Accepted Manuscript

Effects of mindfulness and psychoeducation on working memory in adult ADHD: A

randomised, controlled fMRI study

Katharina Bachmann, Alexandra P. Lam, Peter Sörös, Manuela Kanat, Eliza Hoxhaj,
Swantje Matthies, Bernd Feige, Helge Müller, Jale Özyurt, Christiane M. Thiel,
Alexandra Philipsen
PII: S0005-7967(18)30070-6
DOI: 10.1016/j.brat.2018.05.002
Reference: BRT 3261

To appear in: Behaviour Research and Therapy

Received Date: 2 November 2017

Revised Date: 16 April 2018
Accepted Date: 3 May 2018

Please cite this article as: Bachmann, K., Lam, A.P., Sörös, P., Kanat, M., Hoxhaj, E., Matthies, S.,
Feige, B., Müller, H., Özyurt, J., Thiel, C.M., Philipsen, A., Effects of mindfulness and psychoeducation
on working memory in adult ADHD: A randomised, controlled fMRI study, Behaviour Research and
Therapy (2018), doi: 10.1016/j.brat.2018.05.002.

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 ACCEPTED MANUSCRIPT
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2 Effects of mindfulness and

3 psychoeducation on working memory in
4 adult ADHD: a randomised, controlled
5 fMRI study

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6 Katharina Bachmann1, Alexandra P. Lam1,2, Peter Sörös1,3, Manuela Kanat4, Eliza Hoxhaj5, Swantje
Matthies5, Bernd Feige5, Helge Müller1, Jale Özyurt2,3, Christiane M. Thiel2,3, Alexandra Philipsen1,5,6

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9 Medical Campus University of Oldenburg, School of Medicine and Health Sciences, Psychiatry and

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10 Psychotherapy – University Hospital, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany
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11 Biological Psychology Lab, Department of Psychology, European Medical School, Carl von

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12 Ossietzky Universität Oldenburg, Germany
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13 Research Center Neurosensory Science, University of Oldenburg, Oldenburg, Germany
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14 Section of Health Care Research and Rehabilitation Research, Institute for Medical Biometry and
15 Statistics, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg,
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16 Germany
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17 Department of Psychiatry and Psychotherapy Medical Center – University of Freiburg, Faculty of
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18 Medicine University of Freiburg, Germany

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19 Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
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22 Word count
23 Abstract: 200
24 Text: 5600
25 References: 50
26 Tables & figures: 7
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46 Corresponding author:
47 Katharina Bachmann
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48 Medical Campus University of Oldenburg, School of Medicine and Health Sciences, Psychiatry and
49 Psychotherapy – University Hospital, Karl-Jaspers-Klinik, Bad Zwischenahn, Germany
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50 Postal address: Hermann-Ehlers-Straße 7, 26160 Bad Zwischenahn, Germany.

51 Tel.: 0049-441-9615-1504
52 Fax: 0049-441-9615-1599
53 Email: Katharina.Bachmann@uni-oldenburg.de

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54 Abstract

55 Adult attention-deficit/hyperactivity disorder (ADHD) is a serious mental disorder associated with

56 impaired neurocognitive performance related to working memory function. Recent clinical trials have
57 suggested that mindfulness is a promising intervention in adults with ADHD. We performed a
58 randomised controlled clinical trial to investigate working memory (WM) with an n-back task in
59 adults with ADHD during fMRI before and after an 8-week mindfulness intervention (MAP)
60 compared with psychoeducation (PE). ADHD symptoms were assessed using the self- and observer-
61 rated Conners Adult ADHD Rating Scales (CAARS).

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62 The complete pre–post data of 21 MAP and 19 PE participants were analysed. We found no
63 group difference in ADHD symptoms or task performance at the pre-measurement, but there was a
64 significant decrease in ADHD symptoms and significant improvement in task performance in both

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65 groups at the post-measurement. Furthermore, we found a significant increase in task-related
66 activation in the right parietal lobe, with no difference between groups. Exploratory two-sample paired
67 t-tests revealed significant increased brain activation after MAP in the bilateral inferior parietal lobule,

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68 right posterior insula and right precuneus. A decrease in self-rated ‘Inattention/Memory Problems’
69 after MAP compared to baseline was associated with stronger activation in parts of the left putamen,
70 globus pallidus and thalamus.
71

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72 Keywords: Mindfulness, fMRI, ADHD, Adult, Neuropsychotherapy, Psychoeducation
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73 Funding
74 The project was partly funded by the Federal Ministry for Education and Research
75 (Bundesministerium für Bildung und Forschung, BMBF, 01GV0606).
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76 Trial Registration
77 isrctn.org Identifier: ISRCTN12722296.
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79 Introduction

80 Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects healthy

81 psychological functioning (Volkow & Swanson, 2013), and it is associated with mental health
82 problems, as well as impaired academic and social functioning (Asherson, Buitelaar, Faraone, &
83 Rohde, 2016; NICE, 2013). The DSM characterises ADHD by its three cardinal symptoms:
84 inattention, hyperactivity and impulsivity. Approximately 2.5% of the adult population meets the
85 criteria for ADHD (APA, 2013; Volkow & Swanson, 2013).

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86 Although methylphenidate hydrochloride is recommended as the first-line treatment for
87 ADHD’s core symptoms (NICE, 2013), psychopharmacological treatment with methylphenidate has
88 limitations, such as nonresponse, contraindications, adverse events or patients’ preference for a
89 nonpsychopharmacological treatment. Therefore, nonpharmacological interventions are needed.

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90 Impairments in working memory are a defining and persisting characteristic of ADHD in
91 adulthood (Alderson, Kasper, Hudec, & Patros, 2013; Salavert et al., 2015). Working memory is a
92 vital function for managing everyday life, for instance, in making decisions and plans or storing

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93 information (Owen, McMillan, Laird, & Bullmore, 2005). Difficulties with working memory function
94 can be quite impairing, and they can distort everyday functioning. ADHD-related impairments in
95 working memory have been associated with low academic achievement, inhibition control and social
96 functioning (Fried et al., 2016; Kofler et al., 2017; Tseng & Gau, 2013).

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97 The current research suggests that mindfulness can improve working memory capacity
98 (Chambers, A Lo, Chuen Yee, & Allen, 2008; Fabio & Towey, 2018; Jha, Stanley, Kiyonaga, Wong,
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99 & Gelfand, 2010; Zeidan, Johnson, Diamond, David, & Goolkasian, 2010). For example, a recent
100 study assessed the effect of an intense, 8-week mindfulness programme on executive functioning in an
101 adult ADHD sample. The post-treatment effects indicated a significant improvement in executive
102 functioning, including working memory (Janssen, Vries, Hepark, & Speckens, 2017).
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103 When applied as a clinical intervention, mindfulness is intended to increase one’s awareness
104 of internal and external experiences of the present moment (Kabat-Zinn, 1990). It teaches patients to
105 respond more adaptively to the physiological and psychological processes involved in psychiatric
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106 disorders (Bishop et al., 2004). Research on the behavioural and psychological changes after
107 mindfulness training has shown clear beneficial effects of mindfulness on ADHD symptoms,
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108 improving attention, emotion regulation and quality of life, thereby supporting the application of
109 mindfulness interventions for ADHD (Bueno et al., 2015; Hoxhaj et al., 2018; Mitchell et al., 2017;
110 Mitchell, Zylowska, & Kollins, 2015). For example, a recent meta-analytic review by Cairncross and
111 Miller (2016) has provided preliminary evidence for the effectiveness of mindfulness in reducing core
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112 ADHD symptoms. The findings of this study demonstrated that mindfulness-based therapies
113 significantly reduce the symptoms of inattention and hyperactivity/impulsivity in adults with ADHD.
114 Mindfulness applied as clinical intervention in ADHD is of great interests since it can be
115 considered as a form of mental training that can improve neuropsychological deficits in ADHD, such
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116 as attention control, working memory, and emotion regulation, by strengthening the function of the
117 brain regions thought to underlie these deficits, such as the frontal and parietal brain areas (Bachmann,
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118 Lam, & Philipsen, 2016). Research on ADHD psychopathology suggests that there are structural and
119 functional abnormalities in multiple neuronal systems related to cognitive functions (Cortese et al.,
120 2012; Francx et al., 2016; Frodl & Skokauskas, 2012; Sörös et al., 2017). Specifically, dysfunctions in
121 the prefrontal cortex, parietal brain areas, and basal ganglia are associated with ADHD, and they have
122 been related to impairments in executive functioning and working memory (Frank, Loughry, &
123 O’Reilly, 2001; Norman et al., 2016; van Ewijk et al., 2015).
124 Earlier studies that used an n-back paradigm during functional magnetic resonance imaging
125 (fMRI) to examine the neural correlates of working memory in ADHD found abnormal activation in
126 brain regions associated with working memory. For example, Salavert et al. (2015) found less
127 deactivation of the medial frontal cortex during n-back performance in ADHD patients compared with
128 healthy controls. Another study demonstrated less activation of the left middle frontal gyrus, left

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129 frontal pole and paracingulate gyrus, as well as the right middle frontal gyrus, during the n-back task
130 in adults with ADHD compared with healthy controls (Salavert et al., 2015).
131 Research on the neurobiological effects of mindfulness meditation suggests that mindfulness
132 is associated with changes in brain areas associated with working memory. For example, functional
133 changes in the frontoparietal networks, as well as structural and functional changes in the cingulate
134 cortex and basal ganglia, have been reported after mindfulness training in nonclinical samples (Brewer
135 et al., 2011; Tang, Hölzel, & Posner, 2015). These findings suggest that mindfulness may improve
136 working memory function in adults with ADHD by altering the brain functioning in related brain
137 areas.
138 In the current study the effects of a mindfulness treatment (MAP)1 were compared with the

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139 effects of an active control treatment. The experience of the active control group was closely matched
140 to the training group in terms of effort (same amount of lessons and homework), duration of the
141 treatment and equal amount of attention and interaction time with the therapist. The active control
142 group received psychoeducation about ADHD. Psychoeducation (PE)2 is a psychological intervention

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143 that has demonstrated efficacy in reducing ADHD symptoms (Hoxhaj et al., 2018; Vidal et al., 2013).
144 PE is an approach that aims at improving the patients’ understanding and awareness of the disorder; it
145 can offer insight into past difficulties and can improve the patient’s general functioning (Vidal et al.,

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146 2013). PE’s major objective is to provide patients with information about their disorder. These
147 characteristics distinguish PE from other psychological interventions that focus more on cognitive and
148 behavioural changes, such as cognitive behavioural therapy methods involving cognitive
149 restructuring, behavioural change, or mindfulness meditation practice.

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150 However, research on PE’s neurobiological effects is scarce. We found one published fMRI
151 study that investigated the effects of PE on emotional Stroop task performance in patients with
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152 euthymic bipolar disorder and healthy controls. The results revealed altered frontolimbic activity after
153 PE in the patient group only (Favre et al., 2013). However, we did not find trials investigating PE’s
154 effects on working memory–related brain functioning. Furthermore, there have been no trials
155 investigating the neurobiological effects of mindfulness or PE in adults with ADHD.
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157 The current study aimed to close the identified gap in the literature by investigating the
158 working memory–associated neurobiological effects of MAP compared with an active control group (
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159 PE) in an adult ADHD sample. Based on the research on ADHD pathophysiology and neural effects of
160 mindfulness mentioned above, we predicted stronger brain activation in the frontoparietal regions and
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161 basal ganglia after MAP. We hypothesised that MAP would lead to increased brain activation
162 compared with PE. Finally, we expected stronger improvement in working memory performance for
163 MAP relative to PE.
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165 Methods
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166 Study Design and Participants

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167 The current fMRI study was part of a randomised controlled clinical trial comparing the effects of
168 MAP and PE on the symptomatology and neurobiological correlates of adult ADHD. The study was
169 approved by the local ethics committee and registered in the Current Controlled Trials database
170 (ISRCTN12722296).
171 The subjects were recruited in the adult ADHD outpatient clinic and inpatient units of the
172 Department of Psychiatry and Psychotherapy Medical Center at the University Hospital Freiburg. In
173 addition, the study was announced publicly on the clinic’s website. All the subjects participated in the
174 study voluntarily and provided written informed consent before participation.

1 MAP (Mindfulness Awareness Practice)

2 PE (Psychoeducation)

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175 The inclusion criteria for the current study were as follows: age of 18–65 years, diagnosis of
176 the ADHD combined subtype or inattentive subtype (ADD) according to the DSM-IV criteria, being
177 free from ADHD medication (stimulants or atomoxetine) or any psychotherapeutic treatment 3 months
178 prior to and during study participation and IQ > 85. Participants were excluded if they had the
179 following characteristics: a diagnosis of schizophrenia or bipolar disorder type I, current substance
180 abuse dependence, autism, acute suicidality, self-injurious behaviour or neurological disorders.
181 Additional exclusion criteria were MRI-specific contraindications (e.g. metal implants, current or
182 planned pregnancy).
183 The self- and observer-rated Conners Adult ADHD Rating Scales (CAARS; long German
184 version; (Conners, Erhardt, & Sparrow, 1999) were used as a measure of ADHD symptom severity.

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185 For a detailed description of the diagnostic procedure, see the Supplemental Data.

186 Randomisation and Masking

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187 Eligible patients were randomly assigned to either the PE (n = 37) or MAP (n = 37) group.
188 Randomisation was performed based on a computer-generated allocation sequence (1:1 ratio) by an
189 independent researcher. Two weeks prior to treatment, the participants’ ADHD symptoms were

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190 assessed by means of the CAARS self- and blind observer ratings, and the MRI measurements were
191 performed. After an 8-week treatment period with weekly sessions of 2.5 hours, 27 patients in the PE
192 group and 32 patients in the MAP group were assessed again for ADHD symptom severity via the
193 CAARS self- and blind observer rating, and fMRI measurement was performed a second time. The

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194 data from 8 participants from the PE group and 11 participants from the MAP group had to be
195 excluded from the fMRI analyses due to insufficient behavioural responses or excessive head
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196 movement (defined as maximum absolute displacement, as determined by FSL’s MCFLIRT, at greater
197 than 4 mm in one of the four experimental runs). The statistical analyses revealed no significant
198 differences in mean head movement during fMRI scanning before and after treatment between MAP
199 (mean: 1.14 [SE 0.13]) and PE (1.24 [SE 0.13]; difference 0.10 [95% Cl 0.27 to 0.48]; p=0.58).
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200 To avoid the inclusion of participants that responded randomly, we required a minimum
201 correct response. Patients were excluded if the number of target correct responses was less than 20 or
202 the number of non-target correct responses was less than 40 in one of the four runs. For a more
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203 detailed description of patient enrolment, see Supplemental Data Figure 1.

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204 Treatment

205 Mindfulness Meditation Group

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207 The MAP group was treated with mindful awareness practices. MAP is a group psychotherapy
208 programme for adults with ADHD that aims to teach a mindful mental attitude. With MAP, adults
209 with ADHD learn to focus their attention on the present moment and develop a nonjudgmental,
210 accepting attitude. Furthermore, MAP aims to increase the self-regulation ability and improves the
211 constructive handling of negative emotional states in adults with ADHD (Zylowska et al., 2008). The

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212 participants completed homework, including daily seated meditation and exercises in everyday life. To
213 prevent participants from de-motivation and overburdening, the duration of the homework training
214 sessions was increased gradually over the course of the treatment. In addition, the treatment paid
215 special attention to the discussion of typical problems associated with ADHD, reframing ADHD as a

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216 neurobiological variation and careful consideration of the selection of the didactic resources
217 (visualisation, etc.; see Supplemental Data Table 4 for an overview of the treatment sessions).

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218 Psychoeducation Group
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220 Patients in the PE group received the same duration and intensity of treatment as those in the MAP

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221 group. In the PE group, information on the causes, symptoms and treatment options for ADHD in
222 adulthood was provided in eight weekly sessions. Furthermore, participants were supported in the
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223 activation of organisational skills and stress management techniques, improvement of self-esteem and
224 mutual support among participants for everyday problems. The PE group’s treatment was based on the
225 manual Psychoeducation and Coaching (D'Amelio, 2009). This manual also includes a Zen exercise
226 for relaxation during breaks; for this study, this exercise was removed from the treatment programme.
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227 Furthermore, the first three sessions were combined into one. This was necessary to create comparable
228 conditions for time spent in treatment (see Supplemental Data Table 4 for an overview of the treatment
229 sessions).
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230 MRI Data Acquisition

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231 Structural and functional images of the brain were acquired on a 3 Tesla Siemens Magnetom Trio with
232 a 12-channel head coil at the Freiburg Brain Imaging Center. A T1-weighted image was acquired
233 using a three-dimensional magnetisation-prepared rapid acquisition gradient-echo (MP-RAGE)
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234 sequence with the following parameters: voxel size = 1 x 1 x 1 mm³, field of view (FoV) = 256 mm,
235 256 x 256 matrix, 160 sagittal slices, slice thickness = 1 mm, phase encoding direction of anterior ->
236 posterior, repetition time (TR) = 2200 ms, echo time (TE) = 4.11 ms, nonselective inversion recovery,
237 inversion time (TI) = 1000 ms, flip angle = 12° and no acceleration. During the one-back task, single-
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238 shot gradient-recalled echo-planar T2*-weighted blood oxygenation level–dependent (BOLD) images
239 were obtained with a voxel size of 3 x 3 x 3 mm³, FoV = 192 mm, 64 x 64 matrix, 36 axial slices, slice
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240 thickness = 3 mm, phase encoding direction of anterior -> posterior, TR = 2250 ms, TE = 30 ms, no
241 acceleration and 165 brain volumes per run. The first five scans of each run were discarded for spin
242 saturation.
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244 Working Memory Task

245 The functional images were acquired while participants performed a one-back letter task. The one-
246 back task is a continuous performance task used to investigate working memory. In the current study,
247 a sequence of white letters was shown to the subject on a black screen (visible through a projector and
248 mirror). The participants were instructed to indicate whether the current letter matched the previous

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249 one via a button press. In the case of two identical letters in a row (targets), the subject had to press the
250 right mouse button. Otherwise, the left mouse button had to be pressed (nontargets). The task design is
251 illustrated in Figure 1. Before the fMRI measurement, two test runs built on the same criteria were
252 carried out.
253 The experiment consisted of two runs of 20 blocks each. Each block consisted of 15 stimuli
254 and lasted 15 seconds. One run lasted 6 minutes and 16 seconds. The percentage of targets was
255 distributed differentially across the blocks, varying between 0% and 40% targets. The order of the
256 blocks was pseudorandomised. Accordingly, each run consisted of 300 stimuli, 29% of which were
257 targets. The onset-to-onset interval between the stimuli was 1000 ms. Stimulus durations were
258 variable, lasting 600, 700, 800 or 900 ms, and they were followed by a 400-, 300-, 200- or 100-ms

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259 interstimulus interval. At the beginning and end of each block, a white fixation cross on a black screen
260 was presented for 25 seconds.
261 Because of the demands of the scanning procedure (e.g. extended immobilisation, scanner
262 noise, psychological distress and the heterogeneous educational background of the participants), we

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263 decided to choose the one-back task to avoid underachievement on the task. To check for potential
264 ceiling effects, an analysis of the task performance was carried out.
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266

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268 Figure 1. Schematic overview of the one-back task. The design was presented in two runs á 6 minutes and 16 seconds.
269 Before and after each block a white fixation cross on a black screen was presented for 25 seconds. Each run consisted of a
270 sequence of 20 blocks with 15 stimuli. The participant was required to press the right mouse button when the current letter
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271 matched the previous one (target) and the left button otherwise.

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273 Demographic and Behavioural Data Analysis

274 An analysis of variance (ANOVA), Chi-squared test or Mann–Whitney U test, with the treatments
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275 (MAP vs. PE) as independent variables, was run on the demographic variables and task performance
276 when appropriate.
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277 MRI Data Analysis

278 Analysis of the MRI data was carried out in a multistage process using the FSL software library
279 (http://www.fmrib.ox.ac.uk). Correction of head motion was performed using MCFLIRT. Brain
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280 segmentation and removal of nonbrain tissue was achieved using BET. Spatial smoothing using a
281 Gaussian kernel with a full-width half maximum of 5 mm and mean-based intensity normalisation of
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282 all volumes by the same factor (four-dimensional grand mean scaling to ensure comparability between
283 datasets at the group level) were applied before the statistical analysis. Registration of high-resolution
284 structural images was carried out using FLIRT. Registration from high-resolution structural to
285 standard space (the MNI152_T1_2mm brain template) was then further refined using FNIRT
286 nonlinear registration.
287 The two fMRI runs obtained for each participant were analysed independently using general
288 linear modelling. Six events were modelled as regressors of interest, including correct and incorrect
289 responses and omissions for target and nontarget stimuli. For the brain activation reported here, the
290 contrast between target-correct and nontarget-correct responses was computed. A fixed-effects
291 analysis was then carried out to analyse the effects across the two runs for each patient. Finally,
292 mixed-effects analyses were performed across all participants using FLAME stages 1 and 2 and

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293 automatic outlier de-weighting. For all the statistical maps, cluster-based thresholding was used with a
294 cluster-forming threshold of Z > 2.3 and a (corrected) cluster significance threshold of p = 0.05. We
295 decided to choose a cluster-forming threshold of Z > 2.3 based on the results of a recent paper in
296 which the authors reported acceptable familywise error rates for a two-sample t-test on 2 x 10
297 participants performed with FSL’s FLAME1 and a spatial smoothing of 5 mm (Eklund, Nichols, &
298 Knutsson, 2016) .
299 A one-way repeated measures ANOVA was performed in FSL to test for the effects of the
300 intervention (MAP vs. PE) and time (before vs. after intervention). A two-sample paired t-test was
301 used to compare the brain activation before and after the intervention separately in the MAP and PE
302 group. The scores on the CAARS subscales were added as additional covariates to investigate the

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303 associations between the changes in symptom severity and brain activation before and after the
304 intervention. The anatomical labels of the activated brain regions were retrieved using FSLView 3.0
305 (http://www.fmrib.ox.ac.uk/fsl/fslview/index.html). All brain coordinates refer to the MNI152

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306 standard space T1-weighted average structural template image used by FSL.
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308 Results for the Clinical Data

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309 Demographics

310
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There were no significant differences between the MAP and PE group for any of the demographic
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311 variables of age, gender and education (see Table 1). Furthermore, no significant differences were
312 found in terms of the ADHD symptoms, subtype, comorbidity or medication (see Table 1).

313 Behavioural Data Analyses

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314 The task performance analysis revealed no ceiling effects on the one-back task (see Table 1). Before
315 treatment, the MAP participants had 54.55% (mean: 61.29 [SD: 15.51]) and PE participants had
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316 50.85% (57.13 [14.04]) target-correct responses. After the treatment, the MAP participants had
317 62.35% (70.05 [14.7]) and PE participants had 57.45% (64.55 [15.09]) target-correct responses.
318 Group-by-treatment repeated measures ANOVA showed a significant main effect of time on
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319 task performance, measured as the number of target-correct responses (mean: 59.21 [SE: 2.35] vs
320 67.30 [2.38]; difference: –8.09 [95% CI –11.72 to –4.46]; p < 0.0001) and reaction time of target-
321 correct responses (mean: 562.74 ms [SE: 11.93] vs 522.91 ms [10.94]; difference: –39.83 ms [95% CI
322 25.54 to 54.12]; p < 0.0001). We did not find a significant main effect of therapy or a significant
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323 interaction effect (Table 1).

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325 Table 1
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327 Sample characteristics and baseline versus post-measure of the mindfulness awareness practice (MAP) versus psychoeducation (PE)
328 comparison. ANOVA, the Chi-squared test or the Mann–Whitney U test was applied when appropriate.
MAP (n = 21) PE (n = 19) Test statistic
a 40 (10.58) 40.26 (13.81) t = 0.07, p = 0.095
Age (M, SD)

Education U = 169, p = 0.38

Secondary school (year 5–9) 3 1
Secondary school (year 5–10) 3 8
General qualification for university entrance (year 5–12/13) 8 6

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University degree 5 2
Gender (female) 13 9 χ² = 0.85, p = 0.36

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Subtype
Combined 17 15
Inattentive 4 4

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Medication 3 3
Antidepressant 1 3
Other 2 0

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Comorbid psychiatric disorder (n)
b 13 16 χ² = 2.49, p = 0.12
Current comorbid psychiatric disorder (Yes vs No, n)

Anxiety disorder 3 6
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Minor depressive disorder 12 14

Somatoform disorder 0 1
Obsessive-compulsive disorder 1 0
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Lifetime comorbid psychiatric disorder (Yes vs No, n) 6 5 χ² = 0.03, p = 0.87

Eating disorder 2 0
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Substance abuse 3 3
Personality disorder 2 2
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Baseline (T1) Post-measure (T2)

MAP (n = 21) PE (n = 19) MAP (n = 21) PE (n = 19)
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CAARS Observer rating
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Inattention/Memory Problems (M, SD) 18.71 (9.05) 17.58 (7.51) 16.29 (8.65) 15.53 (7.76)
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Hyperactivity/Restlessness (M, SD) 14.10 (8.20) 17.68 (7.39) 12.48 (7.61) 13.21 (7.58)

Impulsivity/Emotional Lability (M, SD) 13.86 (8.13) 13.11 (7.82) 11.62 (6.15) 9.47 (6.92)

Problems with Self-concept 10.52 (5.94) 11.68 (4.22) 8.10 (5.09) 9.32 (5.12)
(M, SD)
DSM-IV: Inattentiveness Symptoms 13.95 (6.85) 16.89 (5.55) 11.52 (6.52) 12.58 (6.42)
(M, SD)
DSM-IV: Hyperactivity–Impulsivity Symptoms 9.00 (5.75) 10.58 (5.55) 7.19 (4.66) 7.26 (4.11)
(M, SD)
DSM-IV: ADHD Symptoms Total 22.95 (10.97) 27.47 (9.86) 18.71 (9.68) 19.84 (9.12)

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(M, SD)

ADHD Index (M, SD) 17.38 (7.75) 19.26 (5.92) 14.14 (6.49) 13.95 (6.06)
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CAARS Self-rating

Inattention/Memory Problems (M, SD) 19.62 (7.54) 18.68 (6.58) 18.86 (8.18) 14.89 (6.26)
Hyperactivity/Restlessness (M, SD) 15.14 (7.53) 17.26 (8.25) 14.10 (7.85) 14.37 (6.47)
Impulsivity/Emotional Lability (M, SD) 16.00 (8.33) 14.95 (9.55) 14.57 (7.67) 11.42 (6.75)
Problems with Self-concept 12.14 (4.80) 12.58 (3.66) 10.76 (5.11) 11.11 (4.50)
(M, SD)

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DSM-IV: Inattentiveness Symptoms 15.10 (5.68) 15.84 (5.70) 14.33 (6.07) 13.26 (4.63)
(M, SD)
DSM-IV: Hyperactivity–Impulsivity Symptoms 8.57 (5.68) 11.00 (6.66) 8.86 (6.13) 8.37 (5.23)

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(M, SD)
DSM-IV: ADHD Symptoms Total 23.67 (9.21) 26.84 (11.16) 23.19 (10.05) 21.63 (8.17)

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(M, SD)
ADHD Index (M, SD) 19.48 (6.15) 19.58 (6.30) 18.24 (7.34) 16.74 (4.56)

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Correlation: CAARS Observer & Self-rating

Inattention/Memory Problems 0.76*** 0.78***

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Hyperactivity/Restlessness 0.83*** 0.75***

Impulsivity/Emotional Lability 0.79*** 0.81***

Problems with Self-concept 0.79*** 0.79***

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DSM-IV: Inattentiveness Symptoms 0.76*** 0.73***

DSM-IV: Hyperactivity–Impulsivity Symptoms 0.84*** 0.70***

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DSM-IV: ADHD Symptoms Total 0.79*** 0.69***

ADHD Index 0.71*** 0.55***

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One-backf
Reaction time (ms) (M, SD) 555.22 (82.28) 570.27 (66.86) 512.60 (70.06) 533.13 (68.02)
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One-back correct (M, SD) 61.29 (15.51) 57.13 (14.04) 70.05 (14.70) 64.55 (15.37)

One-back correct (%, SD) 54.55 (13.80) 50.85 (12.5) 62.35 (13.1) 57.45 (13.68)
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329 a
The age ranges were as follows: MM, 21–54 years; PE, 19–61. bAt least one comorbid disorder is present, however some patients had more
330 than one comorbid disorder. cCAARS = Conners Adult ADHD Rating Scale. dRepeated measures ANOVA (p ≤ 0.05) indicated that both
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331 groups had significantly lower levels of symptoms on all subscales of the CAARS observer ratings at the post-measurement. The between-
332 subjects comparison revealed no effect of therapy on any subscale, and no significant interaction effect was found. eRepeated measures
333 ANOVA (p ≤ 0.05) indicated that both groups had significantly lower levels of symptoms on all the subscales of the CAARS self-ratings at
334 the post-measurement except on the DSM-IV: Hyperactivity–Impulsivity Symptoms subscale. The between-subjects comparison revealed no
335 effect of therapy on any of the subscales, and no significant interaction effect was found. fRepeated measures ANOVA (p ≤ 0.05) indicated
336 that both groups showed better task performance after treatment; the between-subjects comparison revealed no effect of therapy.
337 *** p ≤ 0.001; ** p ≤ 0.01; * p ≤ 0.05

338

339
340

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341 CAARS Blind Observer Rating

342 Group-by-treatment repeated measures ANOVA revealed significant main effects of time for ADHD
343 symptoms measured with the observer-rated CAARS on all subscales (see Table 2). We did not find
344 evidence for a significant main effect of treatment or a significant interaction effect on any of the
345 subscales (see Table 1).
346
347 Table 2
348
349 Main effects of time for CAARS observer-rated ADHD symptoms with group-by-treatment repeated measures ANOVA (p ≤ 0.05).
Observer-rated CAARS subscales T1 T2 Difference p-

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Mean (SE) Mean (SE) (95% CI) value

Inattention/Memory Problems 18.15 (1.32) 15.91 (1.30) 2.24 (0.18 to 4.31) 0.03
Impulsivity/Emotional Lability 13.48 (1.26) 10.55 (1.03) 2.94 (0.70 to 5.17) 0.01

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Hyperactivity/Restlessness 15.89 (1.24) 12.84 (1.20) 3.05 (0.94 to 5.15) 0.006
Problems with Self-Concept 11.10 (0.82) 8.71 (0.81) 2.40 (1.23 to 3.56) <0.001
DSM-IV: Inattentiveness Symptoms 15.42 (0.99) 12.05 (1.03) 3.37 (1.66 to 5.08) <0.001

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DSM-IV: Hyperactivity–Impulsivity 9.79 (0.89) 7.23 (0.68) 2.56 (1.18 to 3.95) 0.001
Symptoms
DSM-IV: ADHD Symptoms Total 25.21 (1.66) 19.28 (1.49) 5.94 (3.26 to 8.61) <0.001
ADHD Index 18.32 (1.10) 14.05 (0.99) 4.33 (2.07 to 6.48) <0.001
350 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CAARS, Conners Adult ADHD Rating Scale; T1, baseline; T2, post-

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351 measurement after 12 weeks.
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352 CAARS Self-rating

353 Group-by-treatment repeated measures ANOVA revealed significant main effects of time for ADHD
354 symptoms when assessed with the CAARS self- rating on all subscales except ‘DSM-IV:
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355 Inattentiveness Symptoms’ (see Table 3). We did not find evidence for a significant main effect of
356 treatment or a significant interaction effect on any of the subscales (see Table 1).
357
358 Table 3
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359
360 Main effects of time for CAARS self-rated ADHD symptoms with group-by-treatment repeated measures ANOVA (p ≤ 0.05).
Self-rated CAARS subscales T1 T2 Difference p-value
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Mean (SE) Mean (SE) (95% CI)

Inattention/Memory Problems 19.15 (1.12) 16.88 (1.16) 2.28 (0.49 to 4.06) 0.01
Impulsivity/Emotional Lability 15.45 (1.41) 12.99 (1.15) 2.48 (2.53 to 4.70) 0.03
Hyperactivity/Restlessness 16.20 (1.25) 14.23 (1.15) 1.97 (0.26 to 3.69) 0.02
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Problems with Self-Concept 12.36 (0.68) 10.93 (0.76) 1.43 (0.27 to 2.58) 0.02
DSM-IV: Inattentiveness Symptoms 15.47 (0.90) 13.79 (0.86) 1.67 (0.24 to 3.10) 0.02
DSM-IV: Hyperactivity–Impulsivity Symptoms 9.79 (0.98) 8.61 (0.91) 1.17 (-0.31 to 2.66) 0.12
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DSM-IV: ADHD Symptoms Total 25.25 (1.61) 22.41 (1.15) 2.84 (0.10 to 5.59) 0.04
ADHD Index 19.53 (0.99) 17.49 (0.98) 2.04 (0.18 to 3.89) 0.03
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361 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CAARS, Conners Adult ADHD Rating Scale; T1, baseline; T2, post-
362 measurement after 12 weeks.
363
364 The statistical analyses revealed significant correlations between the CAARS self- and observer
365 ratings at the pre- and post-measurement on all subscales (see Table 1).
366

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367 fMRI Results

368 Effect of intervention.

369 A group x time ANOVA across all patients revealed a significant main effect of time, indicating
370 significantly higher activation in the right parietal lobe (peak coordinates: x = 28 mm, y = –58 mm, z
371 = 44 mm; max. Z-value: 3.61) for the contrast target-correct minus nontarget responses during the
372 one-back task after compared with before the intervention. There was no main effect of therapy or a

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373 significant interaction effect. To explore whether the main effect of time was driven by one of the two
374 groups, a two-sample paired t-test was performed separately for each group. This analysis revealed
375 significant higher activation during the post- compared with the pre-mindfulness one-back task in the
376 MAP group (Figure 2). These areas were mainly located in the left and right inferior parietal lobule,

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377 right posterior insula and right precuneus (Table 4). In the PE group, no significant differences in
378 brain activation were found before and after the intervention.
379

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380
381
382 Figure 2. The effect of mindfulness on brain activation in adults with ADHD. Z-statistic images are overlaid onto the mean
383
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structural T1-weighted images of the participants. Brain areas color-coded in red and yellow show significantly stronger
384 activation after compared with before mindfulness for target-correct responses in the one-back letter task. Cluster 1: left
385 inferior parietal lobule; cluster 2: right posterior insula; cluster 2a: right inferior parietal lobule; cluster 3: right precuneus.
386
387
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388 Effect of symptom severity.

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389 An exploratory linear regression revealed that, in the MAP group, a decrease in the score on the
390 ‘Inattention/Memory Problems’ subscale on the self-reported CAARS between the pre- and the post-
391 intervention fMRI experiment was associated with significantly stronger activation in parts of the left
392 putamen, globus pallidus and thalamus (peak coordinates: x = –26 mm, y = 4 mm, z = 0 mm; max. Z-
393 value: 4.23). No significant associations were found between changes in the scores on any other
394 CAARS self-report. In addition, for the MAP group, we found an association between a decrease in
395 the score on the observer-rated CAARS scale ‘Hyperactivity/Restlessness’ and a significantly stronger
396 activation in the bilateral medial prefrontal cortex (peak coordinates: x = –8 mm, y = 28 mm, z = –14
397 mm; max. Z-value: 3.87) and bilateral posterior cingulate cortex (peak coordinates: x = –4 mm, y = –

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398 46 mm, z = 12 mm; max. Z-value: 3.59) (Figure 3). Exploratory linear regression in the PE group did
399 not reveal any association between scores on the CAARS scales and brain activation.
400

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401

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402 Figure 3. The effect of mindfulness on brain activation in adults with ADHD. Brain activation map of patients before and
403 after MAP. In the areas shown in yellow and red, a decrease in the score on the observer-rated CAARS scale
404
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“Hyperactivity/Restlessness” (i.e. an improvement of the symptom hyperactivity/restlessness between the first and second
405 measurement) predicted a significantly stronger activation during the second n-back compared with the first n-back
406 measurement. Significant areas are in the bilateral medial prefrontal cortex and bilateral posterior cingulate cortex. Z-statistic
407 images are overlaid onto the mean structural T1-weighted images of the participants. The upper two rows show axial images
408 of the brain in the radiological convention (the right hemisphere is on the left). The last row shows sagittal images of the left
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409 and right hemisphere.

410
411 Table 4
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412
413 Brain areas showing significantly stronger activation after MAP
Cluster No. Brain area Hemisphere x (mm) y (mm) z (mm) Voxels Maximum Z-value
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1 Inferior parietal lobule (BA 39) Left –36 –64 46 354 3.58

2 Posterior insula (BA 13) Right 36 –18 6 640 3.47

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2a Inferior parietal lobule Right 50 –26 22 3.20

3 Precuneus (BA 31) Right 8 –60 30 319 3.25

414 Abbreviation: BA denotes Brodmann area.

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415
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416 Discussion

417 In our pioneer longitudinal fMRI study, we investigated the neurobiological effects of a highly
418 structured, intense mindfulness programme compared with an active control group (PE) in an adult
419 ADHD sample. Both groups received the same number of treatment sessions and attention. Working
420 memory was assessed by means of a visual one-back memory task during fMRI. Against our
421 hypothesis, MAP was not superior in improving working memory function compared with PE. We
422 found a significant main effect of time, indicating significantly higher activation in the right parietal
423 lobe for target-correct responses, irrespective of the group. However, further exploratory analysis

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424 revealed a task-related significant increase in brain activation in brain areas associated with working
425 memory, such as the bilateral inferior parietal lobule, in the MAP group after the intervention.
426 Furthermore, we found higher neural activation in parts of the basal ganglia that were significantly
427 associated with decreased self-rated inattention and memory problems for the MAP group only. In
428 addition, for the MAP group, we found evidence that a decrease in the score on the observer-rated
429 CAARS scale ‘Hyperactivity/Restlessness’ was significant associated with stronger activation in the
430 bilateral medial prefrontal cortex and the bilateral posterior cingulate cortex. In contrast, no significant
431 pre–post difference of brain activation and no association of activation and symptom reduction were
432 found after PE. Our results are consistent with our hypothesis that the MAP group showed stronger
433 brain activation in brain circuits related to working memory and attention after mindfulness

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434 meditation. We found a mindfulness-related increase in brain activation in brain areas associated with
435 working memory, namely the bilateral inferior parietal lobule, precuneus and right posterior insula.
436 While both groups significantly improved on task performance after treatment, we could not
437 find evidence for better task-related working memory performance after MAP compared with PE.

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438 There are several possible explanations for this. First, it may be that both interventions can improve
439 working memory function, when assessed with an n-back paradigm, and provide effective strategies to
440 improve working memory function in different ways. Second, it can be argued that our finding of

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441 changes in neurobiological activation in the MAP group may primarily point to changes in brain
442 function that do not yet have a visible effect on behaviour. Furthermore, it could be that the observed
443 timeframe was too short, and more MAP practice is needed to detect behavioural changes related to
444 changed neurobiological activation compared with PE. Third, given the small sample size and low

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445 power of the study, possible treatment effects may not have been detectable.
446 Given the current findings, it can be hypothesised that, in the short term, PE and MAP are
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447 equally effective in improving working memory function in ADHD, and differences in brain
448 activation and working memory performance between PE and MAP may emerge after a longer period.
449 However, these explanations are somewhat speculative, since there is no previous research comparing
450 these two interventions. In addition, more research investigating the effects of mindfulness compared
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451 with PE on working memory function in larger adult ADHD samples is needed.
452
453 The results from the fMRI analyses revealed a mindfulness-related increase in brain activation in brain
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454 areas associated with working memory. We found changed brain activation in the bilateral inferior
455 parietal lobule, precuneus and right posterior insula.
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456 The insula is a functionally heterogeneous structure that has been associated with sympathetic
457 activation of the autonomic nervous system during executive task performance (Ruiz Vargas, Sörös,
458 Shoemaker, & Hachinski, 2016); it seems to be involved in regulating cognitive processes (Mrazek,
459 Mooneyham, Mrazek, & Schooler, 2016). Previous research showed increased insula activation after
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460 mindfulness meditation and greater cortical thickness in experienced meditators (Tang et al., 2015). It
461 has been suggested that enhanced insula activation after meditation may represent an increased
462 awareness of the present moment (Tang et al., 2015). In contrast, the inferior parietal lobule plays an
463 important role in working memory and seems to be involved in retaining temporal information,
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464 switching attention and preparedness for task performance (Owen et al., 2005; Sonuga-Barke &
465 Castellanos, 2007; Vannini et al., 2011). In addition, the inferior parietal lobule and precuneus have
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466 been related to the default mode network (DMN; (Buckner, Andrews-Hanna, & Schacter, 2008;
467 Castellanos et al., 2008).
468 The DMN is a brain network that is inactive during task performance and active in the resting
469 state (Bachmann et al., 2016). ADHD has been conceptualised as a disorder of disrupted DMN
470 functioning, where uncontrolled DMN activity disrupts other neural systems during task performance,
471 thereby causing impairments in executive functioning, including attentional processes and working
472 memory (Sonuga-Barke & Castellanos, 2007). It has been shown that meditators show different DMN
473 activation compared with non-meditators, and they may be better able to exert control on the
474 deactivation of non-task-related brain circuits (Brewer et al., 2011; Tang et al., 2015). Based on these
475 observations, our finding of stronger activation of the inferior parietal lobule, precuneus and left

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476 posterior insula under working memory load after MAP may point to improved present-moment
477 awareness and enhanced functioning of brain circuits related to working memory.
478 We also found evidence of a decrease in self-rated symptoms of inattention and memory
479 problems in the MAP group that was significantly associated with stronger activation in parts of the
480 left putamen, globus pallidus and thalamus. Those brain structures are functionally connected, and
481 stronger activation in these areas may point to improved interregulation between these regions. This
482 finding is especially interesting, as it has been suggested that working memory and attention have
483 overlapping mechanisms that are organised by shared neural circuits and that working memory
484 capacity relies on the ability to successfully select and ignore internal and external stimuli (Bayerl et
485 al., 2010). It has been hypothesised that the basal ganglia fulfil a gating function. They regulate the

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486 influence of incoming stimuli, and by their interconnection to the frontal brain regions, also relate to
487 executive function (Frank et al., 2001). Our finding of a significant association of stronger activation
488 in parts of the basal ganglia after MAP and a decrease in self-rated symptoms of inattention and
489 memory problems may point to improved executive functioning in ADHD adults after MAP. This

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490 assumption may also apply to our finding of a significant association between the scores of the
491 observer-rated CAARS scale ‘Hyperactivity/Restlessness’ and stronger activation in the bilateral
492 medial prefrontal cortex and bilateral posterior cingulate cortex, as both regions are involved in

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493 cognitive and behavioural control and are part of the DMN.
494 We could not find evidence for an association of observer-rated symptoms of inattention and
495 memory problems with brain activation for the MAP group. Neither did we find a significant
496 association of self-rated symptoms of hyperactivity and restlessness with brain activation. It may be

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497 that the patients’ self-ratings of inattention and memory problems are a better indicator of changes in
498 brain activation than the observer ratings are. In contrast, the observer-rated symptoms of
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499 hyperactivity and restlessness may better predict brain activation compared with self-ratings. Since
500 inattention and memory are internal processes, they may be more difficult to observe by a rater,
501 whereas hyperactivity is a more external behaviour, where changes may be easier to assess. In
502 addition, based on our clinical impression, the patients seemed to be more aware of and suffer more
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503 from the consequences of their inattention and forgetfulness than from their hyperactivity. Therefore,
504 patients may give a more accurate indication of changed symptoms of inattention.
505
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506 The current results should be considered in view of some methodological limitations. First, our results
507 should be interpreted with caution, as they rely on exploratory analyses, and a significant interaction
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508 effect is missing. This means we cannot rule out that the observed differences in brain activation after
509 mindfulness meditation were moderated by causes other than the treatment, such as a training effect or
510 unspecific treatment effects. However, previous research has shown that mindfulness meditation can
511 alter brain function associated with working memory. Future studies should investigate a longer
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512 treatment period, since 8 weeks of mindfulness practice may be too short to exert a significantly
513 stronger neurobiological effect in adults with ADHD compared with other interventions. Furthermore,
514 it has been reported that mindfulness novices activate different brain areas compared with experienced
515 meditators. For example, areas of the prefrontal and parietal cortices seem to be more active in the
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516 early stages of mindfulness training; in contrast, in the advanced stages, activation in these areas is
517 often reduced, while activation in the striatum, insula and anterior cingulate cortex remains (Tang et
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518 al., 2015). Our findings may reflect neurobiological activation related to a learning process in an early
519 stage of meditation training that relies on more active cognitive regulation and mental effort, while at a
520 more advanced level, mindfulness meditation may be more automatized, with other brain regions more
521 strongly involved. Related to our findings, the nonsignificant interaction effect suggests that, at such
522 an early treatment stage, patients in both groups must still effortfully learn and apply a new strategy,
523 and therefore, engage in stronger reliance on brain areas associated with learning and mental effort.
524 This process of learning may have the same neurobiological underpinnings, regardless of the
525 intervention applied. Future research is needed to reveal whether, at a later point in treatment when
526 mindfulness meditation is applied more automatically, additional significant mindfulness-related brain
527 activation is evoked. In addition, it would be of interest to assess the frequency and duration of

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528 mindfulness practice to investigate whether those who practice more often exhibit stronger effects and
529 whether a certain intensity of practice is needed to alter brain functioning by mindfulness.
530 As we aimed to investigate the neurobiological effects of a mindfulness training programme in
531 comparison with a PE programme, both specifically developed for patients with ADHD, in a head-to-
532 head trial, we chose not to include a healthy control group. Yet, we think future research should
533 further investigate the neurobiological effects of mindfulness meditation in patients with ADHD
534 compared with healthy controls. This could give further insight into the potential therapeutic effects of
535 mindfulness practice on brain functioning in ADHD. For example, such research could clarify whether
536 ADHD adults exert brain functioning that is closer to that of healthy controls after mindfulness
537 practice. In addition, we did not implement either a control group with treatment as usual or a

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538 nontreatment control group. Future researchers may wish to further investigate the neurobiological
539 effects of mindfulness in adults with ADHD in comparison with, for example, psychopharmacological
540 treatment or a nontreatment group. These investigations could show whether mindfulness as a
541 nonpharmacological treatment alternative is superior to nontreatment, or whether it has similar effects

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542 on brain function to medication by, for example, alternating the functioning of the frontal brain areas,
543 anterior cingulate cortex, insula or striatum (Rubia et al., 2014; Tang et al., 2015). Finally, it can be
544 argued that co-occurring comorbid disorders may have confounded our results. However, ADHD is

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545 characterised by high comorbidity. Approximately 80% of the patients do have another psychiatric
546 disorder, especially mood and anxiety disorders (Pitts, Mangle, & Asherson, 2015). In this respect, our
547 sample is quite typical. The selection of only non-comorbid cases would not have been representative
548 of the typical ADHD population (Cubillo & Rubia, 2010). It would be of great interest to investigate

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549 the effects of mindfulness interventions in ADHD in relation to comorbidities in higher-powered
550 studies since the efficacy of mindfulness interventions has been established for anxiety, stress and
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551 depressive disorders that are often comorbid with ADHD (Goldberg et al., 2018). Furthermore, it has
552 been suggested that changes in neural functioning in response to mindfulness interventions might
553 differ in relation to symptoms of the disorder (Young et al., 2018). For example, ADHD patients with
554 symptoms of emotional dysregulation might show different neural changes than ADHD patients
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555 without these symptoms. Also, comorbid symptoms such as anxiety or depression may effect the
556 neurobiological response to mindfulness interventions.
557 In summary, the current results build on the growing body of evidence concerning the
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558 neurobiological effects of mindfulness meditation. This is the first study that could show that
559 mindfulness meditation influences brain regions associated with impaired working memory
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560 functioning and inattention in adults with ADHD. The current findings suggest that MAP may be an
561 effective neuropsychotherapeutic approach for regulating ADHD-related brain dysfunction in adults.
562
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563 References

564
565 Alderson, R. M., Kasper, L. J., Hudec, K. L., & Patros, C. H. (2013). Attention-deficit/hyperactivity disorder (ADHD) and
566 working memory in adults: a meta-analytic review. Neuropsychology, 27(3), 287–302.
567 doi:10.1037/a0032371
568 APA. (2013). Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Washington DC: Amer Psychiatric
569 Association.
570 Asherson, P., Buitelaar, J., Faraone, S. V., & Rohde, L. A. (2016). Adult attention-deficit hyperactivity disorder: key
571 conceptual issues. Lancet Psychiatry, 3(6), 568–578. doi:10.1016/s2215-0366(16)30032-3

PT
572 Bachmann, K., Lam, A. P., & Philipsen, A. (2016). Mindfulness-Based Cognitive Therapy and the Adult ADHD Brain: A
573 Neuropsychotherapeutic Perspective. Front Psychiatry, 7, 10.3389/fpsyt.2016.00117.
574 doi:10.3389/fpsyt.2016.00117
575 Bayerl, M., Dielentheis, T. F., Vucurevic, G., Gesierich, T., Vogel, F., Fehr, C., . . . Konrad, A. (2010). Disturbed brain

RI
576 activation during a working memory task in drug-naive adult patients with ADHD. Neuroreport, 21(6), 442–
577 446. doi:10.1097/WNR.0b013e328338b9be
578 Bishop, S. R., Lau, M., Shapiro, S., Carlson, L., Anderson, N. D., Carmody, J., . . . Velting, D. (2004). Mindfulness: A

SC
579 proposed operational definition. Clinical psychology: Science and practice, 11(3), 230–241.
580 Brewer, J. A., Worhunsky, P. D., Gray, J. R., Tang, Y. Y., Weber, J., & Kober, H. (2011). Meditation experience is associated
581 with differences in default mode network activity and connectivity. Proceedings of the National Academy of
582 Sciences of the United States of America, 108(50), 20254–20259. doi:10.1073/pnas.1112029108
583 Buckner, R. L., Andrews-Hanna, J. R., & Schacter, D. L. (2008). The brain's default network: anatomy, function, and

U
584 relevance to disease. Ann N Y Acad Sci, 1124, 1–38. doi:10.1196/annals.1440.011
585 Bueno, V. F., Kozasa, E. H., da Silva, M. A., Alves, T. M., Louza, M. R., & Pompeia, S. (2015). Mindfulness Meditation
AN
586 Improves Mood, Quality of Life, and Attention in Adults with Attention Deficit Hyperactivity Disorder.
587 Biomed Res Int, 2015, 962857. doi:10.1155/2015/962857
588 Cairncross, M., & Miller, C. J. (2016). The Effectiveness of Mindfulness-Based Therapies for ADHD: A Meta-Analytic
589 Review. J Atten Disord. doi:10.1177/1087054715625301
590 Castellanos, F. X., Margulies, D. S., Kelly, A. M. C., Uddin, L. Q., Ghaffari, M., Kirsch, A., . . . Milham, M. P. (2008). Cingulate
M

591 - Precuneus Interactions: A New Locus of Dysfunction in Adult Attention-Deficit/Hyperactivity Disorder.

592 Biological psychiatry, 63(3), 332–337. doi:10.1016/j.biopsych.2007.06.025
593 Chambers, A., A Lo, R., Chuen Yee, B., & Allen, N. B. (2008). The Impact of Intensive Mindfulness Training on
D

594 Attentional Control, Cognitive Style, and Affect. Cognitive Therapy and Research, 32, 303-322.
595 Conners, C. K., Erhardt, D., & Sparrow, E. P. (1999). Conner's Adult ADHD Rating Scales (CAARS) Toronto, ON: Multi-
596 Health Systems.
TE

597 Cortese, S., Kelly, C., Chabernaud, C., Proal, E., Di Martino, A., Milham, M. P., & Castellanos, F. X. (2012). Towards
598 systems neuroscience of ADHD: A meta-analysis of 55 fMRI studies. The American journal of psychiatry,
599 169(10), 10.1176/appi.ajp.2012.11101521. doi:10.1176/appi.ajp.2012.11101521
600 Cubillo, A., & Rubia, K. (2010). Structural and functional brain imaging in adult attention-deficit/hyperactivity
601 disorder. Expert Rev Neurother, 10(4), 603–620. doi:10.1586/ern.10.4
EP

602 D'Amelio, R. (2009). Psychoedukation und Coaching ADHS im Erwachsenenalter: Manual zur Leitung von Patienten-und
603 Angehörigengruppen: Elsevier, Urban&FischerVerlag.
604 Eklund, A., Nichols, T. E., & Knutsson, H. (2016). Cluster failure: Why fMRI inferences for spatial extent have inflated
605 false-positive rates. Proceedings of the National Academy of Sciences of the United States of America, 113(28),
C

606 7900–7905. doi:10.1073/pnas.1602413113

607 Fabio, R. A., & Towey, G. E. (2018). Long-term meditation: the relationship between cognitive processes, thinking
AC

608 styles and mindfulness. Cogn Process, 19(1), 73-85. doi:10.1007/s10339-017-0844-3

609 Favre, P., Baciu, M., Pichat, C., De Pourtales, M. A., Fredembach, B., Garcon, S., . . . Polosan, M. (2013). Modulation of
610 fronto-limbic activity by the psychoeducation in euthymic bipolar patients. A functional MRI study.
611 Psychiatry Res, 214(3), 285–295. doi:10.1016/j.pscychresns.2013.07.007
612 Francx, W., Llera, A., Mennes, M., Zwiers, M. P., Faraone, S. V., Oosterlaan, J., . . . Beckmann, C. F. (2016). Integrated
613 analysis of gray and white matter alterations in attention-deficit/hyperactivity disorder. Neuroimage Clin,
614 11, 357–367. doi:10.1016/j.nicl.2016.03.005
615 Frank, M. J., Loughry, B., & O’Reilly, R. C. (2001). Interactions between frontal cortex and basal ganglia in working
616 memory: A computational model. Cognitive, Affective, & Behavioral Neuroscience, 1(2), 137–160.
617 doi:10.3758/cabn.1.2.137
618 Fried, R., Chan, J., Feinberg, L., Pope, A., Woodworth, K. Y., Faraone, S. V., & Biederman, J. (2016). Clinical correlates of
619 working memory deficits in youth with and without ADHD: A controlled study. J Clin Exp Neuropsychol,
620 38(5), 487-496. doi:10.1080/13803395.2015.1127896

18
 ACCEPTED MANUSCRIPT
621 Frodl, T., & Skokauskas, N. (2012). Meta-analysis of structural MRI studies in children and adults with attention deficit
622 hyperactivity disorder indicates treatment effects. Acta Psychiatr Scand, 125(2), 114–126.
623 doi:10.1111/j.1600-0447.2011.01786.x
624 Goldberg, S. B., Tucker, R. P., Greene, P. A., Davidson, R. J., Wampold, B. E., Kearney, D. J., & Simpson, T. L. (2018).
625 Mindfulness-based interventions for psychiatric disorders: A systematic review and meta-analysis. Clin
626 Psychol Rev, 59, 52-60. doi:10.1016/j.cpr.2017.10.011
627 Hoxhaj, E., Sadohara, C., Borel, P., D'Amelio, R., Sobanski, E., Muller, H., . . . Philipsen, A. (2018). Mindfulness vs
628 psychoeducation in adult ADHD: a randomized controlled trial. Eur Arch Psychiatry Clin Neurosci.
629 doi:10.1007/s00406-018-0868-4
630 Janssen, L., Vries, A. M. d., Hepark, S., & Speckens, A. E. M. (2017). The Feasibility, Effectiveness, and Process of Change
631 of Mindfulness-Based Cognitive Therapy for Adults With ADHD: A Mixed-Method Pilot Study. J Atten Disord,
632 0(0), 1087054717727350. doi:10.1177/1087054717727350

PT
633 Jha, A. P., Stanley, E. A., Kiyonaga, A., Wong, L., & Gelfand, L. (2010). Examining the protective effects of mindfulness
634 training on working memory capacity and affective experience. Emotion, 10(1), 54–64.
635 doi:10.1037/a0018438
636 Kabat-Zinn, J. (1990). Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness.

RI
637 New York, NY: Deltacorte Press.
638 Kofler, M. J., Sarver, D. E., Spiegel, J. A., Day, T. N., Harmon, S. L., & Wells, E. L. (2017). Heterogeneity in ADHD:
639 Neurocognitive predictors of peer, family, and academic functioning. Child Neuropsychol, 23(6), 733-759.
640 doi:10.1080/09297049.2016.1205010

SC
641 Mitchell, J. T., McIntyre, E. M., English, J. S., Dennis, M. F., Beckham, J. C., & Kollins, S. H. (2017). A Pilot Trial of
642 Mindfulness Meditation Training for ADHD in Adulthood: Impact on Core Symptoms, Executive Functioning,
643 and Emotion Dysregulation. J Atten Disord, 21(13), 1105-1120. doi:10.1177/1087054713513328
644 Mitchell, J. T., Zylowska, L., & Kollins, S. H. (2015). Mindfulness Meditation Training for Attention-

U
645 Deficit/Hyperactivity Disorder in Adulthood: Current Empirical Support, Treatment Overview, and Future
646 Directions. Cognitive and behavioral practice, 22(2), 172–191. doi:10.1016/j.cbpra.2014.10.002
647 Mrazek, M. D., Mooneyham, B. W., Mrazek, K. L., & Schooler, J. W. (2016). Pushing the Limits: Cognitive, Affective, and
AN
648 Neural Plasticity Revealed by an Intensive Multifaceted Intervention. Front Hum Neurosci, 10,
649 10.3389/fnhum.2016.00117. doi:10.3389/fnhum.2016.00117
650 NICE. (2013). Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people
651 and adults. Nice clinical guideline 72. Retrieved from https://www.nice.org.uk/guidance/cg72.
M

652 Norman, L. J., Carlisi, C., Lukito, S., Hart, H., Mataix-Cols, D., Radua, J., & Rubia, K. (2016). Structural and Functional
653 Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A
654 Comparative Meta-analysis. JAMA Psychiatry, 73(8), 815–825. doi:10.1001/jamapsychiatry.2016.0700
655 Owen, A. M., McMillan, K. M., Laird, A. R., & Bullmore, E. (2005). N-back working memory paradigm: a meta-analysis of
D

656 normative functional neuroimaging studies. Hum Brain Mapp, 25(1), 46–59. doi:10.1002/hbm.20131
657 Pitts, M., Mangle, L., & Asherson, P. (2015). Impairments, diagnosis and treatments associated with attention-
658
TE

deficit/hyperactivity disorder (ADHD) in UK adults: results from the lifetime impairment survey. Arch
659 Psychiatr Nurs, 29(1), 56–63. doi:10.1016/j.apnu.2014.10.001
660 Rubia, K., Alegria, A. A., Cubillo, A. I., Smith, A. B., Brammer, M. J., & Radua, J. (2014). Effects of Stimulants on Brain
661 Function in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis. Biological
662 psychiatry, 76(8), 616-628. doi:10.1016/j.biopsych.2013.10.016
EP

663 Ruiz Vargas, E., Sörös, P., Shoemaker, J. K., & Hachinski, V. (2016). Human cerebral circuitry related to cardiac control:
664 A neuroimaging meta‐analysis. Annals of Neurology, 79(5), 709–716.
665 Salavert, J., Ramos-Quiroga, J. A., Moreno-Alcazar, A., Caseras, X., Palomar, G., Radua, J., . . . Pomarol-Clotet, E. (2015).
666 Functional Imaging Changes in the Medial Prefrontal Cortex in Adult ADHD. J Atten Disord,
C

667 10.1177/1087054715611492. doi:10.1177/1087054715611492

668 Sonuga-Barke, E. J., & Castellanos, F. X. (2007). Spontaneous attentional fluctuations in impaired states and
AC

669 pathological conditions: a neurobiological hypothesis. Neurosci Biobehav Rev, 31(7), 977–986.
670 doi:10.1016/j.neubiorev.2007.02.005
671 Sörös, P., Bachmann, K., Lam, A. P., Kanat, M., Hoxhaj, E., Matthies, S., . . . Philipsen, A. (2017). Inattention Predicts
672 Increased Thickness of Left Occipital Cortex in Men with Attention-Deficit/Hyperactivity Disorder. Frontiers
673 in Psychiatry, 8(170). doi:10.3389/fpsyt.2017.00170
674 Tang, Y. Y., Hölzel, B. K., & Posner, M. I. (2015). The neuroscience of mindfulness meditation. Nat Rev Neurosci, 16(4),
675 213–225. doi:10.1038/nrn3916
676 Tseng, W. L., & Gau, S. S. (2013). Executive function as a mediator in the link between attention-deficit/hyperactivity
677 disorder and social problems. J Child Psychol Psychiatry, 54(9), 996-1004. doi:10.1111/jcpp.12072
678 van Ewijk, H., Weeda, W. D., Heslenfeld, D. J., Luman, M., Hartman, C. A., Hoekstra, P. J., . . . Oosterlaan, J. (2015). Neural
679 correlates of visuospatial working memory in attention-deficit/hyperactivity disorder and healthy controls.
680 Psychiatry Res, 233(2), 233–242. doi:10.1016/j.pscychresns.2015.07.003

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681 Vannini, P., O'Brien, J., O'Keefe, K., Pihlajamaki, M., Laviolette, P., & Sperling, R. A. (2011). What goes down must come
682 up: role of the posteromedial cortices in encoding and retrieval. Cereb Cortex, 21(1), 22–34.
683 doi:10.1093/cercor/bhq051
684 Vidal, R., Bosch, R., Nogueira, M., Gomez-Barros, N., Valero, S., Palomar, G., . . . Ramos-Quiroga, J. A. (2013).
685 Psychoeducation for adults with attention deficit hyperactivity disorder vs. cognitive behavioral group
686 therapy: a randomized controlled pilot study. J Nerv Ment Dis, 201(10), 894–900.
687 doi:10.1097/NMD.0b013e3182a5c2c5
688 Volkow, N. D., & Swanson, J. M. (2013). Adult attention deficit–hyperactivity disorder. New England Journal of
689 Medicine, 369(20), 1935–1944.
690 Young, K. S., van der Velden, A. M., Craske, M. G., Pallesen, K. J., Fjorback, L., Roepstorff, A., & Parsons, C. E. (2018). The
691 impact of mindfulness-based interventions on brain activity: A systematic review of functional magnetic

PT
692 resonance imaging studies. Neurosci Biobehav Rev, 84, 424-433. doi:10.1016/j.neubiorev.2017.08.003
693 Zeidan, F., Johnson, S. K., Diamond, B. J., David, Z., & Goolkasian, P. (2010). Mindfulness meditation improves cognition:
694 evidence of brief mental training. Conscious Cogn, 19(2), 597-605. doi:10.1016/j.concog.2010.03.014
695 Zylowska, L., Ackerman, D. L., Yang, M. H., Futrell, J. L., Horton, N. L., Hale, T. S., . . . Smalley, S. L. (2008). Mindfulness

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696 meditation training in adults and adolescents with ADHD: a feasibility study. J Atten Disord, 11(6), 737–746.
697 doi:10.1177/1087054707308502
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700 Declaration of Interests
701 KB, PS, MK, EH, BF, HM, JÖ and CMT declare that the research was conducted in the absence of
702 any commercial or financial relationships that could be construed as a potential conflict of interest.
703 APL declares that she received travel grants in the last year from MEDICE Arzneimittel Pütter GmbH
704 and Co. KG. SM received a speaker’s fee from Jansen-Cilag and was involved in clinical trials
705 conducted by Janssen-Cilag and Lilly as a study physician in 2007–2009. AP declares that she served
706 on advisory boards, gave lectures, performed phase 3 studies and received travel grants in the last 3
707 years from Eli Lilly and Co., Lundbeck, MEDICE Arzneimittel, Pütter GmbH and Co. KG, Novartis,
708 Servier and Shire; she has authored books and articles on ADHD published by Elsevier, Hogrefe,

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709 Schattauer, Kohlhammer, Karger and Springer.
710

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711 Authors’ Contributions

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712 KB, PS: Literature search, figures, data analysis, data interpretation, writing
713 APL, HM, JÖ, CMT: Literature search, data interpretation
714 MK, EH: Literature search, figures, data collection
715 BF: Literature search, figures, data collection, data interpretation

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716 SM, AP: Literature search, figures, study design, data collection, data analysis, data interpretation,
717 writing, supervision
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Highlights:
• Psychoeducation and mindfulness exercises improve ADHD symptoms and working memory
performance.
• Psychotherapeutic interventions affect brain functioning in adults with ADHD.
• Mindfulness exercise can be associated with a stronger activation in brain areas related to working
memory and attention.

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