitation in the injured hemisphere. (3) Increasing excitation in the injured hemisphere through a combination of movement training of the paretic hand and anesthesia of the paretic upper arm. (4) Directly increasing excitation in the injured hemisphere. (5) Directly reducing excitation in the non-injured hemisphere.*

respectively, at the stimulation site. Regarding the efficacy of these methods, Hsu et al. [17] performed a meta-analysis that showed that rTMS was effective in motor function recovery in stroke patients. It was also reported in the 2011 Cochrane Review [18] that tDCS improved ADL function poststroke. At present, it has been established that the effects of rTMS and tDCS work on cortical neuromodulation and do not cause direct recovery from paresis. In other words, these methods are used for preconditioning to create a more plastic state in the brain or to stabilize the activity of the cerebral cortex. It is thought that these effects can be demonstrated with a combination of motor therapy, which is based on the process of motor learning. Constraint-induced movement therapy (CI therapy), established by Wolf et al. [19] and Taub et al. [20], is representative methods (1) and (2). In CI therapy, the non-paretic upper limb is first restrained in a sling or with a mitten to create a situation in which the patient is forced to use the paretic upper limb. Voluntary movement is then induced on the paretic side with intensive tasks of incremental difficulty levels leading to improvement in motor function. Regarding the results of this method, the 2009 Cochrane Review [21] confirmed the shortterm effects on the recovery of motor function in stroke patients directly after CI therapy intervention. A meta-analysis by Langhorne et al. [22] about the effects of various rehabilitation methods on upper limb paresis in stroke patients also found that CI therapy had better intervention effects than other methods and that there was little variation among such effects. In addition, recent studies have used randomized comparative experiments to study the effects of behavioral strategies for the utilization of function acquired through CI therapy in daily life (transfer

package) [23, 24], as well as research examining the effects of motor therapy, which combines CI therapy with the abovementioned rTMS and tDCS [25, 26]. In this way, it is essential that motor therapy in the rehabilitation of stroke patients be developed with sufficient consideration to the imbalance in interhemispheric inhibition between the left and right cerebrum.
