Limitaciones de los métodos y técnicas utilizadas

Examining the balance between possible efficacy and safety is an important component of a phase 2 study design. To assess the degree to which sensory side-effects were reported we compared each sensory side-effect (tingling, itching, burning, headache and pain) between each of the three stimulation conditions using a Wilcoxon signed-rank test. Moreover, a Mann-Whitney U was performed to compare between both groups reported sensory side-effects.

In the HFA group, majority of the sensory side-effects were reported as ≤3 out of 5 in terms of severity, 84% reported tingling, 36% itching, 44% burning, 24% headache and 24% pain. Only a small percentage reported sensory side-effects as ≥4 out of 5, 4% reported tingling, 12% itching, 4% burning, 0% headache and 4% pain. In the TD group, 60% reported tingling, 52% itching, 36% burning, 12% headache, 16% pain of which were reported as ≤3 out of 5 in terms of severity. While 28% reported tingling, 12% itching, 8% burning, 0% headache, and 0% pain as a ≥4 out of 5 severity,

indicating that the tDCS was generally well tolerated in both HFA and TD groups (Fig. 35 and 36). These results are presented in Table 16 and 17.

Figure 35 Percentages of sensory side-effects reported as ≤3 out of 5 during stimulation.

Figure 36 Percentages of sensory side-effects reported as ≥4 out of 5 during stimulation.

0 10 20 30 40 50 60 70 80 90

Tingling Itching Burning Headache Pain

P er ce n tag es o f rep o rts HFA TD 0 5 10 15 20 25 30

Tingling Itching Burning Headache Pain

P er ce n tag es o f rep o rts HFA TD

Table 16 Percentages of sensory side-effects reported as ≤3 out of 5 severity during active tDCS in

HFA and TD group.

Groups Tingling Itching Burning Headache Pain

HFA 84% 36% 44% 24% 24%

TD 60% 52% 36% 12% 16%

Table 17 Percentages of sensory side-effects reported as ≥4 out of 5 severity during active tDCS in

HFA and TD group.

Groups Tingling Itching Burning Headache Pain

HFA 4% 12% 4% 0% 4%

TD 28% 12% 8% 0% 0%

Interestingly, during sham stimulation, both groups reported side-effect session. The HFA group reported tingling 48%, itching 16%, burning 28%, headache 20% and pain 24% as ≤3 out of 5 in terms of severity. As well as tingling 16%, itching 4%, burning 4%, headache 0% and pain 0% as ≥4 out of 5 in terms of severity. In the TD group, 52% tingling, itching 28%, burning 12%, headache 4% and pain 4% as ≤3 out of 5 in terms of severity and 16% tingling, 4% itching, 0% burning, 0%

headache, and 0% pain as ≥4 out of 5 in terms of severity. Of the 50 participants, none correctly guessed which of the 3 sessions involved Sham tDCS (Fig 37 and 38). These results are presented in Table 18 and 19.

Table 18 Percentages of sensory side-effects reported as ≤3 out of 5 severity during sham stimulation

in HFA and TD group.

Groups Tingling Itching Burning Headache Pain

HFA 48% 16% 28% 20% 24%

Table 19 Percentages of sensory side-effects reported as ≥4 out of 5 severity during sham stimulation

in HFA and TD group.

Groups Tingling Itching Burning Headache Pain

HFA 16% 4% 4% 0% 0%

TD 16% 4% 0% 0% 0%

Figure 37 Percentages of sensory side-effects reported as ≤3 out of 5 during sham.

Figure 38 Percentages of sensory side-effects reported as ≥4 out of 5 during stimulation.

0 10 20 30 40 50 60

Tingling Itching Burning Headache Pain

P er ce n tag es o f rep o rts HFA TD 0 2 4 6 8 10 12 14 16 18

Tingling Itching Burning Headache Pain

P er ce n tag es o f rep o rts HFA TD

In the HFA group, a Wilcoxon signed-rank test showed no significant difference between majority of the sensory side-effects reported between stimulation conditions (p>0.05) apart from significantly more itching sensation during cathodal stimulation when compared to sham (Z=2.1, p=0.036, d=0.87) as well as significantly more tingling sensation during cathodal stimulation when compared to anodal stimulation (Z=2.3, p=0.022, d=1.02). In the TD group, a paired sample t-test showed no significant difference between the sensory side-effects reported between stimulation conditions (p>0.05).

However, there was significantly more burning sensation during cathodal stimulation when compared to sham (Z=2.64, p=0.008, d=1.31), significantly more burning sensation during anodal stimulation when compared to sham (Z=2.23, p=0.026, d=1.06), significantly more itching sensation during anodal stimulation when compared to sham (Z=2.16, p=0.031, d=0.97).

A Mann-Whitney U test demonstrated no significant difference in sensory side effect severity reported between both groups in any of the stimulation conditions (p>0.05), apart from the HFA group reporting more pain sensation during sham (U= 248.5, p=0.039, d=0.89).

In addition, in an attempt to characterise parameters that led to a physical sensation of tDCS current, relationships between sensations and demographic variables were examined using Pearson

correlation. These variables included measures of head size (inion to nasion) and age. While sleep deprivation has been suggested to change pain perception (Lautenbacher et al., 2006), it was not explored as majority of the participants did not report any sleep deprivation or variation in their sleeping patterns before stimulation. Moreover, the 7 participants (all individuals with HFA) that reported not getting enough sleep the night before did not report any pain side-effect during any of the stimulation conditions.

The analysis demonstrates that there is no correlation in the HFA group between age and any sensory side-effect (p>0.05). In the TD group, there was no correlation between age and majority of the sensory side-effect, apart from a moderate negative correlation between age and burning sensation (r=-0.519, N=25, p=0.008) showing that the younger the participants the higher report of burning sensation (Fig. 39). A simple linear regression was carried out to test if age significantly predicted scores on the WMQ. The results of the regression indicated that the model explained 27% of the variance and that the model was significant, F(1, 24) = 8.5, p=0.008. Furthermore, the analysis

demonstrates that there is no correlation in the HFA and the TD group between head size and any sensory side-effect (p>0.05).

Figure 39 shows the relationship between age and burning sensation during stimulation in the TD

group.

Furthermore, additional side-effects were reported after the anodal stimulation session. These

reported side-effects are based on participants volunteering the information themselves without being specifically asked. Seven participants reported that they felt they had better attention for the rest of the day. Two parents and five partners reported that their son/partner were more sociable for the rest of the day and were generally in a better mood. One participant reported that he felt way better and focused and asked if he can keep receiving tDCS.

These result demonstrate that tDCS did not cause any adverse side effect, showing that 72% of all the participants reported a ≤3 out of 5 in terms of severity on the sensory side-effects regardless of the simulation condition, while 28% of the all participants reported a ≥4 out of 5 in terms of severity on the sensory side-effects. Interestingly, 76% of the HFA group reported a ≤3 out of 5 in terms of

severity on the sensory side-effects and 24% reported a ≥4 out of 5, while 68% of the TD group reported a ≤3 out of 5 in terms of severity on the sensory side-effects and 32% reported a ≥4 out of 5, demonstrating that TD individuals were more sensitive to the stimulation while individuals with ASD are reported to have increased pain sensitivity and increased touch sensitivity (Riquelme, Hatem and Montoya, 2016). Moreover, none of the participants verbally report any discomfort or request for the stimulation to end at any point during the session or experiment, reported any adverse side effect after each session or had any physical signs of heating effects/burning, irritation, or skin abrasion.

5.4 Discussion

This phase II clinical trial found that recruitment of individuals with HFA for tDCS studies is feasible, however only when having and using the appropriate resources. It would not have been possible for us to recruit the sum of participants we did had we not gone via the NHS, as stated in section 5.2.3, we were unable to recruit a single participant in the first year of this study, without NHS ethics. However, there is a possibility of using additional recruitment points in the future e.g, autism charities, support groups and schools.

Our findings from this phase II clinical trial demonstrated that 15 minutes of anodal tDCS at an intensity of 1.5 mA led to an improvement in WM performance scores when administered over the left DLPFC when compared to baseline, cathodal and sham stimulation of the same area in adults with HFA. This was revealed by greater correct responses, fewer errors and faster reaction times in identifying the target and non- target during and post anodal stimulation, showing that tDCS on WM was effective. While there was a significant difference in the HFA group, the TD group did not show any statistical difference on WM performance in accuracy and error rate on the task during and post anodal, cathodal and sham stimulation. However, there was significantly faster RT during and post anodal stimulation when compared to baseline, cathodal and sham stimulation. These findings were consistent with our hypothesis.

Baseline comparison between the two groups demonstrated that individuals with HFA were further impaired in WM when compared to the TD group, emphasising the importance of taking into account baseline task performance in the design of non-invasive brain stimulation protocols. Yet, there was no difference between the two groups post stimulation. As evident by the changes in scores, individuals

with HFA benefited more from the stimulation than the TD group. Furthermore, the findings revealed a relationship between the 3-back task and IQ (as measured with the WASI) in the HFA group, showing that individuals with higher IQ scores had greater scores on the 3-back task. There was also a relationship between age and the scores on the WMQ in the TD group. The results demonstrate that as participants in the TD group age increased they reported more issues with WM (as increased scores on the WMQ).

As per the reports of participants’ sensory side-effects, tDCS was tolerable and did not cause

discomfort or inconvenience to the participants. Participants could not differentiate between active or sham stimulation, as the analysis showed no significant difference between the sensory side-effects reported between stimulation conditions, although some participants reported greater sensory side- effect (tingling and burning) during active stimulation. The analysis investigating parameters that led to a physical sensation revealed that the younger the TD participants were the higher report of

burning sensation during stimulation. Additional side-effects were reported after the anodal stimulation session such as better attention, more sociability, improved mood and greater focus. However, these reports should be interpreted with caution as the current experiment was not

investigating these additional side-effects. The reports were not based on a standardised method, but rather the individuals volunteering the information themselves without being specifically asked.