Keywords Coma - traumatic brain injury - cerebrovascular accident - tDCS - physiotherapy
Introduction
Altered levels of consciousness resulting from a vascular deficit to the brain can
vary from confusion to coma.[1 ] Confusion is a state marked by a loss of ability to think clearly even after repetitions,
to notice, respond to, and retain current stimulus along with disorientation.[2 ] Clouding of consciousness is the state that exists between regular consciousness
and confusion.[2 ] Delirium is defined as a state of significantly altered consciousness, motor restlessness,
transitory hallucinations, disorientation, and often delusions.[3 ] Stupor is defined as a state in which the patient has little or no spontaneous activity
but conscious.[4 ] Patients will awaken with a little motor activity and may likely be unable to talk.[3 ] According to the bedside behavioral test, coma and vegetative state are unconscious
brain states. Patients with these states are completely unresponsive to external stimuli
and are unable to commence goal-oriented behaviours.[2 ] According to Plum and Posner, defined coma as a state of unresponsiveness in which
the patient lies with eyes closed and even vigorous stimulus cannot make a awaken
response.[5 ]
Major causes of unconsciousness seen in the intensive care unit are unconsciousness
after taking the sedative drug with or without alcohol, hypoxic–ischemic insult as
a result of cardiac arrest or anesthetic accident, and result of cerebrovascular accidents
(CVAs, either hemorrhage or ischemic) and traumatic brain injury (TBI).
TBI is a major public health issue.[6 ] In India and other developing countries, TBIs are the major cause of mortality,
disability, and financial fatalities.[7 ] Every year, an average of 1.5 to 2 million people are injured in India, with a high
mortality rate. TBIs are the most commonly caused by road traffic accidents (60%)
followed by falls (20-25%) and violence (10%). A history of alcohol intake is present
at the time of injury in 15 to 20% of cases of TBIs.[8 ] The most severe TBI causes serious mental, and emotional difficulties, and even
altered levels of consciousness. About 17% of patients, who survive a TBI, experience
a period of total unconsciousness or altered state of consciousness.[9 ]
In low- and middle-income nations like India, stroke is a main cause of premature
mortality and disability.[10 ] Stroke prevalence rates in rural areas range from 84 to 262/per 100,000, while in
urban areas they range from 334 to 424/100,0000.
The state of altered consciousness is mainly due to a disruption in the function of
the brain stem reticular activating system, or both cerebral hemispheres and thalamai.[3 ] Depending on the severity of the brain damage, a state of altered consciousness
can last anywhere from hours to days, and sometimes months to years.[5 ]
There are various protocols available for attaining post-comatose motor responses.
Various researches have exemplified that coma arousal therapy shall be beneficial
in improving the Glasgow coma scale (GCS) of the patient. Currently, available literature
emphasizes that sensory stimulation can result in alleviating disorders of consciousness.
Most of the studies revealed the fact that along with medical management of unconscious
patients after TBI and CVA, multimodal sensory stimulation is used to produce arousal
response. These studies aimed at attaining arousal responses but not motor responses.
Transcranial direct current stimulation (tDCS) is a type of noninvasive neurostimulation
technique in which a weak polarizing current is used to adapt cortical excitability.[11 ] It is noninvasive stimulation of brain that is economical and simple to operate.
In a study by Estraneo A et al. in craniocerebral injury subjects with motor skills
and language impairment, a 1 to 2 mA tDCS has shown that there are no significant
adverse effects.[12 ] A constant weak direct current can pass through the skull and stimulate the cortex
behind it. In the brain, it regulates the excitability in the cerebral hemispheres.
This study is aimed at finding the effect of tDCS on motor recovery in altered conscious
patients after TBI and CVA. The objectives of the study are to assess the level of
motor responses in altered consciousness after TBI or CVA by the GCS and to find out
whether there is an improvement in motor responses on the GCS scale and modified Ashworth
scale of spasticity (MAS) scales after tDCS application.
Materials and Methods
Enrollment and Recruitment
A total of 100 patients who had altered conscious levels due to TBI and CVA were screened
at the department of neurology and neurosurgery in association with the physiotherapy
department of the university hospital. This study was conducted at the department
of neurology and neurosurgery in association with the physiotherapy department of
the university hospital from February 2021 to May 2021. It is a single-blinded randomized
control trial where the subjects were blinded. Forty subjects (n = 40) satisfied inclusion criteria and were recruited for the study after informed
consent from the caregiver. The subjects were randomly divided into two groups: group
A (experimental) (n = 20) and group B (control; n = 20) by computerized randomization. Both males and females having altered levels
of consciousness for more than 6 hours after TBI or CVA (bleeding not more than 30 mL)
with GCS less than or equal to 8, altered consciousness that lasts for more than a
week, stable cardiac functioning, magnetic resonance imaging showing no midline shift,
patients with decompressive craniectomy, no structural damage, no thalamic lesions
with lesions in each lobe not exceeding 30% of the scope of one side of the brain
are included in this study. Patients having unconsciousness other than TBI or CVA,
cardiac pacemaker, electric implant in the brain Deep brain stimulation (DBS), scalp
dermatitis, infections to central nervous system, and previous history of epilepsy
are excluded from the study.
This study got ethical clearance from the institutional ethical committee and the
trial is registered with Clinical trials of India.
Intervention
Group A Experimental : After taking the preliminary assessment, anodal transcranial direct current stimulation
is applied to the motor area (C3/C4 ipsilesional), sensory area (P3/P4 ipsilesional),
and left dorsolateral prefrontal cortex (F3) according to the 10/20 electroencephalogram
montage ([Fig. 1 ]). The electrodes used are 1.6 cm2 in area, self-adhesive, and conductive. The individual leads connecting the active
electrodes are fused into a single channel by a port and connected to the positive
terminal of the machine. The current used in this study is direct continuous in nature
having intensity 2.0 mA. Cathode is placed at the opposite shoulder as a reference
electrode. tDCS was given for two sessions of 20min/day for 7 consecutive days.[9 ] Routine physiotherapy was also given similar to that of group B. No seizure activity
was observed during or later stage of treatment sessions.
Fig. 1 Electrode placement for transcranial direct current stimulation.
Group B controlled : Routine physical therapy was given for 30 minutes twice daily for 7 consecutive
days. The therapy included the following:
1. Passive movements—10 repetitions of full range of motion of each joint.
2. Bed making and change of positions
3. Electrical muscle nerve stimulation
Both group A and group B received chest physiotherapy and medical care as per the
guidelines of neurologist or neurosurgeon of the university hospital.
The subjects in group A and group B received interventions under the same environment
and handled by the same physiotherapist.
Outcome Measures
All the demographic characteristics of the subjects were recorded at the time of enrollment
and recruitment of subjects. The motor responses were recorded by best motor responses
subsection of GCS and MAS at the time of enrollment (t0), and after 7 days post-intervention
(t1). Inter-rater reliability of GCS is good.[8 ]
[11 ]
Statistical Analysis
In this study to analyze the role of tDCS on motor recovery of altered consciousness
patients, the preliminary outcome variables were compared using Mann–Whitney U test
and assessed for normality ([Table 1 ]). All pre-test and post-test scores of motor responses on GCS and MAS were expressed
as median and analyzed by Mann–Whitney U test among the groups ([Table 2 ]) and one way analysis of variance (ANOVA) with k = 2 independent treatments with
Tukey Honest Significant Difference (HSD) as post-hoc comparison for between the groups
at 5% level of significance ([Table 3 ]). To explore the practical significance of group differences, the effect size was
calculated. The established criteria of the ES, which reflects the effect of treatment
within a population of interest, are small (<0.41), medium (0.41 to 0.7), or large
(> 0.70; [Table 4 ]).
Table 1
Baseline demographic characteristics of group A and group B
Characteristics
Group A (experimental) (n = 20)
Group B (control)
(n = 20)
p -Value
Age[a ]
38 ± 10.95
43.2 ± 12.84
> 0.05
Sex (male:female)
13:7
14:6
> 0.05
Side of injury (right:left)
12:8
11:9
> 0.05
Type of management
Conservative: Surgical (craniectomy, VP shunt, etc.)
13:7
15:5
> 0.05
TBI:CVA
13:7
11:9
> 0.05
Number of days between incidence of TBI/CVA and recruitment[a ]
7.2 ± 1.8
7.6 ± 1.2
> 0.05
SBP[a ]
129 ± 9.49
130.9 ± 7.64
> 0.05
DBP[a ]
80.52 ± 6.48
84.9 ± 6.05
> 0.05
Pulse (BPM)[a ]
75.17 ± 6.15
79.35 ± 6.36
> 0.05
Temperature (°F)[a ]
97.69 ± 1.29
78.17 ± 0.97
> 0.05
Respiratory rate (cycles per minute)[a ]
19.82 ± 2.26
21 ± 1.91
> 0.05
Abbreviations: BPM, beats per minute; CVA, cerebrovascular accident; DBP, diastolic
blood pressure; SBP, systolic blood pressure; SD, standard deviation; TBI, traumatic
brain injury.
a Mean ± SD.
Table 2
Comparison of pre-test and post-test best motor response (GCS and MAS) in group A
and B
Variable
Group A
Pretest[a ]
Group A
Posttest[a ]
Group B
Pretest[a ]
Group B
Posttest[a ]
U–value
p -Value
GCS
3
4
1
1
48
<0.05
MAS
4
4
0
0
20
<0.05
Abbreviations: GCS, Glasgow coma scale; MAS, modified Ashworth scale of spasticity.
a Median.
Table 3
One-way ANOVA with Tukey HSD post-hoc comparison of GCS (best motor response) between
group A and B
Treatments pair
Tukey HSD Q statistic
Tukey HSD p -value
Tukey HSD interference
A vs. B
5.0596
0.0072128
p < 0.01
Abbreviations: ANOVA, analysis of variance; GCS, Glasgow coma scale; HSD, Honest Significant
Difference.
Table 4
One-way ANOVA with Tukey HSD post-hoc comparison of MAS scores between group A and
B
Treatments pair
Tukey HSD Q statistic
Tukey HSD p -value
Tukey HSD interference
A vs B
4.8990
0.0085175
p < 0.01
Abbreviations: ANOVA, analysis of variance; HSD, Honest Significant Difference; MAS,
modified Ashworth scale of spasticity.
Results
A total of 20 subjects in each group completed the study. The data was analyzed for
statistical significance. At baseline, there were no significant group differences
in the baseline characteristics. The groups passed the normality test ([Table 1 ]).
The pre-test best motor response for GCS and MAS median of group A is 3 and 4 and
post-test response is 4 and 4, while for group B the pretest and posttest response
is 1 and 0 and 1 and 1, respectively ([Table 2 ]). The results were analyzed for statistical difference by Mann–Whitney U -test. The results were statistically significant at p -value less than 0.05 ([Table 2 ]).
The results were tested for statistical significance between the groups by one way
ANOVA and Tukey HSD for post-hoc comparison; the results were statistically different
with p -value less than 0.05 ([Tables 3 ] and [4 ]).
To explore the practical significance of group differences and the impact of tDCS
on motor recovery in altered conscious patients, the effect size was calculated by
Cohen's d, and the results showed that there is a large effect of tDCS on motor recovery
([Table 5 ]).
Table 5
Effect size tDCS on motor recovery
Cohen's d = (0.4–1.6) ⁄ 0.54 = 2.222222
Glass's delta = (0.4–1.6) ⁄ 0.54 = 2.222222
Hedges' g = (0.4–1.6) ⁄ 0.54 = 2.222222
Large effect
Abbreviation: tDCS, transcranial direct current stimulation.
Discussion
To assess the effect of tDCS on motor responses in altered conscious patients, the
results in this study revealed that tDCS when given to altered consciousness subjects,
the motor recovery was faster with improved motor responses on GCS scales and MAS
scores than that of a control group that was statistically significant at 95% confidence
interval (p < 0.05). The effect size revealed that tDCS has a large effect and practical significance
on motor recovery in altered conscious patients. Even though the sample size was small
due to the coronavirus disease 2019 pandemic, the large effect indicates the high
significance of tDCS on motor responses and recovery. tDCS is a type of noninvasive
neurostimulation technique in which a weak polarizing current is used to adopt cortical
excitability.[13 ] Anodal stimulation increases cerebral excitability by depolarizing the neuron and
cathodal stimulation decreases cerebral excitability by hyperpolarizing the neuron.[13 ] tDCS changes the electrical neuronal membrane potential along with a change in N-methyl-d-aspartate
(NMDA) and gamma-amino-butyric acid (GABA) receptor's effectiveness.[14 ] It shows long-term potentiation (LTP) plasticity and long-term depression plasticity.
Anodal stimulation decreases GABAergic activity and increases glutamatergic activity,
hence showing LTP, while cathodal stimulation increases GABAergic activity and decreases
glutamatergic activity, hence showing LDP.[10 ] Anodal stimulation releases the glutamate at the presynaptic neuron by depolarizing
the neuron membrane and glutamate that binds to NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptors. This leads to depolarization and increase in intracellular Ca+2 at post-synaptic neurons, which can activate protein kinases, like calcium/calmodulin-dependent
kinase. Protein kinase adopts most of the neuronal signaling pathways leading to the
transcription, translation, and insertion of new glutamate receptors. In a long-term
mechanism, Calcium/Calmodulin-dependent Kinase (CaKM) activates cAMP-response element
binding protein (CREB) (transcription factor), which mediates gene transcription and
the formation of new protein.[15 ] tDCS induces long-lasting effects by changing the excitability of the motor cortex
in humans,[14 ] which enhances motor skill learning by increasing synaptic plasticity.[9 ] It works spontaneously on the excitability of the cortex. The excitability is mainly
due to constant change in the polarity that causes depolarization and hyperpolarization
of the cortex.[9 ] The study by Nitsche et al concluded that tDCS interferes with brain excitability
through modulation of intracortical and corticospinal neurons, thus increasing motor
function.[7 ]
[17 ] Another study by Feng et al found that tDCS application over the motor cortex in
post-stroke patients improves motor functions.[13 ] Li et al interpreted that tDCS application increases the level of consciousness
in the disorder of consciousness.[18 ] The study done by Thibaut et al concluded that anodal tDCS over the left dorsolateral
prefrontal cortex increases the level of consciousness hence increasing motor functions.[9 ]
Conclusion
We conclude, based on the results of this study, that tDCS can be effective in motor
recovery in altered consciousness patients. It is noninvasive, cost-effective with
minimal contraindications, and does not interfere with other modalities in the intensive
care unit. Hence, it can be administered safely under the supervision of a qualified
therapist.
