1The Effect of Hypnotic Suggestion on Sleep, Patient-Reported Outcomes, and Awareness

2following Acquired Brain Injury

4Authors:

5Jonas Kristoffer Lindeløv1,2*, Rikke Overgaard2, Morten Overgaard2

7Affiliations:

81Centre for Cognitive Neuroscience, Department of Communication and Psychology, Aalborg

9University, Aalborg, Denmark

102CNRU, CFIN, Health, Aarhus University, Aarhus, Denmark

11

12* Corresponding author.

13jonas@hum.aau.dk, Kroghstræde 3, 9220, Aalborg Øst, Denmark

14

15Counts:

1633.002 characters with spaces.

174.953 words.

183 figures.

192 tables.

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21The Effect of Hypnotic Suggestion on Sleep, Patient-Reported Outcomes, and Awareness

22following Acquired Brain Injury

23 Hypnosis has been successfully applied in neurorehabilitation, including for motor

24 disorders, aphasia, pain, and vertigo. However, cognitive rehabilitation using hypnosis has

25 received little attention. Here, we report the interview-data from an RCT on 49 patients with

26 chronic cognitive sequalae following acquired brain injury. Patients were randomized to two

27 groups, who initially received suggestions either from a classical hypnosis tradition

28 (“targeted”) or from a mindfulness tradition (“non-targeted”). After four sessions of

29 hypnosis and a 7-week follow-up period, the median need for sleep and rest improved from

30 8.58 hours to 8.00 hours and from 8.30 hours to 7.38 hours in the two groups respectively.

31 Patients set goals in their everyday lives, and after eight sessions of hypnosis, they indicated

32 large improvements with “same” (13 %), “better” (44 %), “much better” (18 %), or “not a

33 problem anymore” (25 %). The experience of “not a problem anymore” exclusively

34 occurred after the targeted hypnotic suggestion treatment. An exploratory factor analysis

35 showed no relationship between objective improvements and self-reported improvements (all

36 |Kendall’s τ| < .2), indicating that subjective reports following hypnotic suggestion should be

37 interpreted with caution. Based on our findings and converging evidence from the literature,

38 we conclude that hypnotic suggestion is a promising method in cognitive neurorehabilitation

39 following acquired brain injury, but it should be regarded as experimental until at least one

40 further high-quality RCT is published.

41Data and analysis script are available at https://osf.io/sz6bw/.

42
43Keywords: stroke, TBI, hypnosis, cognition, sleep
44
45
46Introduction

47 Stroke and traumatic brain injury combined currently constitutes the second-largest health-
48related expense in the U.S. (Ma, Chan, & Carruthers, 2014) with around 1.5 million new victims each
49year. This unflattering status is in large part due to the chronic disability experienced by many
50survivors.
51 The strongest predictors of return to work and quality of life following acquired brain injury are
52found in the cognitive domain while physiological characteristics such as etiology, location, and lesions
53size are weaker predictors (Carroll et al., 2004; Cumming, Marshall, & Lazar, 2013; Donker-Cools,
54Wind, & Frings-Dresen, 2016; Serino et al., 2006). Important cognitive sequelae include impairments
55in the executive domain (Dunning, Westgate, & Adlam, 2016) which are correlated with increased
56fatigue (Parcell, Ponsford, Rajaratnam, & Redman, 2006; Ponsford et al., 2012) and has a relatively
57strong prognostic value for recovery in general (Hermann & Bassetti, 2016).
58

59Expectations of brain injury sequelae

60 Cognitive sequelae can in part be attributed to expectations of injury sequelae formed pre-
61injury. In other words, the expected sequelae become a self-fulfilling prophecy (Craig et al., 2016;
62Mittenberg, DiGiulio, Perrin, & Bass, 1992), likely through a mechanism with high similarity – if not
63identity – to the nocebo effect (Polich, Iaccarino, Kaptchuk, Morales-Quezada, & Zafonte, 2018).
64Therefore, injury expectation may be important targets in rehabilitation, counseling, and psychotherapy
65to improve the patients’ functioning, activities, and participation in society (Bilbao et al., 2003). In this
66article, we report the effects of using a hypnotic procedure to change such negative expectations in the
67chronic phase following acquired brain injury. Changing expectations of psychological and behavioral
68outcomes may be integral to how hypnosis works (Kirsch, 1985; Lifshitz, Howells, & Raz, 2012).
69Since expectation is the main driver of placebo effects (at least in the mental domain), it is no surprise
70that hypnosis and placebos are highly similar, to the degree that hypnosis may be regarded as a
71systematic exploitation of the placebo effect (Raz, 2007). If cognitive sequelae are caused or sustained
72by negative expectations and nocebo effects, hypnosis could be well suited to counter such effects.
73 Most speech-based interventions have at least a component of expectation modification through
74suggestions. We opted to use mindfulness meditation is an active control group because it is one of the
75most closely related intervention modalities.
 76

77Hypnosis vs. mindfulness meditation

78 Hypnosis is a broad term referring to widely varying practices. Therefore, it is superficial to

79analyze identities and discrepancies between hypnosis and mindfulness meditation at a general level
80(Jamieson, 2016; Vaitl et al., 2005). American Psychological Association define hypnosis as “A state
81of consciousness involving focused attention and reduced peripheral awareness characterized by an
82enhanced capacity for response to suggestion”. Suggestion is “suggested alterations in physiology,
83sensations, emotions, thoughts, or behavior during hypnosis.” (Elkins, Barabasz, Council, & Spiegel,
842015, p. 6)
85 As with hypnosis, Mindfulness meditation is a broad term which may refer to widely varying
86practices (Sedlmeier et al., 2012) but one standardized treatment program, Mindfulness-Based Stress
87Reduction (MBSR), define Mindfulness as a psychological state characterized by Focused Attention
88and Open Monitoring (Sedlmeier et al., 2012; Travis & Shear, 2010). Attention is focused when it can
89stay with a particular object or thought for an extended time, with little or no distraction from other
90objects or thoughts. Open Monitoring is observing the stream of thought without judging them or
91acting on them, however disturbing or salient they may be. For brain-injured patients, such thoughts
92may include unfavorable comparisons between the current state and the pre-morbid state as well as the
93concurrent desire to return to pre-morbid functioning.
94 While both hypnosis and mindfulness typically include a state of focused attention, the
95difference is in the suggestions provided to the client: mindfulness meditation typically seeks to align
96expectations with the real mental, bodily, and physical circumstances. This is called “insight” or
97“awareness” (Dienes et al., 2015). On the other hand, hypnosis typically seeks align expectations to the
98reality proposed by the hypnotist, thereby achieving congruent mental, bodily, and physical effects as a
99self-fulfilling prophecy. This might be called “strategic self-deception”, without the negative co-
100notations of the term (Dienes et al., 2015). To illustrate, a typical mindful approach to smoke cessation
101would focus on noticing and understanding the craving for nicotine without being absorbed by it. A
102typical hypnotic approach, on the other hand, would be the suggestion that there is no craving in the
103first place. In the present experiment, we suggest to brain-injured participants that their brain plastically
104re-organizes to be similar to the pre-injury brain and that the patient’s abilities and experiences will
105return to the pre-injury level as well (Lindeløv, Overgaard, & Overgaard, 2017).
106 Returning to the importance of expectations of brain injury sequelae, we speculate that
107mindfulness typically help the patient by downplaying the importance of existing expectations while
108hypnosis directly changes expectations to the benefit of the patient. In the process, hypnosis may even
109enhance the role of these “new” expectations. In this way, expectation is an important mediator for
110mindfulness and hypnosis alike (Jamieson, 2016) at a general level, but they typically seek different
111kinds of expectation modifications.
112

113Review: cognitive rehabilitation using hypnosis and mindfulness1

114 The idea that hypnotic suggestion could be used in neurorehabilitation has been suggested
115multiple times in the academic literature (Fromm, Sawyer, & Rosenthal, 1964; Laidlaw, 1993; Oakley
116& Halligan, 2009). Hypnosis has been successfully applied in motor rehabilitation (Irawan, Mardiyono,
117Suharto, & Santjaka, 2018; Spankus & Freeman, 1962), aphasia (Thompson, Hall, & Sison, 1986),
118pain, vertigo, and a range of related sequelae (Appel, 2003; Cedercreutz, Lähteenmäki, & Tulikoura,
1191976). Indeed, patients with stroke or concussion has been shown to be as hypnotizable as a non-
120injured reference sample (Kihlstrom, Glisky, McGovern, Rapcsak, & Mennemeier, 2013; Laidlaw,
1211993).
122 However, cognitive rehabilitation using hypnosis has received limited attention. We begin by
123reviewing the existing literature that uses parallel-groups. We then proceed to present new empirical
124evidence from a randomized controlled trial (Lindeløv et al., 2017).
125 A recent single-blinded randomized controlled trial with 68 acquired brain injury patients found
126that hypnotic suggestion improved working memory performance with large effect sizes of d = 1.55
127and d = 2.03 (Lindeløv et al., 2017) on two multi-test indices relative to passive controls. Furthermore,
128the effect did not wane in the follow-up period of 7 weeks. Using an active control group in addition to
129passive controls, this study identified the contents of the suggestions as a selective driver of the effect
130over and above non-specific effects such as expectancy, the hypnotic state, etc. Surprisingly, hypnotic
131suggestion improved working memory to just above the population average, indicating a complete
132recovery in this respect.
133 To our knowledge, just a handful of other studies have used parallel-groups designs to
134investigate the effect of hypnotic suggestion on cognitive impairment following acquired brain injury.

11 A full and continuously updated list of literature on hypnosis for motor rehabilitation, aphasia, dementia, etc., is available
2at http://lindeloev.net/scientific-papers-on-hypnosis-and-brain-injury/
135All include suggestions that a particular negative consequence of acquired brain injury no longer
136applies, which is likely to induce this expectation in the patient.
137 Milos (1975) used hypnotic age regression to alleviate amnesia for the events surrounding
138automotive TBI and succeeded in seven out of 20 patients with severe injuries. However, the reports
139were not verified, so it is unclear whether these recollections reflect a genuine alleviation of amnesia or
140a more liberal response criterion (Dywan & Bowers, 1983; Klatzky & Erdelyi, 1985).
141 Sullivan et al. (1974) recruited 24 brain-injured patients (unspecified origin) in the chronic
142phase with an IQ between 50 and 75 at baseline and stratified them into three groups. The treatment
143group received a very short 7-sentence anxiety-reducing hypnotic suggestion, including “From now on
144you will not feel nervous or afraid while doing things. You will feel very relaxed. You will be able to
145do jobs better than before.” (Sullivan et al., 1974, p. 97) Even from this very brief intervention,
146Sullivan et al. observed an improvement (Cohen’s d ~ .2) on one out of two neuropsychological tests
147compared to an active and a passive control group.
148 In a later study, Cui-Ping (2011)2 conducted individualized hypnotic treatment with 71 stroke
149patients in the sub-acute phase between one and twelve weeks following incidence. The outcome was
150compared to 49 patients in a passive control group. They observed large positive effects (d ~ 1) on
151overall functioning, anxiety, and depression compared to the control group.
152 Although Sullivan et al. (1974) and Cui-Ping (2011) do lend some support to the findings of
153Lindeløv et al. (2017), they are severely underreported, leaving out important information about
154participants, randomization, blinding of testers, statistical procedures, etc. In particular, it is not clear
155whether Cui-Ping (2011) was peer-reviewed, there is no information about the hypnotic suggestions,
156and it does not report the interaction effect between gains in the treatment group and control group
157(Nieuwenhuis, Forstmann, & Wagenmakers, 2011; Redick, 2015). For these reasons, we think that
158more evidence is needed to assess the consistency and magnitude of the effect of hypnotic suggestion
159on patients with acquired brain injury.
160 Several studies have aimed at (and succeeded in-) decreasing fatigue and increasing motivation
161for physical rehabilitation following acquired brain injury using hypnotic suggestion (Crasilneck &
162Hall, 1970; Diamond, Davis, Schaechter, & Howe, 2006). As such, improved cognitive functioning
163need not be an outcome per se as it can also be used as a means to facilitate other aspects of
164rehabilitation.

32 The original manuscript is Chinese. An English translation is available at http://lindeloev.net/scientific-papers-on-

4hypnosis-and-brain-injury/
165 There is convincing evidence from two RCTs that MBSR can reduce average fatigue following
166acquired brain injury (B. Johansson, Bjuhr, & Rönnbäck, 2012; Birgitta Johansson, Bjuhr, Karlsson,
167Karlsson, & Rönnbäck, 2015). Three RCTs indicate that mindfulness suggestion has only small or no
168average effect on cognitive test performance (Azulay, Smart, Mott, & Cicerone, 2013; Birgitta
169Johansson et al., 2015; McMillan, Robertson, Brock, & Chorlton, 2002) as has also been found in the
170general population (Sedlmeier et al., 2012). As a potential exception, Johansson et al. (2012) did
171observe large average positive within-group effects in the treatment group, but the authors did not
172conduct the critical interaction test whether these effects exceeded that of the control group
173(Nieuwenhuis et al., 2011).
174 In the following, we build on this literature by reporting new empirical findings on the use of
175hypnosis for chronic cognitive sequelae of acquired brain injury.
176
177Methods

178 The method and the primary outcomes of this RCT has been reported in Lindeløv et al. (2017).
179Here, we report all quantitative secondary outcomes.

180Interventions

181 The hypnosis was written to a manuscript as dictated by the hypnotist to reduce experimenter
182effects. Thus, the treatment was not individualized. The induction and termination was identical for all
183participants. We administered two hypnosis protocols. Each protocol was four one-hour treatment
184sessions with new manuscripts each session, including the induction and the termination.
185 The “targeted” hypnotherapy received suggestions about regaining pre-morbid abilities. We
186used various techniques towards this end, including regression to the pre-morbid state, suggestions
187about extensive brain plasticity during hypnosis, and suggestions about an ongoing experience of ease
188and automaticity of thought. We call these “targeted” suggestions because they directly target the core
189problem of improving working memory-related functioning.
190 The “non-targeted” hypnotherapy served as an active control to the “targeted” therapy.
191Following the standardized hypnotic induction, the “non-targeted” hypnosis borrowed suggestions
192from Mindfulness meditation, asking participants to cultivate their attention to stay directed at the
193present moment and accepting any pleasant and unpleasant thoughts or sensations as they are, without
194judging them or acting on them. There was no direct mentioning of the brain injury or working
195memory-related functioning, though the termination of the hypnosis did include the post-hypnotic
196suggestion that patients would awake “refreshed and feel better”. As mentioned in the introduction,
197Mindfulness meditation has shown small- or no improvement on cognitive tests, and thus the non-
198targeted group served as an active control to the targeted group.
199 There was a passive control group, which is not reported here because they did not participate
200in the interviews.
201

202Procedure

203 This study is an RCT with a parallel-groups phase including a follow-up phase. This is followed
204by a second phase of intervention where both groups received the targeted intervention. Participants
205were assigned to the two groups using a coin toss.
206 The “targeted-first” group received targeted suggestion in both phase 1 and phase 2. The
207“targeted-last” group received non-targeted suggestion in phase 1 and crossed over to receive targeted
208suggestion in phase 2. Thus, targeted-last group serves as an active control to isolate the effect of
209“targetedness” in phase 1 and after the break. Both groups received four sessions of targeted suggestion
210in phase 2, and this phase mainly serves to see dose-response effects in the targeted-first group as well
211as addressing the possibility that unresponsive patients were, by chance, randomized to the targeted-last
212group.
213 Participants were tested and interviewed before and after each phase.
214

215Outcomes

216 Semi-structured interviews were conducted before and after each treatment phase. Here, we
217report on the results from the closed questions.
218 Sleep: We asked participants to report their daily duration of nightly sleep, daily sleep, and
219daily rest at each of the four testing sessions.
220 Patient-Reported Outcomes (PRO): At baseline, patients were asked to define a set of PROs.
221They were followed up in the subsequent interviews, asking for progress on each PRO using the
222ordinal scale “Much worse”, “Worse,” “Same” (no progress), “Better,” “Much better,” and “Not a
223problem anymore” (maximum progress, henceforth called “Achieved” for brevity). Rehabilitation
224science, in general, has recently moved toward a larger focus on patient-reported outcomes (PRO).
225Rather than having the experimenter decide on the important outcomes, PRO let the patients define the
226outcomes and report their progress towards achieving these outcomes (Snyder et al., 2012).
227 WAIS-III Working Memory Index (Wechsler, Coalson, & Raiford, 1997) is an index score
228which is computed from the performance on three tasks: digit span (forwards and backwards), letter-
229number sequencing, and mental arithmetic.
230 Trail Making Test log(B – A) index: patients draw lines between consecutive numbers to test
231psychomotor speed (form A) and alternating between consecutive numbers and letters to test the
232additional cost of task switching (form B). The difference in completion times (B – A) operationalizes
233task switching ability (Sánchez-Cubillo et al., 2009) and the logarithm renders our data normally
234distributed.
235 Subjective experience of progress: Participants were asked to evaluate their performance in the
236Working Memory and Trail Making tests (see above) which preceded the interview. They reported
237their performance relative to the baseline test performance using the ordinal scale “much worse,”
238“worse,” “same,” “better” or “much better.” This constituted their perceived improvement while the
239actual change in test performance constituted the objective improvement. The degree to which the two
240correspond (their correlation) was taken as an index of metacognitive accuracy with Kendall’s τ = 1
241being fully accurate and τ = 0 being no meta-cognitive information. A one-sided Kendall correlation (τ)
242with a stretched-beta prior width = .5 was used for computing p and BF (van Doorn, Ly, Marsman, &
243Wagenmakers, 2017), the prior expressing a weak skepticism of strong correlation coefficients given
244prior literature on this correspondence (Knight, Harnett, & Titov, 2005; Schiehser et al., 2011).
245 Participants were unaware that there were two treatment groups, and were thus blinded to this
246contrast. The neuropsychological tester was blinded to the allocation of each participant. The sleep and
247PRO data was collected by the hypnotist, who was not blinded. We discuss blinding in the “limitations”
248section.
249
250
251
252

253Results

254Participants

255 Patient characteristics are presented in Table 1. The patient group was heterogeneous because
256we had no a priori knowledge or hypothesis that patient characteristics were important for the effect.
257We have previously shown that age, hypnotizability, etiology, and duration since injury did not
258modulate the effect (Lindeløv et al., 2017).
259

260
261 [TABLE 1 HERE]

262

263Sleep and rest

264 The interviews elicited complete reports from 16 participants in the targeted-first group and 8
265participants in the targeted-last group.
266 Figure 1 show the individual and summarized sleep- and rest-trends. We used the total daily
267duration of sleep and rest per individual as a crude index. We conducted a Bayesian Wilcoxon Signed
268Rank test on the change from baseline to the follow-up session. Hypnotic suggestion reduced daily
269sleep and rest by around an hour in the targeted-first group (Mdn = -57.5 minutes) and in the targeted-
270last group (Mdn = -52.5 minutes), p = .0008, BF = 30.9 (see priors and posteriors in the Supplementary
271materials). There was no (strong) evidence that these effects differed (W = 73, p = .60, BF = 0.5) as
272assessed using a Bayesian two-tailed Mann-Whitney U test on change scores (van Doorn et al., 2017).
273 The self-reported duration of sleep did not correlate to the self-reported “Problems with sleep”
274item from the European Brain Injury Questionnaire at any of the four testing sessions (Kendall’s τ
275= .09, -.14, -.12, and -.03 for session 1 through 4).
276
277 [FIGURE 1 HERE]
278

279Patient-Reported Outcomes

280 Frequent PROs included regaining the ability to (1) take part in a conversation with multiple
281people or with one person amidst background chatter, (2) reading without quickly tiring, (3)
282remembering new names, phone numbers or characters in fiction, (4) do grocery shopping.
283 The distribution of progress reports can be seen in Figure 2. The categories “Much worse” and
284“worse” were not used and are omitted from further analysis. There was only anecdotal evidence of a
285difference in the distributions of progress reports between the targeted-first group and the targeted-last
286group after phase 1 (X2 = 10.82, df = 3, p = .013, BF = 2.8) but the evidence was very strong for a
287difference at follow-up (X2 = 18.25, df = 3, p = .00039, BF = 333.6). At the final test, when all patients
288had received the targeted intervention, the evidence is ambiguous as to whether the distribution of
289improvements are identical or different between the two groups (X2 = 6.28, df = 3, p = .099, BF = .58),
290but a visual inspection show that any differences are small because they concern adjacent categories
291rather than a general skew.
292 Only after targeted suggestions did the participants begin to report that they had achieved their
293PROs (after phase 1 in the targeted-first group and after phase 2 in the targeted-last group). The
294magnitude of the effect following the full 8-session program is substantial with the achievement of
29525.4% of the PROs initially set by the participants, and just 13.6% of the PROs lack progress.
296
297 [FIGURE 2 HERE]
298
299 These results indicate that the effect of targeted suggestions differs from the effect of the
300mindfulness-like non-targeted suggestions. While both improved progress on goals, targeted suggestion
301has better long-term effects and exclusively lead to the achievement of the PROs.
302

303Perceived and Objective Test Performance

304 We observed no correlation between perceived and objective changes in performance in neither
305of the two groups at post-test and follow-up (see Table 2). In fact, there was no correlation between
306perceived and objective changes in performance when collapsing all data from all testing sessions and
307both groups on the Working Memory Index (τ = -.01, p = .57, BF = .17) nor the Trail Making Test (τ
308= .05, p = .28, BF = .36), as is also evident in Figure 3. In other words, the participants had little or no
309information about the magnitude of their improvements or deteriorations in their performance on the
310neuropsychological tests. This is surprising considering that most patients experienced large
311improvements of z > 1.5 in both tests (see Figure 3; grid lines represent z scores of 1, 2, 3, ...). This is
312particularly evident in the targeted-first group where the majority of the participants perceived no
313change in their testing performance immediately following the targeted-suggestion phase even though
314this was the most rapid increase in objective performance at any point in the experiment.
315
316 [TABLE 2 HERE]
317
318 [FIGURE 3 HERE]
319
320

321One Latent Improvement?

322 Above, we found a low validity of perceived improvement on the neuropsychological tests as
323an index of actual improvement. We have no such objective measures of other outcomes (sleep, PROs,
324reports by relatives, etc.), but an assessment of convergent validity between effects on in all dependent
325variables can be used to infer the structure of the underlying improvement(s). At one extreme, there is a
326hypothesis of one latent improvement. In an exploratory factor analysis, this should yield one factor
327with strong loadings from all dependent variables. At the other extreme, there is no systematicity
328resulting in weak joint loadings of dependent variables in a factor analysis.
329 We used a Bayesian exploratory factor analysis (Conti, Frühwirth-Schnatter, Heckman, &
330Piatek, 2014) on the treatment effects reported in the previous sections: the Working Memory Index,
331the Trail Making Test, perceived neuropsychological improvement, total sleep and rest duration, and
332average progress on PROs. In addition to this, we add the self-rated European Brain Injury
333Questionnaire (EBIQ) core scale (Sopena, Dewar, Nannery, Teasdale, & Wilson, 2007; Teasdale et al.,
3341997) and the relative-rated EBIQ core scale. Two hundred out of 1029 data points were missing and
335imputed using the corresponding conditional (posterior predictive) distribution during MCMC
336sampling.
337 A one-factor solution was strongly preferred including just three outcome measures: the
338Working Memory Index (mean loading = .56, 95% CI = [0.29, 0.91]), the Trail Making Test (mean
339loading = .67, 95% CI = [0.35, 0.96]), and the relative-rated EBIQ with a more moderate factor loading
340(mean loading = .26, 95% CI = [0.00, 0.46]). Pairwise correlations between all outcomes are available
341in the Supplementary information.
342 This analysis confirms that the improvements on the working memory and the Trail Making test
343reflected a latent working memory improvement, which also moderately expresses itself in overt
344behavior as assessed by relatives on the EBIQ. Interestingly, all outcomes reported by the participants
345themselves failed to reach this convergent validity, including the self-rated EBIQ.
346

347Discussion

348 We have presented evidence that there is a large positive effect of targeted hypnotic suggestion
349on real-life goals and fatigue following acquired brain injury. The effects of “targetedness” of the
350hypnotic suggestion has previously been shown to be instrumental for improvement on
351neuropsychogical tests (Lindeløv et al., 2017), and we find a similar effect on achieving specific
352behavioral goals. We found positive evidence that while hypnosis reduced the need for sleep with
353around one hour daily, “targetedness” of the hypnotic suggestions did not enhance or diminish that
354positive effect notably. Given that most participants reported that these sequelae had been stable for
355years, we consider it likely that the improvement can be causally attributed to the hypnotic procedures.
356 The use of hypnosis was motivated by the observation that expectations of acquired brain injury
357sequelae seem to be important predictors of manifest impairment (Craig et al., 2016; Mittenberg et al.,
3581992). Since changing expectations of psychological and behavioral outcomes may be integral to how
359hypnosis works (Kirsch, 1985; Lifshitz et al., 2012), the use of hypnosis could also be effective in
360neurorehabilitation. The current study is not designed to evaluate the credibility of this motivation, but
361one result does lend support it: participants erred on the side of being too pessimistic about their
362objective improvements, which may be a consequence of a “negative surprise” if they expected to be
363able to perform even better. This potential mechanism remains to be tested directly. If true, this would
364indicate that the positive effects on sleep in both treatment groups could be due to common factors in
365the two treatments, e.g., relaxation and reduced worrying.
366 The literature to date has found unanimous positive findings when using hypnotic suggestion
367for cognitive rehabilitation (Cui-Ping, 2011; Milos, 1975; Sullivan et al., 1974), but we advanced our
368methodological reservations about these findings in the introduction. More peripheral evidence from
369Sapp’s (1992) successful anxiety-reduction in stroke- and TBI patients, as well as the major reduction
370of vertigo in concussed patients by Cedercreutz et al. (1976), does add further support to the hypothesis
371that hypnotic suggestion can be effective following acquired brain injury. The report of the
372neuropsychological test results from the present RCT similarly found large effect sizes, while
373addressing many of the methodological shortcomings in the previous literature. Effects of the
374magnitudes observed in the present article and in prior research are occasionally observed in the
375literature on cognitive rehabilitation, but we find their consistency across studies and outcome
376measures to be striking in the case of hypnotic suggestion.
377 Taken at face value, the close-to-zero correlation between objective performance and perceived
378performance implies that the participant’s reports are invalid as a measure of manifest improvement.
379This could imply that hypnosis in general may induce a lack of self-insight. However, we have since
380learned that poor self-insight is a general feature of the healthy (Schmidt, Berg, & Deelman, 2001; Zell
381& Krizan, 2014) as well as brain-injured patient populations (Knight et al., 2005; Schiehser et al.,
3822011) with similar correlation coefficients. Thus, we argue that the poor correspondences should not be
383attributed to hypnosis. The weak correlation could also imply that the results from the other subjective
384outcome measures are invalid. However, a meta-analysis by Zell et al. (2014) showed that the
385correlation is stronger for performances closer to activities of daily living (r ~ .3) than for mental
386abilities (r ~ .15), so the reports on sleep and patient-reported outcomes may have a higher validity than
387the reports on cognitive performance. Future studies would do well verify subjective reports using
388relatives’ (subjective) reports as well.
389 We found evidence that self-reported on sleep and rest, patient-reported outcomes, and
390symptoms are not related (see also supplementary Figure S1). That is, there is no tendency across
391participants in how each of these improvements relate to other improvements, with the exception that
392there is a correlation between “outside” observations from relatives and neuropsychological tests. This
393lack of a general latent improvement factor is evidence that individuals with acquired brain injury have
394very different subjective experiences of the treatment effects. The practical implication of this, if true,
395is that we currently cannot predict how each patient will perceive the effects, other than that the
396experiences will generally be positive. The self-reported performance on the neuropsychological tests
397systematically erred on the side of being too pessimistic, so patients may tend to report smaller effects
398than objectively true.
399 We believe that these observations highlight a need for observable outcome measures when
400assessing the effect of hypnosis – and possibly of (mindfulness) meditation – following acquired brain
401injury.
402

403Limitations

404 The evidence presented here is primarily limited by small sample sizes. Future studies could
405additionally improve on the present work by differentiating sleep quality and sleep duration and should
406include objective measures of functioning and participation in society, e.g., return-to-work, caregiver
407burden, and observations of functional independence.
408 Lindeløv et al. (2017) tested a number of sources of individual differences, including age at
409injury, current age, time since injury, injury type, baseline cognitive performance, and hypnotizability,
410but neither of these predicted differences in improvement on the outcomes. While this could indicate
411that hypnotic suggestion is a versatile therapeutic method for a large group of patients, it does leave us
412in limbo concerning the mechanisms underlying the improvements.
413 The demand characteristics in a clinical trial generally encourage participants in the treatment
414groups to report improvements, though a review found that participants are not biased by this demand
415(McCambridge, Bruin, & Witton, 2012). If they were, however, this would induce positive correlations
416between outcomes, which would result in one latent factor spanning all interview-data. This was not
417observed, so the effect of any demand characteristics are likely to be small in the present study.
418 Similarly, this is evidence that the non-blinded interviewer did not systematically bias the
419results. The lack of blinding in RCTs generally cause a small-to-medium effect size inflation of around
420d = 0.3 in general patient populations (Holman, Head, Lanfear, & Jennions, 2015) and for brain-injured
421patients (Lindeløv, 2015). The observed effects of hypnotic suggestion go beyond the effect of
422blinding, and were also observed by the completely blinded tester. Taken together, the fact that the
423interviewer was not blinded may have inflated the effect sizes, but not to the degree that it qualitatively
424changes the interpretation of the large effect sizes observed in the present RCT.
425

426Cost-Effectiveness

427 Considering the brevity of the intervention (4-8 sessions) and the fact that manualized versions
428require little preparation, it is promising from a cost-effectiveness perspective. As a crude index of
429cost-effectiveness, the Number Needed to Treat can be multiplied with the hours needed per treatment
430to obtain the cost per successful treatment as Hours Needed to Treat (HNT). For PRO, we can define a
431successful outcome as “much better” or “not a problem anymore”. At after eight sessions, the PRO
432success rate was 43% for both groups, translating to HNT = 8 / 0.43 = 18.6 hours therapist time needed
433for a successful rehabilitation concerning the patients achieving their set goals. For sleep and rest, we
434could define a success 45 minutes of more active time. We get HNT = 8 / 0.37 = 21.6 hours for both
435groups. For the neuropsychological tests, we define success as an improvement > 1 SD on both
436outcomes, resulting in HNT = 8 / 0.67 = 11.9 hours. The comparable costs for RCTs on Attention
437Process Training, Mindfulness-Based Stress Reduction, computer-based training, and physical exercise
438are in the hundreds of hours for patients with acquired brain injury – either due to small effect sizes or
439expensive treatments (Lindeløv, 2015). Hypnotic suggestion compares favorably.
440

441Clinical Implications

442 We believe that the current evidence justifies using hypnotic suggestion as an experimental
443adjunct to existing treatment. More evidence is needed before deciding whether hypnotic suggestion
444could be implemented as a standard treatment or replace existing treatments. In other words, one
445should be ready to discontinue the treatment if it fails to replicate in high-quality RCTs. We are
446currently conducting one such RCT.
447

448Acknowledgments

449 The authors would like to thank Lars Evald for thorough comments on an early draft and an
450anonymous reviewer for suggestions greatly enhancing the clarity of the manuscript.
451

452Funding

453 This study was supported by the European Research Council funding number 241111 and the
454Karen-Elise Jensen foundation.
455

456Author contributions

457 JKL, MO, and RO designed and collected the data. RO administered the treatment. JKL
458analyzed the data and wrote the manuscript. All authors approved the final manuscript.
459
460
461

462
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651Tables

652

N and gender Cause of injury Age (SD) Years since Hypnotizability WAIS-III
TBI / Stroke / injury [IQR] SHSS:C (SD) Working
Other Memory
Index (SD)

Targeted-first 27 (12 males) 18 / 5 / 4 45.2 (13.0) 5.0 [4-11] 7.7 (2.1) 81.7 (12.8)

Targeted-last 22 (8 males) 12 / 5 / 5 47.0 (14.1) 6.5 [2-11] 6.8 (3.3) 80.4 (11.7)

653

654Table 1. Participant characteristics at baseline. Years since the injury is represented by means and [25-

65575 % Inter-Quartile Range] since it is not normally distributed. SHSS:C is the Stanford Hypnotic

656Susceptibility Scale Form C (Weitzenhoffer and Hilgard, 1962).

657
658
Test Targeted-first (N=25) Targeted-last (N=31)

Working Memory Index τ = -.22, p = .93, BF = .13 τ = .02, p = .44, BF = .39

Trail Making Test τ =-.15, p =.14, BF = 1.2 τ = -.08, p = .29, BF = .59

659
660Table 2. Kendall correlations between perceived and objective improvements on two

661neuropsychological tests at post-test and follow-up relative to baseline performance.

662
663
664
665Figure 1. Self-reported hours of nightly sleep, daily sleep and daily rest for 24 participants where full

666datasets were available. The rightmost panel is the medians and inter-quartile ranges for total sleep- and

667rest duration per day. In the other panels, each line represents an individual’s progression on nightly

668sleep, daily sleep, and daily rest respectively. A small vertical jitter of +/- 2 minutes is added to

669visualize the density of overlapping lines – in particular at zero (no sleep or rest).

670
671

672

673
674Figure 2. Reports of improvements on Patient-Reported Outcomes relative to baseline. Each panel

675sums to 100% of the responses given for that group-phase combination. The numbers on each bar are

676the percentages and counts. There are evident improvements in both groups. Notably, only a few of the

677PROs maintain a “Same” status, and the achievement of the goals occur only following treatment with

678targeted suggestion.

679
680

681

682
683Figure 3. Changes on perceived performance change (shape) and objective performance change since

684baseline (symbol location) on the two neuropsychological tests for each phase and group. The dots near

685the intersection between the solid lines in each panel correspond to no improvement on the objective

686outcomes while the dots in the upper right correspond to large improvement on both outcomes. The

687grid lines correspond to standardized mean differences of 0, 1, 2... where differences larger than .8 are

688conventionally labeled as “large” effects (Cohen, 1992). While changes on the two tests are correlated,

689reflecting a general improvement in working memory performance, categories of perceived

690improvement are completely overlapping, indicating that the participants had little or no information

691about their objective improvement on these tests.