Cyril R Pernet
email: cyril.pernet@ed.ac.uk

Nikolai Belov

Arnaud Delorme

Alison Zammit

Mindfulness related changes in grey matter: a systematic review and meta-analysis

Keywords: Mindfulness meditation, Systematic review, Meta-analysis, MRI, Grey matter

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The relatively recent increase in the popularity of meditation in the Western world has received much attention, with many claiming associated mental health benefits. Concerns about the qualities of studies and potential harm to patients have nevertheless also been raised [START_REF] Farias | Has the science of mindfulness lost its mind?[END_REF] given that up to a quarter of meditators have reported unpleasant and potentially deleterious meditation-related experiences [START_REF] Schlosser | Unpleasant meditation-related experiences in regular meditators: Prevalence, predictors, and conceptual considerations[END_REF]. Medical intervention using meditation (in various forms) has been used predominantly in the treatment of chronic pain, and to a lesser extent in the treatment of obesity, aging, dementia, and psychiatric disorders. Literature reviews and meta analyses show some evidence for lowering perceived pain along with improving associated symptoms such as depression and anxiety [START_REF] Edwards | Comparative effects of meditation and exercise on physical and psychosocial health outcomes: A review of randomized controlled trials[END_REF] or sleep disorders [START_REF] Kwekkeboom | A systematic review of relaxation, meditation, and guided imagery strategies for symptom management in heart failure[END_REF], usually with no change in actual symptoms [START_REF] Hood | Mindfulness-based interventions in inflammatory bowel disease[END_REF]; see however [START_REF] Ball | Does mindfulness meditation improve chronic pain? A systematic review[END_REF]. Such intervention seems also ineffective in 'heavy' patients such as those in palliative care [START_REF] Latorraca | Mindfulness for palliative care patients. Systematic review[END_REF]. Meditation has shown benefits in promoting better eating behaviours therefore assisting weight regulation [START_REF] Dunn | Mindfulness approaches and weight loss, weight maintenance, and weight regain[END_REF], enhancing cognitive efficiency in healthy aging [START_REF] Sperduti | Meditation and successful aging: Can meditative practices counteract agerelated cognitive decline? Geriatrie et Psychologie Neuropsychiatrie[END_REF]) and reducing cognitive decline in dementia [START_REF] Russell-Williams | Mindfulness and meditation: Treating cognitive impairment and reducing stress in dementia[END_REF]. Finally, there is also evidence that meditation improves patients with mental illnesses, with reductions in psychotic symptoms, depression scores, and improved level of functioning [START_REF] Potes | Mindfulness in severe and persistent mental illness: A systematic review[END_REF]. In most reviews, meditation has been shown to improve quality of life [START_REF] Edwards | Comparative effects of meditation and exercise on physical and psychosocial health outcomes: A review of randomized controlled trials[END_REF][START_REF] Hilton | Mindfulness meditation for chronic pain: systematic review and meta-analysis[END_REF][START_REF] Hood | Mindfulness-based interventions in inflammatory bowel disease[END_REF][START_REF] Potes | Mindfulness in severe and persistent mental illness: A systematic review[END_REF][START_REF] Russell-Williams | Mindfulness and meditation: Treating cognitive impairment and reducing stress in dementia[END_REF]. Accumulating evidence for benefits, risks and mechanisms of meditation is therefore valuable to improve patients' health whilst reducing interventions and healthcare costs [START_REF] Innes | Meditation as a therapeutic intervention for adults at risk for Alzheimer's Disease -Potential benefits and underlying mechanisms[END_REF].

ElectroEncephaloGraphy (EEG) and structural/functional Magnetic Resonance Imaging (MRI) have been used extensively to study brain changes underpinning behavioural effects of meditation. A previous meta-analysis by [START_REF] Boccia | The meditative mind: a comprehensive meta-analysis of MRI studies[END_REF] suggests functional changes in meditators relative to controls in the thalamus, striatum and frontal cortex along with structural changes in some of these regions. The mechanism leading to grey matter (GM) changes is unknown, although EEG findings support the hypothesis that meditation increases neuronal communication which in turn causes GM changes via synaptic plasticity. For instance, meditation tends to increase fast oscillations of 12-30 Hz, which are usually associated with high vigilance levels [START_REF] Braboszcz | Lost in thoughts: Neural markers of low alertness during mind wandering[END_REF][START_REF] Laufs | Where the BOLD signal goes when alpha EEG leaves[END_REF]) and increase in phase-locking gamma-band oscillations [START_REF] Lutz | Long-term meditators self-induce high-amplitude gamma synchrony during mental practice[END_REF]. Such increases in neural communication and connectivity might mediate observed long term brain structural changes.

Our review focused on studies looking at GM and aimed at (1) investigating the strength of reported associations and (2) establishing evidence for local GM changes due to meditation. Meditation is here strictly defined as the practice of focused attention or awareness with the aim of cultivating a calm and stable mental state, which typically corresponds to what has been termed mindfulness. Consequently, we excluded from our analyses any studies that included movement therapies, such as yoga alongside meditation [START_REF] Boccia | The meditative mind: a comprehensive meta-analysis of MRI studies[END_REF][START_REF] Fox | Is meditation associated with altered brain structure? A systematic review and meta-analysis of morphometric neuroimaging in meditation practitioners[END_REF][START_REF] Last | The effects of meditation on grey matter atrophy and neurodegeneration: a systematic review[END_REF]) since these additional practices may act as confounding factors [START_REF] Colcombe | Aerobic exercise training increases brain volume in aging humans[END_REF][START_REF] Erickson | Physical activity, fitness, and gray matter volume[END_REF]. Since proposed meditation interventions often hypothesize brain changes that will regulate different aspects of behaviour, it is essential to establish which brain regions show changes. For example, if patients show an alteration in one brain region, imaging can address whether an intervention may re-establish a normal range of values in this region or if behavioural changes are mediated by compensatory mechanisms [START_REF] Bishop | Research review: Emanuel Miller Memorial Lecture 2012 -neuroscientific studies of intervention for language impairment in children: interpretive and methodological problems[END_REF]. Although many brain changes are functional by nature (change in activation level, frequency of activity or activity coupling), we focused here on structural Grey Matter (GM) changes only, because it provides evidence of neural plasticity for long term mental health changes.

Material and method

Systematic review

Search strategy The Ovid interface was used to search MEDLINE, EMBASE, PsycINFO, AMED and Global Health. The following terms were searched separately on the 10th of October 2018, using the multi-field search tool with "All Fields" enabled: (1) Meditat* OR Mindfulness (2) Magnetic Resonance Imaging OR MRI OR MR Imaging OR sMRI OR Neuroimaging (3) Grey Matter OR Grey Matter OR GM OR Cortical Thickness OR Cortex OR Brain. Searches 1-3 were combined with a Boolean AND function. The high number of hits returned from PsycINFO was reduced by consulting relevant subject headings, and performing an advanced search (as follows) with 'map to subject headings' and 'Auto Explode' enabled: (1) Meditation OR Mindfulness (2) Magnetic Resonance Imaging or Neuroimaging (3) Grey Matter or Cerebral Cortex. Again, searches 1-3 were combined using a Boolean AND function.

Inclusion criteria Articles included must have met the following criteria: (i) Involve meditation or mindfulness (ii) Use structural MRI (iii) Measure GM density, volume or thickness.

Exclusion criteria To produce a focused report and avoid confounding effects, the exclusion criteria comprised of (i) Articles involving physical movement alongside meditation: For example, the mindfulness-based stress reduction (MBSR) program developed by Kabat-Zinn, which incorporates yoga [START_REF] Santorelli | Mindfulness-Based Stress Reduction (MBSR) Authorized curriculum guide[END_REF]), (ii) Articles where structural MRI was not performed, and (iii) Articles that do not measure grey matter volume (GMV)/density (GMD) or cortical thickness (CTh): Measurement outcomes such as WM changes and gyrification patterns were not included.

Bias analysis Articles were assessed for bias using the Clinical Appraisal Skills Programme checklists https://casp-uk.net/ casp-tools-checklists/. We report here specifically on selection, information and attrition biases.

Meta-analyses

Amplitude of morphological changes? For each study included, the maximum reported effect was extracted (e.g. t-values, regression slope or Pearsons' r correlation coefficients) either directly from the text or inferred from figures. Importantly, the maximum effect size was used irrespective of the location in space, thus establishing a generic evidence for an effect of meditation on GM. For [START_REF] Chételat | Reduced ageassociated brain changes in expert meditators: A multimodal neuroimaging pilot study[END_REF] and [START_REF] Murakami | The structure of mindful brain[END_REF] data points were extracted from scatter plots using WebPlotDigitizer [START_REF] Rohatgi | WebPlotDigitizer (Version 4.2)[END_REF]) while for [START_REF] Kumar | Effect of SOHAM meditation on human brain: a voxel-based morphometry study: effect of SOHAM meditation on human brain[END_REF], t-value was taken from the maximum of the figure color scale. From these values and number of participants, Hedges' g effect sizes were obtained and a random-effect meta-analysis (Maximum-likelihood as estimator) was computed using the dmetar R package [START_REF] Harrer | Dmetar: Companion R package for the guide "Doing meta-analysis in R". R package[END_REF]). An additional meta-analysis was also conducted for the right insula, based on the a-posteriori observation of the spatial distribution of reported effects. From the meta-analyses effect sizes, Hedges' g was transformed to Cohen's d using Eq. 4 from [START_REF] Lakens | Calculating and reporting effect sizes to facilitate cumulative science: a practical primer for t-tests and ANOVAs[END_REF] and G-power [START_REF] Faul | G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences[END_REF][START_REF] Faul | Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses[END_REF] was used to estimate the number of subjects needed for 80 % and 95 % statistical power of a two-samples t-test.

Where in the brain can we see changes? For each study showing structural brain differences in meditators, and when available, coordinates from significantly different regions were entered into an anatomic likelihood estimation analysis using GingerALE version 3.02 [START_REF] Eickhoff | Activation likelihood estimation meta-analysis revisited[END_REF][START_REF] Eickhoff | Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: A random-effects approach based on empirical estimates of spatial uncertainty[END_REF][START_REF] Turkeltaub | Minimizing within-experiment and within-group effects in activation likelihood estimation meta-analyses[END_REF], which estimates the likelihood that a region contains an effect taking into account both reported locations and sample sizes (here using the degrees of freedom of the test from which coordinates were used). Since the analysis is focused on spatial analyses, only whole brain studies are used, but using all coordinates. The ALE map was thresholded at a p-value of 0.05 after family-wise error cluster correction with 1000 permutations and the default p = .001 cluster forming threshold. Since structure and function of the human brain are intricately linked through multiple levels and modes of brain connectivity [START_REF] Sporns | The human connectome: A structural description of the human brain[END_REF], we sought to gain further insight of meditation induced neuroplasticity by using functional connectivity maps from NeuroSynth [START_REF] Yarkoni | Large-scale automated synthesis of human functional neuroimaging data[END_REF]. The functional connectivity maps represent resting-state functional connectivity analysis performed on 1,000 human subjects [START_REF] Buckner | Brain Genomics Superstruct Project (GSP)[END_REF], with voxel seeds from 7 study coordinates in and around the region found significant by the ALE analysis. These coordinate-based connectivity maps were then binarized (thresholded at 0.2) and summed, and this final map thresholded for significance at 88 %, i.e. above the 95 % upper bound of the chance level confidence interval.

Results

Search results

The total number of references gathered was 867 (MEDLINE = 234, Embase = 545 AMED = 3, Global Health = 2, PsycINFO = 83). After deleting duplicates this was reduced to 698. Of these, 530 were excluded following abstract screening based on the criteria defined previously. The full texts of 143 articles were examined, of which 25 met inclusion criteria (see Table 1). Cross-checking with other reviews (e.g. [START_REF] Boccia | The meditative mind: a comprehensive meta-analysis of MRI studies[END_REF] revealed a high number of matches, which was taken as evidence of a good search strategy.

Study range and characteristics

The sum of the participants included in the 25 selected studies was 1646. Accounting for overlapping samples reduced this to 1406 participants (mean: 56.24, range: 19-247). Participant age ranged from 12 to 87 years old, and various meditation/mindfulness disciplines were studied.

Strength of associations and bias

Twenty-three out the 25 included studies reported quantitative changes associated with meditation. Nineteen of them compared directly meditators to non-meditators (only 18 used in the analysis as 1 study only reported values of the difference between patients, even if controls were present) and the six remaining studies reporting associations with the amount of meditation. The meta-analysis random-effect-model across all 23 studies from which we had data, for the strongest effect independently of the brain area and design, showed an estimated effect of g = 0.8244 [95 % CI 0.4495 1.1994] (t = 4.56, p = .0002) with an estimated variance τ 2 = 0.1709 and heterogeneity I 2 = 77.9 % (Q(22) = 99.45, p < .0001). Looking only at the 18 studies comparing directly meditators to control (N = 395 vs. 454), the effect size was slightly larger: g = 1.025 [0.6055 1.4445] t = 5.16 p < .0001, τ 2 = 0.1053 I 2 = 75.4 % Q(17) = 69.11, p < .0001 (Fig. 1).

Selection bias Unrepresentative samples limit our ability to generalise results, which was apparent in most of the studies in this review. Examples include the use of healthcare workers as controls, samples consisting solely of volunteers or college students and geographically-limited recruitment. There are also instances where recruitment procedures are not described.

A number of studies have included controls from databases of healthy adults, and while these may seem appropriate, there is concern over their prior experience with meditation given around 8 % of the general (western societies) population meditation [START_REF] Clarke | Trends in the use of complementary health approaches among adults: United States, 2002-2012[END_REF]. Since this is not specified, in some studies, it is not possible to assess whether or not the controls are appropriate [START_REF] Martínez-Mesa | Sampling: How to select participants in my research study?[END_REF]). Another issue is the inclusion of participants from various or unspecified meditation backgrounds within the same study, which implies that various meditation/mindfulness disciplines are equal in effect as only acknowledged as a limitation in only one study [START_REF] Chételat | Reduced ageassociated brain changes in expert meditators: A multimodal neuroimaging pilot study[END_REF]. Information bias is commonly seen with self-reporting, which may reduce study validity [START_REF] Althubaiti | Information bias in health research: Definition, pitfalls, and adjustment methods[END_REF]. Most studies in this review recorded participants' prior meditation experience in hours or years, this may be problematic because reliance on memory and honesty reduces objectivity, and increases the risk of including incorrect information. Studies using mindfulness questionnaires may also add to this problem, for example the five facet mindfulness questionnaire (FFMQ), which was shown to have issues with construct validity [START_REF] Goldberg | Does the Five Facet Mindfulness Questionnaire measure what we think it does? Construct validity evidence from an active controlled randomized clinical trial[END_REF]. Furthermore, questionable classification methods increase the risk of biased or incorrect information: for example, one study divides participants into high versus low frequency meditation/prayer groups based on no established classification method.

Attrition bias Several cases of unaccounted dropouts have, again, limited the formation of a definite conclusion regarding meditation and GM. Although there are situations where dropouts may not affect bias [START_REF] Bell | Differential dropout and bias in randomised controlled trials: When it matters and when it may not[END_REF], this review includes cases where bias is likely (see Table 2).

Blinding The majority of studies were observational, retrospective and cross-sectional, where participant blinding was not performed since it was unnecessary. Of the studies that were longitudinal in nature, one did not mention participant blinding and the other did not involve any intervention, rendering this unnecessary. Investigator blinding was not required in studies using automatic methods of GM measurement, however those using semi-automatic measurement, or manual delineation of GM would require blinding since over/ underestimation is possible with knowledge of the participant group. Some studies included here employed manual methods with no mention of observer blinding, which could lead to confirmation bias [START_REF] Althubaiti | Information bias in health research: Definition, pitfalls, and adjustment methods[END_REF].

Publication bias as expected from analyzing maxima and illustrated on the funnel plot, the meta-analysis effect size is biased such as studies follow the expected null slope with weaker effects for higher precision studies and conversely stronger effects for lower precision studies. Importantly, no non-significant maxima were present because all studies, but one found effects, and the one not finding a difference did not report on effect size.

Spatial meta-analysis and connectivity

Of the 25 studies included, 16 provided anatomical coordinates of regions showing significantly increased GM in meditators or following an intervention. Four studies had overlapping samples, with however no overlapping coordinates. The meta-analysis from all data demonstrated one significant cluster in the short insular gyrus extending to the claustrum (from [26 8-18] to [38 14 -8] with a peak at [32 10-14]). Overall, 6 studies reported effects in the right insula, but only 3 of them participated in the ALE cluster. All 6 studies were nevertheless neighbouring coordinates, all were used to create a summary functional connectivity map. This analysis showed significant association (i.e. above the 88 % chance level) of the left insular cortex, the left/right inferior post-central gyri, the anterior cingulate gyrus and adjacent paracingulate gyri with the right insula (Fig. 2). Lowering the threshold to the 'chance level' 50 % also show possible association with left and right frontal poles.

Discussion

Our meta-analysis indicates that meditation has a medium to large effect on grey matter (Cohen's lower estimate ~0.45 for all studies to higher estimate of ~1.5 for studies comparing directly controls to meditators) with however a large heterogeneity in effect sizes (~76 %) and in location throughout the brain (Fig. 1). The only one area showing spatial consistency, i.e. the right anterior ventral insula (Fig. 2), have an effect size estimate between 0.2 and 1.4. Our results are concordant with both, an effect of meditation on expected brain areas, and a high spatial variance caused by methodological biases.

Effect of meditation

The ALE meta-analysis reveals a significant cluster over the right anterior insula, going over the extreme capsule to the claustrum, an overlap from ROI from et al. 2010). Lazar and colleagues (2005) were the first to observe important structural changes associated with sustained meditation practice in this region (although not included in the ALE analysis because no coordinates were reported in the article), but also the auditory, somatosensorial and prefrontal cortices. The other studies reviewed reporting right insular differences [START_REF] Grant | Cortical thickness and pain sensitivity in zen meditators[END_REF], Hotzel et al. 2008[START_REF] Luders | The underlying anatomical correlates of long-term meditation: Larger hippocampal and frontal volumes of gray matter[END_REF], 2015a, b) were more posterior or dorsal, sub-regions associated with sensori-motor afference or empathy [START_REF] Kurth | A link between the systems: Functional differentiation and integration within the human insula revealed by meta-analysis[END_REF], altogether arguing for GM changes associated with classical cognitive effects of meditation (Srinivasan 2019). While such insular changes can be expected from meditation experience, it is important to note that our meta-ALE-analysis is likely lacking statistical power with 16 studies included while estimates suggest ~20 studies for reliable results [START_REF] Eickhoff | Behavior, sensitivity, and power of activation likelihood estimation characterized by massive empirical simulation[END_REF]. However, the proximity of these 4 additional studies to the ALE cluster and the functional connectivity results (see below) lead to conclude to a true effect rather than a false positive. In this context, it is also interesting to note that cognitive traits associated to the right insula are also typically associated with the left insula, which we showed to be functionally connected with the right insula. Four studies in our review also reported left insular changes [START_REF] Engen | Structural changes in socio-affective networks: Multi-modal MRI findings in long-term meditation practitioners[END_REF][START_REF] Fahmy | Mindfulness-based interventions modulate structural network strength in patients with opioid dependence[END_REF], Grant et al. shows the unthresholded summary map while slices display significant regions only. Effect sizes from these 7 studies were also entered into a meta-analysis (bottom right) to estimate sample size for future studies (power curves with black horizontal bars representing the 95 % CI bounds of the meta-analysis effect transforming Hedges'g reported in the forest plot to Cohens'd)

2010, Luders et al. 2015a, b) but they were spatially too dispersed to show significant ALE overlap (Fig. 2). Similarly, about 1/3 of studies (Chetelat et al. (2017), [START_REF] Engen | Structural changes in socio-affective networks: Multi-modal MRI findings in long-term meditation practitioners[END_REF], [START_REF] Fahmy | Mindfulness-based interventions modulate structural network strength in patients with opioid dependence[END_REF], [START_REF] Grant | Cortical thickness and pain sensitivity in zen meditators[END_REF], [START_REF] Grant | Cortical thickness, mental absorption and meditative practice: Possible implications for disorders of attention[END_REF], Kurth et al. (2015a), [START_REF] Lu | The brain structure correlates of individual differences in trait mindfulness: A voxel-based morphometry study[END_REF]) showed activations over the (broadly speaking) anterior cingulate/ paracingulate cortices, without enough spatially consistency to be a significant region in the ALE analysis, but coordinates overlap with the functional connectivity maps. Given that this region has also been linked to meditation in other reviews (see [START_REF] Boccia | The meditative mind: a comprehensive meta-analysis of MRI studies[END_REF] we therefore recommend to also considered it as a-priori region of interest in future studies.

Spatial heterogeneity of effects More often than not, the strongest effects were observed in different locations in the brain which may be partly attributed to a lack of statistical power. In our main effect size meta-analysis, only the strongest effects were used leading to a dispersion of effects (Hedges' g from 0.18 to 2.07 -excluding [START_REF] Vestergaard-Poulsen | Long-term meditation is associated with increased gray matter density in the brain stem[END_REF]) along the expected null line of the funnel plot. This indicates that the population effect size is overestimated, calling to use the lower bound of the confidence interval as a safe assumption on how many subjects are needed to properly estimate/quantify the effect of the influence of meditation on grey matter. For 95 % statistical power, 62 subjects per group (124 in total) would be necessary, which is more participants than most studies have used. If one were to plan a study focusing on the insula, our analysis suggests up to 417 subjects per group (834 subjects in total using the lower bound of the CI). Because lack of power increases false positives [START_REF] Button | Power failure: Why small sample size undermines the reliability of neuroscience[END_REF][START_REF] Pernet | Null hypothesis significance testing: A guide to commonly misunderstood concepts and recommendations for good practice[END_REF]) and because of the nonstationary nature of the grey matter values derived from the MRI signal [START_REF] Hayasaka | Nonstationary cluster-size inference with random field and permutation methods[END_REF], larger effects than real ones (i.e. false positives) can be observed at random locations, explaining the observed spatial heterogeneity. Other factors related to design and analysis might also contribute to this variability (see below).

Strengths and weaknesses of methods This systematic review utilised multiple databases for the literature search and excluded studies that involved movement therapy as part of the meditation/mindfulness intervention. These factors increase the likelihood that all relevant studies were included and that the results obtained were not affected by confounding factors. On the other hand, it should be noted that of the studies included here, some involve participants with pain disorders and other illnesses, as well as adolescents, all of which could possibly bias results. Compared with the most recent ALE analysis [START_REF] Boccia | The meditative mind: a comprehensive meta-analysis of MRI studies[END_REF], we included more studies and used the updated software version that has a stricter type 1 Family-Wise error rate (permutation of maxima rather than FDRwhich is the recommended setting, [START_REF] Eickhoff | Behavior, sensitivity, and power of activation likelihood estimation characterized by massive empirical simulation[END_REF], and thus it would not be reasonable to expect too many similarities given those restrictive criteria.

Moving forward research on the effect of mindfulness on the brain The biggest concern on the observed results is the spatial variability across studies. As discussed above, the total sample size is an important contributing factor and future studies must power up if one wants, for instance, to demonstrate up or down regulation of a given brain region by meditation in patients. The bias analysis also revealed issues with (i) demographics, (ii) analyses, (iii) reporting, and (iv) experimental design. Variation in age, sex, ethnicity, education, socioeconomic status, handedness and illnesses may confound the data, leading to the creation of inaccurate results. Apart from this, many studies did not include important demographic information, creating additional ambiguity surrounding the data and any conclusions that may be drawn from it. It is also important to consider the impact of neurological and psychiatric illnesses, as these may affect GM. The studies reviewed that did not report these were excluded, and of those that do mention exclusion, not all specify the measures used to assess such illnesses. Another important issue is the variability of meditation practices. It may be possible that some practices have more profound effects than others. Since only a limited number of studies with different meditation practices is available, it is not possible to assess whether this is true, or if any differences among practices exist at all. When studying meditation, we must acknowledge that experienced participants are likely to have had exposure to many practices over the years, and so it may be incorrect to assume that the practice measured at the time of the study is responsible for the differences seen. Furthermore, one must also keep in mind that accurate measurement of meditation itself is not entirely possible and concerns surrounding the validity of the various measurement tools used have been raised [START_REF] Park | Mindfulness: A systematic review of instruments to measure an emergent patientreported outcome (PRO)[END_REF].

Because of the variability in demographics, it is also essential to include covariates in the brain data analyses. Less than half of studies however reported the inclusion of factors such as age, gender and total intracranial volume although those are essential to interpret results, no matter if significantly different between groups [START_REF] Pernet | The general linear model: Theory and practicalities in brain morphometric analyses[END_REF]. While a few articles made data available, most do not mention data sharing. Essential to reproductive and cumulative science [START_REF] Nichols | Best practices in data analysis and sharing in neuroimaging using MRI[END_REF]), details of the analyses are often missing (for instance having to figure out if and what covariates were used) and summary statistics maps never available (for instance sharing on NeuroVault [START_REF] Gorgolewski | NeuroVault.org: A web-based repository for collecting and sharing unthresholded statistical maps of the human brain[END_REF] the unthresholded tvalue map of difference controls vs. experts which would allow computing effect sizes for any brain region). Finally, in terms of design, the majority of studies that met the inclusion criteria were cross-sectional and observational. Although this is enough to show the presence of an effect, there is a need for more randomised controlled trials and longitudinal studies to demonstrate therapeutic benefits. Longitudinal studies should span lengthy periods of time, and involve regular scan intervals in order to examine effects over time. Despite their appeal, there are also a number of issues making them problematic. Such studies were performed over a condensed period of time, due to cost and time limitations, and an increased likelihood of drop-outs, making it difficult to determine long-term effects. At present, there is no defined interval time after which it is agreed that the effects of meditation should be apparent, and we have not yet concluded whether the effects of meditation practice are cumulative, that is, whether the reported changes are related to the amount of experience alone. Furthermore, we have not come to a conclusion on whether the effects are long-lasting beyond the intervention time frame. Improvements in study design, such as blinding are also essential in order to move forward.

Conclusions

There is mounting evidence that meditation induces functional and structural changes in the brain. Our review shows that effects are relatively strong for structural changes ([0.45 1.5]) with consistent changes observed in the right insula, but methodological improvements are required to establish mindfulness meditation as a therapeutic tool.

Fig. 1

 1 Fig.1Whole brain maxima analyses. The left side of the figure shows location of maxima reported anywhere in the brain for studies comparing directly meditators to controls (n = 18), leading to estimate an overall strength of evidence (forest plot of maximamiddle left) from which one can estimate how many subjects are needed in future studies (power

  Fahmy et al. (2018 -opioid patients meditators > opioid patients control in the claustrum), Hernández et al. (2016 -mediators > controls in the short insula gyrus) and Murakami et al. (2012 -correlation with mindfulness in the short insula gyrus), a sub-region typically associated with emotion (Kurth

Fig. 2

 2 Fig. 2 ALE analysis and derived results. The top of the figure shows the z-scores ALE for all coordinates entered into the analysis, leading to a significant result over the right short insular gyrus. From this region, coordinates from 7 studies (3 studies in the ALE results + 4 located posterior and dorsally) were used to obtain functional connectivity maps (bottom left) showing overlap with observed coordinates over the left insular and anterior cingulate/paracingulate cortices. The brain render

Table 1

 1 List of the 25 studies included in the systematic review (*denotes those included in the ALE analysis) with the number of control subjects (C), the number of meditators (M), and the effect tested and the corresponding statistical test and result (TP = temporo-parietal, ACC = Anterior Cingulate Cortex, SMG: supramarginal gyrus)

	Studies	C M Effect tested and	Statistical test
			used in the	and result at
			systematic review	maximum
			and meta-analyses
	Chételat et al. 2017	67	6 Differences in gray	t-test (adjusted
	(quantitative data		matter volume in	for brain size,
	from figure)		elderly population	age,
				education):
				meditators>
				controls, left
				TP junction
	Engen et al. 2018 * 15 17 Differences in	t-test: meditators
			cortical thickness	>controls, left
				insula
	Fahmy et al. 2018 *	9 10 Differences in gray	t-test: meditators
			matter volume of	>controls, left
			opiate dependent	ACC
			patients receiving
			meditation as part
			of their treatment
	Fayed et al. 2017	10 11 Differences in gray	t-test
	(no quantitative data)		matter volume	(adjusted for
				TIV, age, and
				gender):
				inferior
				temporal
				cortex
	Friedel et al. 2015	0 82 Association between	regression
			mindfulness and	(adjusted for age
			cortical thickness	and total avg
				thickness):
				left anterior
				insula
	Grant et al. 2010 *	18 17 Differencesin	t-test (adjusted
			cortical thickness	for age):
				ACC
	Grant et al. 2013 *	18 18 Differencein	t-test
			relations between	(adjusted for age
			cortical thickness	and gender):
			and attentional	left SMG
			absorption
	Hernandez et al.	23 23 Differences in gray	t-test (adjusted
	2016 *		matter volume	for TIV, age,
				and gender):
				meditators>
				controls
				Right Insula
	Holzel et al. 2008 * 20 20 Differences in gray	t-test: right
			matter volume	hippocampus
	Kober et al. 2017	20 20 Differences in gray	t-test: no
			matter volume	difference
			between the high
			vs. low
			prayer/meditation
			groups
	Kumar 2014 *	14 14 Differences in gray
			matter volume

Table 1

 1

	(continued)			Table 1 (continued)
	Studies	C M Effect tested and	Statistical test	Studies	C M Effect tested and	Statistical test
		used in the	and result at		used in the	and result at
		systematic review	maximum		systematic review	maximum
		and meta-analyses			and meta-analyses
	(quantitative data		t-test: left			scores, right
	from figure)		ventral			insula
			pallidum	Pagnoni and Cekic	13 13 Differences in the	t-test (gp * age
	Kurth 2015a *	0 Association between	Pearson	2007 *	association gray	interaction
		years of mediation	correlation		matter volume	adjusted for
		and gray matter	(adjustment for		and age	TIV): left
		volume	age): intra			putamen
			parietal sulcus	Taren et al. 2013	0 155 Association between mindfulness and	Pearson correlation:
	Kurth et al. 2015b	50 Differences in gray	ANOVA (group		regional gray	right
		matter volume	* age):		matter volume	amygdala
	Lazar et al. 2005	correlation with 15 Differences in age	t-test: right hippocampus	et al. 2009 * Vestergaard-Poulsen	matter volume 10 10 Differences in gray	t-test: brain stem
		cortical thickness	insula
	Leung et al. 2013 * 15 Differences in gray	t-test (adjusted
		matter volume	for global
			brain size
			during
			normaliza-
			tion): right
			angular
			gtyrus
	Lu et al. 2014 *	0 Association between	regression
		mindfulness and	(adjusted for
		gray matter	gender and
		volume	TIV): ACC
	Luders et al. 2009 * 22 Differences in	t-test: right
		regional gray	hippocampus
		matter volume
	Luders et al. 2012	30 Differences in	t-test: left
		hippocampal	hippocampus
		volume
	Luders et al. 2013 * 50 Differences in gray	t-test
		matter volume	(adjusted for
			age, and
			gender): left
			hippocampus
	Luders et al. 2015a 15 Differences in	t-test: left
		hippocampal	hippocampus
		volume per sex
		(here only males)
	Luders et al. 2015b * 50 Differences in the	t-test (gp * age
		association gray	interactions
		matter volume	adjusted for
		and age	sex and TIV):
			posterior
			visual
			network
	Murakami	0 Association between	regression
	et al. 2012 *	mindfulness and	(adjusted for
	(quantitative data	gray matter	age and sex):
	from figure)	volume	bigger
			volumes for
			higher
			mindful

Table 2

 2 Bias analysis showing for each of the 25 studies (✓

		Selection	Information bias	Attrition	Confirmation bias
	indicates bias, X indicates no bias,	bias		bias
	? unclear)
	Chételat et al. 2017	✓	? Most likely that	X	✓
			info was obtained
			by interviewing
			participants
	Engen et al. 2018	✓	✓	X	✓? No mention of blinding
	Fahmy et al. 2018	✓	✓ MBI which was	✓	? No mention of blinding, but
			adapted from the		also no mention of manual
			original MBSR		input
	Fayed et al. 2017	✓	✓	X	X (check in text citations to
					match this)
	Friedel et al. 2015	X	✓	✓ (245	✓
				agreed,
				82 final)
	Grant et al. 2010	✓	✓	X	X
	Grant et al. 2013	✓	✓	X	X
	Hernandez et al.	✓	✓	X	? No mention of blinding during
	2016				manual input
	Holzel et al. 2008	✓	✓	X	X
	Kober et al. 2017	✓	✓	X	X
	Kumar et al. 2014	✓	✓	X	? Methods not clear-possible
					manual input. Blinding not
					mentioned.
	Kurth 2015a	✓	✓	X	X
	Kurth et al. 2015b	✓	✓	X	X
	Lazar et al. 2005	✓	✓	X	? Not mentioned
	Leung et al. 2013	✓	✓	X	? Not mentioned
	Lu et al. 2014	✓	✓	✓scans	? Not mentioned
				with
				artifacts
				not
				included
	Luders et al. 2009	✓	✓	X	X
	Luders et al. 2012	✓	✓	X	X
	Luders et al. 2013	✓	✓	X	✓ likely. Manual input.
					Blinding Not mentioned
	Luders et al. 2015a	✓	✓	X	N o t m e n t i o n e d
	Luders et al. 2015b	✓	✓	X	✓ likely. Manual input and no
					mention of blinding
	Murakami et al. 2012 ✓	✓	X	X
	Pagnoni and Cekic	✓	✓	✓image	X
	2007			with
				artifact
				was not
				included
	Taren et al. 2013	✓	✓	✓10	?
				excluded due to missing data	semi-automated ROI segmentation. No mention of blinding.
	Vestergaard-Poulsen	✓	✓	X	X
	et al. 2009				No mention of manual input
					during segmentation.
					However the authors used
					histological samples.

Acknowledgements Thank you to D. Lakens for publishing YouTube tutorial videos on meta-analysis and bias.

Author contributions CP and AZ conceptualized the review and conducted the ALE analysis, AZ conducted the systematic review and bias analysis, CP and NB conducted the statistical meta-analyses and AD helped edit the manuscript. All co-authors have contributed to the preparation of the manuscript, provided important intellectual content and read and approved the final version.

Funding NB received funding from the European Union Erasmus exchange fund.

Data availability All of the data necessary to replicate what is presented here is available @ https://github.com/CPernet/meta_meditation (extracted data, R scripts, functional connectivity maps and Matlab code).

Compliance with ethical standards

Conflict of interest None of the authors have a conflict of interest to declare.

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Ariane Bazan

Filip Geerardyn

Veroniek Knockaert

David Van Bunder

Gertrudis Van

Introduction

Major advances in the understanding of language dynamics have been achieved the last ten years and continue to come to us each day, originating from disciplines as diverse as medicine, neuroscience, evolutionary biology and phenomenological research in language development. The present contribution has no claim in the further elaboration of these domains, but proposes a more clinical or psychological approach to language dynamics. In clinical work, as in everyday psychopathology, the acute concern is not so much the exact neuronal trajectory of language, but far more the way a subject's emotional experience is influenced by or has influence on his or her particular language dynamics. The focus is therefore precisely this emotional language processing and the way it is proposed to be at the origin of the typically human unconscious mind.

Problem Presentation

Clinical observations

There has been, since F REUD (1960, 1975) and in particular with L ACAN (1957), a particular interest and attention paid to the literal language patients use when talking about themselves or their problems in consultation. This is illustrated in Freud's clinical oeuvre from the start with, for example, his illustrative cases presented in the "Psychopathology of Everyday Life" (F REUD 1960). The forgetting of the name "Signorelli" for example seemed not to be motivated by some conflicting semantics connected with the painter "Signorelli", but, curiously, with the semantics of a phonological variant of the word "Signorelli", in this case signor or "master". In "The interpretation of dreams" F REUD (1975) introduced the concept that dreams are frequently to be taken literally and that these literal transcripts are subsequently to be Ariane Bazan/Filip Geerardyn/Veroniek Knockaert/David Van Bunder/ Gertrudis Van de Vijver

Language as the Source of Human Unconscious Processes

A neuropsychoanalytic framework is proposed for the study of unconsciously determined human behavior as expressed in psychic symptoms and dreams. First, some clinical observations are operationalized in an analytical F REUDO -L ACANIAN perspective. In particular the notion of the human unconscious as a linguistically structured dynamic system is presented. Second, these psychoanalytical notions are integrated with current neuroscientific insights on language. This framework essentially conceives human language as the one object of two evolutionarily radically different neurological processing circuits, acting partially in parallel. The oldest pathway processes the "objective " or phonemic qualities of language input subcortically while the second and typically human pathway processes language neocortically on its semantic qualities. The affective processing of raw phonemic material therefore is thought to operate in relative autonomy from the semantic processing and thereby able to induce so-called "false connections". It is further proposed that (1) meaningful access to language is essentially a(n articulatory) motor event, (2) imagined speech also induces this motor activation and (3) unspoken phonemes give rise to "linguistic phantoms". In final, a structural hypothesis for the F REUDO -L ACA-NIAN unconscious is proposed conceiving this system as a raster of latent phonemic phantoms, eventually functioning as "attractors" for the subject's affective attention.

Language, unconscious, phonemes, emotion, signifier, read as rebuses. That the same principle also pertains to symptoms, as F REUD proposes, is clearly illustrated in a letter to Fliess (F REUD 1897 **NOT IN REFS**, pp316-331) which is given here as a paradigmatic example:

"A little interpretation came my way… Mr. E. had an anxiety attack at the age of ten when he tried to catch a black beetle… The meaning of this attack had thus far remained obscure. Now, dwelling on the theme of "being unable to make up one's mind", he repeated a conversation between his grandmother and his aunt about the marriage of his mother… from which it emerged that she had not been able to make up her mind for quite some time; then he suddenly came up with the black beetle, which he had not mentioned for months, and from that to ladybug [Marienkäfer] (his mother's name was Marie); then he laughed out loud… Then we broke off and next time he told me that before the session the meaning of the beetle [Käfer] had occurred to him; namely: que faire? = being unable to make up one's mind… meschugge! "You may know that here a woman may be referred to as a nice "beetle". His nurse and first love was a French woman; in fact, he learned to speak French before he learned to speak German".

As is made clear in the scheme on Figure 1, it seems that the literal forms of the words function as carrier of affects, more or less independently of their semantics.

In the neuropsychoanalytic research unit at the University of Ghent a number of clinical observations of this kind were systematically recorded in collaboration with diverse clinicians. Three typical examples of this phenomenon are presented briefly:

(1) a dream: a woman dreams that she is sitting in front of her therapist and that their feet are touching; the meaning of the dream becomes clear when she formulates its content as "we sat sole to sole"; (2) an anxiety: a woman gets an anxiety attack when her friend, promising her a hot time together, whispers to her: "Je te montrerai les sommets de la merveille" ("I will show you the top of the record"); upon analysis, it seems that the phonological carrier [lae m ε rv ε :j ] was for the young woman also referring to "la mère veille": i.e., mother is watching; (3) a dream: a pregnant woman dreams she is driving a big Mercedes down a spiral driveway; while she is driving the car, the driveway gets narrower and at one point her car gets stuck; upon analysis, it seems that the phonological carrier [lae m ε :rs ε :d ε s ] was for the woman also referring to: "la mère cède" (i.e., "the mother fails"). The woman was at that moment preparing for the presentation of her Ph.D. thesis and therefore experiencing some conflict between this energy consuming achievement and her imminent motherhood. Constant in these examples is that the origin of the symptom or dream is phonologically-and not semantically-related to the actual form in which the dream or symptom presents itself.

Psychoanalytical framework

In a F REUDO -L ACANIAN framework the reference to a human unconscious refers to the idea of an unconscious that is structured like a language (L ACAN 1972-1973; V AN B UNDER et al. 2002), and to the dynamic system thought to be at the origin of signifier mediated affective "mismatches" as illustrated in the aforementioned examples. For F REUD (1978), the word form or "word-representation" implicates an acoustic component, "the acoustic image" and a motor component or "speech movement representation", the kinesthetic incoming information of the articulatory system. This word-representation level has therefore a finite number of components and is as such to be distinguished from the "object-representation" level. This object-representation level has an infinite number of components, including e.g., visual, acoustic and tactile recordings of the object. The similarity of this model with the model of D AM- ASIO et al. (1996) and C ARAMAZZA (1996) is remarkable. The word-representation level can be considered as corresponding to the lexical level, to be situated in the left basal temporal lobe, while the object-representation level obviously corresponds with the semantic level, to be situated distributed over the temporo-parieto-occipital areas of both hemispheres. For L ACAN (1957), the word form or "signifier" is a phonemic carrier in the Saussurian sense, without any predetermined signification. The signi- 2002, Vol. 8, No. 2 Language as the Source of Human Unconscious Processes fier is an "empty" lexical position depending on the context for its conscious signifying. In his later seminars (L ACAN 1972-1973; see also V AN DE V IJVER 2002), the signifier is not any longer this empty or neutral but is carrier of an unconscious sense through its phonemic articulation with the body.

Two Evolutionary Pathways for Language

The idea that language is also a carrier of sense apart from its semantic sense is implicit in these clinical examples above: it seems to be carrier of affect, in particular of anxiety or arousal, independently of its semantics, i.e., the phonemic carrier induces bodily changes on an affective level, apart from the access to semantics. Language therefore seems to be the carrier of two more or less independent levels of signification: a semantic one and an affective one.

The possibility of relative independence between the affective and "scenic" (or "declarative") content of the same input material is actually central to L EDOUX ' theory on emotional processing (L EDOUX 1993(L EDOUX , 1994)). Central to his view is the wedge-like splitting of the neuronal trajectory of a single input train into two categorically different pathways, one subcortical or limbic and the other at the level of the neocortex. The limbic trajectory is both phylogenetically old and ontogenetically early: the systems are functional from birth on (and probably earlier) and immediately start establishing an emotional memory on the basis of conditioning of raw input material (L EDOUX 1993, 1994). The neocortical trajectory is both phylogenetically more recent and ontogenetically late: cortical maturation is not achieved until six to ten years after birth. Therefore, it is only with some delay that an articulate mature "cognitive" analysis of the input material can be fully achieved and stored in the semantic fields.

L EDOUX ' scheme has some remarkable similarities with F REUD 's idea of the "splitting of consciousness" as he formulates it in "The neuro-psychoses of defense" (F REUD 1961, p51-52): "If someone with a disposition [to neurosis ] lacks the aptitude for conversion, but if, nevertheless, in order to fend off an incompatible idea, he sets about separating it from its affect , then that affect is obliged to remain in the psychical sphere. The idea , now weakened, is still left in consciousness, separated from all association. But its affect , which has become free, attaches itself to other ideas which are not in themselves incompatible; and thanks to this "false connection", those ideas turn into obsessional ideas".

The notion of the "splitting of consciousness" thus implies the splitting of an idea or experience in its content on the one hand and its affect or excitation sum on the other. The sum of excitation is invested in body innervations in conversion hysteria, or into other ideas in obsessional neurosis. The principle, however, remains the same: one and the same experience can psychologically be conceived as a "complex" of separable elements, with different dynamic characteristics, different fates and different output systems, which, without being completely independent from each other, nevertheless possess a relative autonomy.

It is therefore tempting to explain the above illustrated signifier mediated mismatches in a similar manner. Language is as appropriate an input stimulus as another (a non-language auditory or a visual stimulus) and is therefore also considered to be subject to "emotional conditioning". This emotional conditioning is relatively independent from semantics, which is considered an operation of the higher associative neocortical areas. At the level at which language is thought to be emotionally conditioned, clinical work teaches us that there is no difference between "soul" and "sole". Language is at that level not treated as a fundamentally ambiguous system that has to be contextually interpreted, but as any other object, i.e., unambiguously or objectively. Like other objects, the language object automatically activates a number of proper sensory and motor associations correlated with its particular phonemic form (and not with its semantic meaning) and the emotional activation is thought to be effective at the level of these, most probably, motor associations.

Incoming Phonemes Are Motor Programs "Affective mismatch" operates at the phoneme level

Clinical work teaches us more than that. First, it seems clear that the substratum for emotional activation is not the raw acoustic material of language, but obviously its phonemic transcription. What is effective in eliciting an emotional activation does not seem to be necessarily endowed with some particular acoustic qualities; apparently, what does seems important, however, are the phonemic invariants of the message. Second, it appears that this emotional processing mechanism does not seem to respect word boundaries. In " la merveille " e.g., the relevant activating substratum ([la mer veij ] ) can ei- ther be packed in one word or in a complete sentence.

These indications help us to speculate on the exact nature of the physiological language substratum responsible for the emotional activation. In a comprehensive model for the neural basis of auditory sentence processing F RIEDERICI (2002) situates the process of identification of phonemes as the second step, immediately after the primary acoustic analysis. In her scheme, this identification of phonemes involves a projection from the left temporal Brodmann area 42 (adjacent to H ESCHL 's gyrus or the primary auditory cortex) to the left prefrontal Brodmann area 44 or B ROCA area and is completed within the first 100 ms of auditory processing. Immediately after this step, a number of lexical operations are then exerted on the phonemic material, implying between others the identification of word form and of word category. As neither word form, nor word category, nor, a fortiori , any semantic identification, is relevant in the described signifier-mediated affective mismatches, I speculate that emotional processing responsible for these mismatches takes place after phonemic processing but before lexical processing of language, i.e., during the first 100 ms after presentation.

Phoneme identification involves motor activation

Even if in the literature there might be some confusion about the exact extent of implication and about the exact brain locus of interest (for a review, see B URTON 2001), there seems to be large agreement that phonemic identification does involve motor areas situated either prefrontally in the B ROCA area (H ICKOK /P OEPPEL 2000) or subcortically, i.e., implicating basal ganglia and/or cerebellar pathways (I VRY /J USTUS 2001). This observation therefore gives weight to L IBERMAN 's motor theory of speech perception" (L IBERMAN et al. 1967; L IBERMAN /M AT-TINGLY 1985). This theory, based on phonological research, holds that the basis of speech perception is not the actual sound of speech, but rather the "articulatory gestures" made by the speaker. It argues that listeners identify spoken words through using that information to access their speech motor system. This is supported by the fact that the speech phones, the smallest units we can hear in words, link to articulatory and not auditory-related invariants. Phoneticians classify and characterize phones nearly entirely in terms of how they are articulated and not in terms of how they sound. The theory thereby accounts for our ability to perceive the in-variant articulatory events that form the speech stream, in spite of the great variability in the acoustic signal.

There has been a more recent neural instantiation of this motor theory by R IZZOLATTI /A RBIB (1998). These researchers report that in monkeys a part of the premotor cortex (F5) contains neurons that discharge both when the monkey grasps or manipulates objects and when it observes the experimenter making similar actions. Recent studies suggest that a similar system exists in humans. F ADIGA et al. (1995) reported evidence for motor activation when human subjects merely observed an action, and the muscles activated were those that would have been used had they performed the action themselves. R IZZOLATTI /A RBIB (1998) also show that there are neurons in F5 in the monkey's brain that respond both when the animal makes lipsmacking movements and when it observes them in others. Of particular importance is the fact that these authors note that area F5 in the monkey is the probable homologue of B ROCA 's area in humans. Z ATORRE et al. (1992,1996) have indeed argued that the mapping of the incoming speech stream onto the linguistically relevant units, which are thought to be the corresponding articulatory gestures, activates B ROCA 's area. There is some parallel argumentation, especially coming from CORBALLIS (1999), that the origins of human language might be situated in manual gesture rather than in vocalization. Recently, [START_REF] Callan | Mirror neuron system activity and audiovisual speech perception[END_REF] have shown that the presence of such mirror neurons in speech motor areas of the brain may explain why lip-reading enhances the intelligibility of what a person is saying. This finding adds strength to the argument that human speech evolved from a primitive gestural system of communication, rather than from simple vocalizations. For all these reasons, RIZZOLATTI/ARBIB (1998) propose that the development of the human speech circuit is a consequence of the fact that the precursor of BROCA's area was endowed, before speech appearance, with a mechanism for recognizing actions made by others.

This idea of perception-action linking already stood central in FREUD's "Project for a scientific psychology" (FREUD 1995, pp333-334): "While one is perceiving the perception, one copies the movement oneself-that is, one innervates so strongly the motor image of one's own which is aroused towards coinciding [with the perception], that the movement is carried out. Hence one can speak of a perception having an imitation-value. (…) Thus judging, which is later a means for the cognition of an object that may possibly be of practical importance, is originally an associative process between cathexes coming from outside and arising from one's own body-an identification of information or cathexes from [the perception] and from within". More generally, this suggests that external stimulation only makes sense for the brain if reprocessed into something self-initiated (GEERAR-DYN 2002). In his study on aphasia, FREUD (1978, pp91-92) then suggested that in language this movement might be thought of as articulation: "Understanding of spoken words is probably not to be regarded as simple transmission from the acoustic elements to the object association; it rather seems that in listening to speech for understanding, the function of verbal association is stimulated from the acoustic elements at the same time, so that we more or less repeat ourselves the words heard, thus supporting our understanding with the help of kinaesthetic impressions. A higher measure of attention in listening will entail a higher degree of transmission of speech heard on to the tract serving the motor execution of language".

A comprehensive framework for the mechanism of "affective mismatches"

In summary, I suggest that in the signifier-mediated affective mismatches as illustrated above, the phonemic transformation of the incoming linguistic material is the effective substratum and that this phonemic transformation involves language motor pathways, and therefore that the significant "affective mismatch" is to be situated at the motor-limbic interface. The full mechanism of these affective mismatches is understood as follows. Any time affectively colored phonemes are actualized in the ongoing discourse, be it not in the right original semantic context, affect is nevertheless aroused and may be falsely connected to the actual semantics (e.g., the anxiety aroused by the beetle is falsely attributed to the appearance of the beetle). The selection process for the pertinent semantic interpretation can be conceived as an active inhibitory process, which "represses" contextually non-valid semantic alternatives (cf. SIMPSON/KANG 1994; FAUST/GERNSBACHER 1996; GORFEIN/BERGER/BUBKA 2000). Since, however, affective activation is thought not to be subject to this cortical inhibition process (cf. the automaticity of affect, [START_REF] De Houwer | An affective variant of the Simon paradigm[END_REF][START_REF] Fazio | On the automatic activiation of associated evaluations: An overview[END_REF], it may be the case that this irrepressible affect is experienced in the "wrong" semantic context and therefore gives rise to falsely connected symptoms in psychopathology.

Hypothesis: The Unconscious is Affect Aroused by Phonemic "Phantoms"

Imagined speech is motor activation. Speech motor areas are not only activated in case of speech production or active speech perception, but in a number of other conditions where speech is imagined but not effectively produced, including inner speech [START_REF] Mcguire | Functional anatomy of inner speech and auditory verbal imagery[END_REF], auditory verbal imagery [START_REF] Mcguire | Functional anatomy of inner speech and auditory verbal imagery[END_REF]) and hallucinations in schizophrenia [START_REF] Liddle | Patterns of cerebral blood flow in schizophrenia[END_REF]CLEG-HORN et al. 1992; MCGUIRE/SHAH/MURRAY 1993). As imagining movements leads to increased cerebral blood flow in motor areas concerned with their execution [START_REF] Decety | Mapping motor representations with positron emission tomography[END_REF][START_REF] Stephan | Functional anatomy of the mental representation of hand movements in healthy subjects[END_REF], the activity in regions which control speech motor systems may be due to imagined speech in these conditions.

DECETY/GRÈZES (1999) define motor imagery as a dynamic state during which the representation of a given motor act is internally rehearsed within working memory without any overt motor output. It has been proposed that such a simulation process corresponds to the conscious counterpart of many situations experienced in everyday life, such as watching somebody's action with the desire to imitate it, anticipating the effects of an action, preparing or intending to move, refraining from moving, and remembering an action (JEANNEROD/DECETY 1995;[START_REF] Decety | Neural representations for action[END_REF].

All of these tasks involve motor representations that recruit neural mechanisms specific to action planning. GEORGIEFF/JEANNEROD (1998) and DE-CETY/GRÈZES (1999) remark that comparison of brain activation during several modalities of action representation (including observation and imagining) reveals a common network to which the inferior parietal lobule (area 40), part of the supplementary motor area (SMA), the ventral premotor area, the cingulate gyrus and the cerebellum contribute. The ventral premotor area corresponds to a crossroads between the ventral part of area 6 and areas 44 and 45 (BROCA's area), a cortical zone which bears some homology with the monkey ventral area 6 where mirror neurons are recorded [START_REF] Rizzolatti | Premotor cortex and the recognition of motor actions[END_REF]. For all these reasons, it is expected that, similar to what is proposed for the signifier mediated affective mismatches, the substratum for speech imagery also involves the phonemic motor pathways.

Imagined motor activation induces phantoms

The phantom limb syndrome refers to the strong perception that a missing limb is still there, to the sense of being able to move it and to reported feelings arising from it such as intense pain. RAMACHAN-DRAN (1994) suggests that the relevant signaling maintaining the phantom are the sensations arising from reafference signals derived from the motor commands sent to the muscles of the phantom. Pain could especially be linked to the missing of the corresponding sensory feedback that would confirm the movement execution. The concepts of "efference copy", as introduced by HELMHOLTZ (1995) suggests that a copy of one's intended movement is used every time a voluntary action is planned, such that the sensory consequences of the action can be anticipated and eventually cancelled [START_REF] Blakemore | Central cancellation of self-produced tickle sensation[END_REF]. Most contemporary accounts of efference copy have claimed that it is unconscious, or acts to cancel percepts rather than generate them. Nevertheless, some clinical and experimental observations suggest that this information, in particular the state of the motor system, can influence subjective perception of the body. In deafferentiation, people still gesticulate while talking, even when the sight of these gestures is blinded to them and their interlocutor (COLE/PAILLARD 1996). It is suggested that, in agreement with MERLEAU-PONTY (1945) and IVER-SON/GOLDIN-MEADOW (1998), the gesticulation when talking is for the subject's own linguisticthought processes and not just for communicative purposes and that the informative signals here are not the (absent) somatosensory signals but, remarkably, the efference copies of the hand muscles. [START_REF] Mcgonigle | Whose arm is it anyway? An fMRI case study of supernumerary phantom limb[END_REF] recently report the case of E. P., a right-handed female stroke patient with a right frontomesial lesion who sporadically experiences a supernumerary "ghost" left arm. Their results suggest that areas traditionally classified as part of the motor system can influence the conscious perception of the body and they propose that, as a consequence of her injury, E.P. is aware of the position of the phantom limb in its "action space" on the basis of the efference (motor) copies while also continuing to be aware of the true position of her real limb on the basis of afferent somatosensory information. Focusing on the desired goal of an ac-tion, JEANNEROD (1994, p201) suggests that neurons encoding the "final configuration" of the body would continue firing "until the goal has been reached". If the goal were not reached, "the sustained discharge would be interpreted centrally as a pure representational activity and give rise to mental imagery" (JEANNEROD 1994, p201). In the case of E.P. sustained activity in a traditionally motor area of the brain (the SMA) correlates with her perception of a phantom arm [START_REF] Mcgonigle | Whose arm is it anyway? An fMRI case study of supernumerary phantom limb[END_REF]. All these observations suggest that phantoms arise when motor commands are consistently given, and that phantom pain could especially be linked to the missing of confirmatory sensory feedback.

Hypothesis: A linguistic unconscious

As a hypothesis, it is therefore proposed that recurrent unspoken phonemes, the motor circuitry of which is regularly activated, either by directed speech perception, by linguistic imagery or by refraining from speaking them ("repression"), could similarly create "phantom" phonemes in a linguistic "action space". These "phantom phonemes" which would be often or lastingly internally rehearsed in the phonological loop of working memory, would, if not spoken (enough), be interpreted centrally as representational activity, giving rise to mental imagery. This mental imagery then is not to be conceived as primarily semantically structured, but would rather have a primarily phonemic structure.

It is difficult to further speculate on the nature of such a phonemic mental imagery, but as phonemes were proposed to be affect-carrying substrates, it makes sense to conceive that although executing the motor plan is subject to inhibition, the associated affective activation is not. In this perspective, it is interesting to note that motor imagery activates heart and respiration control mechanisms in proportion to the actual effort that would be required for the real action [START_REF] Decety | Vegetative response during imagined movement is proportional to mental effort[END_REF][START_REF] Decety | Central activation of autonomic effectors during mental simulation of motor actions in man[END_REF]; WANG/MOR-GAN 1992). Such an autonomic response in a situation where no muscular work is produced can only be attributed to a central influence similar to that observed during motor preparation. As the autonomic system is by definition independent of voluntary control and cannot be held under inhibition, central influences on this system become recordable at the periphery [START_REF] Jeannerod | The representing brain: Neural correlates of motor intention and imagery[END_REF].

Ariane Bazan, Psychiatric Center, Sint-Amandus, Beernem, Belgium, and In conclusion, I propose the following structural hypothesis regarding the FREUDO-LACANIAN unconscious: phonemes of particular importance in one's personal history (e.g., the proper name) need not to be actualized per se in the ongoing discourse but have formed throughout the individual's particular history a raster of phonemic "phantoms", that are continuously functioning as "attractors" for the subject's affective attention.

Figure 1 .

 1 Figure1. "The inability of mother to make up her mind concerning her marriage" = origin of the (current) anxiety.

  Research Unit in Neuro-Psychoanalysis at the Department for Psychoanalysis and Clinical Consulting, University of Ghent, Belgium. Evolution and Cognition | 7 | 2002, Vol. 8, No. 2 Language as the Source of Human Unconscious Processes

Email: ariane.bazan@rug.ac.be

Author's address