Correlating Objective Third-Person Brain fMRI Measures with Subjective First-Person Identification of Specific Somatosensory Sensations

This is a seriously geeky paper that seeks to identify and correlate objective brain imaging with subjective experiences of focused attention. Here is the major finding:

These results provide evidence that the frontopolar prefrontal cortex has dissociable functions depending on specific cognitive demands; i.e. the dorsal portion of the frontopolar prefrontal cortex in conjunction with primary somatosensory cortex, temporopolar cortex, inferior parietal lobe, hippocampus, insula and amygdala are involved in the processing of spontaneous general subjective somatosensory experiences disclosed by focused and sustained attention.

Translation: They found that a specific area of the prefrontal cortex (the dorsal portion of the frontopolar prefrontal cortex) works with other higher level brain regions (primary somatosensory cortex, temporopolar cortex, and inferior parietal lobe) as well as elements of the limbic system (hippocampus, insula and amygdala) to process focused attention on subjective somatosensory experiences.

This might seem like a whole lot of who cares, but understanding these processes might lead us to better and more effective models of somatic therapy for trauma. In trauma survivors, the connections between the limbic system (emotional processing) and the prefrontal cortex (executive functions such as planning, understanding eventual outcomes to current actions, and so forth) is often compromised in some way. Mindfulness of bodily experiences can help repair this, but knowing which other brain regions are involved might help us refine our tools to make them more effective.

Full Citation: 
Bauer CCC, Barrios FA, Díaz J-L. (2014, Aug 28). Subjective Somatosensory Experiences Disclosed by Focused Attention: Cortical-Hippocampal-Insular and Amygdala Contributions. PLoS ONE; 9(8): e104721. doi:10.1371/journal.pone.0104721

Subjective Somatosensory Experiences Disclosed by Focused Attention: Cortical-Hippocampal-Insular and Amygdala Contributions

Clemens C.C. Bauer, Fernando A. Barrios, José-Luis Díaz

Abstract

In order to explore the neurobiological foundations of qualitative subjective experiences, the present study was designed to correlate objective third-person brain fMRI measures with subjective first-person identification and scaling of local, subtle, and specific somatosensory sensations, obtained directly after the imaging procedure. Thus, thirty-four volunteers were instructed to focus and sustain their attention to either provoked or spontaneous sensations of each thumb during the fMRI procedure. By means of a Likert scale applied immediately afterwards, the participants recalled and evaluated the intensity of their attention and identified specific somatosensory sensations (e.g. pulsation, vibration, heat). Using the subject's subjective scores as covariates to model both attention intensity and general somatosensory experiences regressors, the whole-brain random effect analyses revealed activations in the frontopolar prefrontal cortex (BA10), primary somatosensory cortex (BA1), premotor cortex (BA 6), precuneus (BA 7), temporopolar cortex (BA 38), inferior parietal lobe (BA 39), hippocampus, insula and amygdala. Furthermore, BA10 showed differential activity, with ventral BA10 correlating exclusively with attention (r(32) = 0.54, p = 0.0013) and dorsal BA10 correlating exclusively with somatosensory sensation (r(32) = 0.46, p = 0.007). All other reported brain areas showed significant positive correlations solely with subjective somatosensory experiences reports. These results provide evidence that the frontopolar prefrontal cortex has dissociable functions depending on specific cognitive demands; i.e. the dorsal portion of the frontopolar prefrontal cortex in conjunction with primary somatosensory cortex, temporopolar cortex, inferior parietal lobe, hippocampus, insula and amygdala are involved in the processing of spontaneous general subjective somatosensory experiences disclosed by focused and sustained attention.

Introduction

Before attempting to explain how and why neurophysiological processes relate to consciousness traits, it seems necessary to find consistent correlations between subjective phenomenological features and brain activity patterns [1]. For example, it is now possible to correlate introspective evaluations of sensory aspects of subjective experience with imaged local brain activations [2]. Such neurophenomenological program depends on the development of dynamic approaches to cerebral activity in conjunction to standardized and rigorous measurements of subjective experience obtained from first-person reports [3], [4]. A particular difficulty concerning the subjective character of conscious experience is the neural substrate of sensorial qualia features such as color, sound, scent, taste, touch, pain, and the like [5]. It has been suggested that the ventral prefrontal cortex is necessary, but not sufficient, for the generation of subjective experiences [6]–[8] and that there may be different areas involved depending on their specific character (e.g. auditory, tactile, emotional) [9], [10]. Other studies also report signal increases in frontopolar prefrontal cortex during different self-referential processing tasks [11]–[13] and the magnitude and time course of its activation predicts whether information is consciously perceived or slips away unnoticed [6].

Bilateral activations of temporopolar cortex were found during object encoding, tactile perception and self-related processing [14]–[16]. Furthermore, the phenomenal character of perceiving some objects as different from others is associated with right temporopolar activation [15].

The ability to voluntarily direct, concentrate, and sustain attention can bring into focus and enhance bottom-up qualitative processes of either a somatosenory/external or proprioceptive/internal nature [17]–[21]. A form of insight meditation requiring sustained awareness of subtle somatic sensations spontaneously arising from different body parts increases parieto-occipital gamma activity, a marker for enhanced sensory awareness [22]. Tactile attention also biases the processing of selected stimuli relevant features by amplifying somatosensory cortex responses [23]. Attention towards particular somatic stimuli, in turn, selectively enhances domain-specific cortical representations that probably are determinant for their conscious perception [21], [24].

Based on previous studies implicating several brain regions in the generation of subjective experiences [6]–[8], [14], [15] and the evidence that top-down attention control can be used to define particular sensory targets [21], [22], [24], we hypothesized that focusing attention on subtle pre-reflective somatosensory experiences would activate frontopolar prefrontal and temporopolar cortices, and, specifically, that the objectively measured brain activity within these regions would correlate with subjective sensory experience reports.

Materials and Methods

Subjects

All subjects gave written informed consent for the experimental procedure, and the protocol follows the principles expressed in the Declaration of Helsinki and was authorized by The Bioethics Committee of the Neurobiology Institute (Comité de Bioética del Instituto de Neurobiología, Universidad Nacional Autónoma de México). After standard exclusion criteria for functional magnetic resonance imaging (fMRI) were applied, 37 healthy volunteers participated in the study (16 female and 21 male, mean age 35.58 years, SD 7.97, 14 left handed and 23 right handed). Subjects were evaluated with digital versions of the Symptom Checklist 90 and Edinburgh Inventory to exclude psychological and/or psychopathological symptoms, and to evaluate handedness [25], [26]. All subjects gave informed consent for the experimental procedure, and the protocol had IRB approval.

Experimental design

Brain activation was examined during covert focused attention directed towards either the right or left thumb under two experimental conditions: (a) External-Stimulus Condition (manual caressing of either thumb with a 2-cm sponge brush at 1–2 Hz and stimulation aftereffect) and (b) Spontaneous-Sensation Condition in absence of any external stimulation (Figure 1). Resting periods without attention tasks separated both experimental conditions. Subjects were instructed to focus their attention on either thumb during the two experimental conditions and to abstain from moving it during the whole experiment. The instructions emphasized that, in the absence of touch stimuli, the subjects should focus their attention on the spontaneous sensations arising from either thumb rather than visualizing or imagining this body part. The protocol consisted of a block design paradigm alternating between focusing of attention towards the External-Stimulus of either thumb (60 sec blue block in Figure 1) or focusing of attention towards Spontaneous-Sensation of the same body part in the absence of external stimuli (60 sec yellow block in Figure 1). The length of the blocks was decided after a pilot study where the response showed that the subjects started to feel clear and distinct sensations ~20–40 sec after the instruction. Right and left thumbs were run in separate procedures and the order of the thumb was randomly counterbalanced (Left thumb first 52%). The External-Stimulus block was further divided into a 30 sec Touch-Stimulus Condition (shown as a dark-block in Figure 1) and a 30 sec Stimulation Aftereffect Condition (shown as a light-blue block in Figure 1). External-Stimulus and Spontaneous-Sensation conditions were separated by 30 sec resting intervals to ensure no overlapping brain activity. Each run lasted 540 sec and consisted of three epochs. One epoch was a 180 sec sequence of Rest, Touch-Stimulus, Stimulation Aftereffect, Resting, and Spontaneous-Sensation. While in the scanner, the subjects received a previously agreed one-word instruction (“attention” or “rest”) via MRI compatible audio equipment (NordicNeuroLab, Bergen, Norway) directing them to focus their attention on the target thumb, or to rest. Subjects had their eyes closed during the whole experiment.

Figure 1. Single run experimental paradigm for either thumb.
Touch-Stimulus (TS, in dark-blue), Stimulation-Aftereffect (SA, in light-blue) and Spontaneous-Sensation (SS, in yellow). Focusing attention (FA, in grey) was required during every condition. No attention task was required during resting periods between conditions (gaps). doi:10.1371/journal.pone.0104721.g001

Immediately after the scanning procedure all subjects were submitted to a Phenomenology Questionnaire to assess first-person Subjective Sensations experienced during the Spontaneous-Sensation Condition. The Phenomenology Questionnaire was designed to reflect the participant's subjective assessment of their experience through all the blocks. It consisted of a qualitative free description of the experienced sensations followed by a quantitative section where attention strength and intensity of specific sensory qualia experienced across all Spontaneous-Sensation blocks were assessed by means of a 1 to 5 Likert scale (see below and Table 1 in Results section for details).

Table 1. Phenomenology Questionnaire.
doi:10.1371/journal.pone.0104721.t001

During the scanning an examiner closely monitored the subject's thumb to ensure there was no motion. If there was any perceptible movement the run was discarded. Only six runs from 3 subjects (all right handed) were discarded due to involuntary thumb movement, and the results presented were obtained from the remaining 34 subjects.

Imaging protocol

fMRI imaging was performed on a 3.0T GE MR750 instrument (General Electric, Waukesha, WI) using a 32-channel head coil. Functional imaging included 35 axial slices, acquired using a T2*-weighted EPI sequence with TR/TE 3000/40 ms, a 64×64 matrix and 4-mm slice thickness, resulting in a 4×4×4 mm³ isometric voxel. High-resolution structural 3D-T1-weighted images were acquired for anatomical localization (resolution of 1×1×1 mm³, TR = 2.3 sec, TE = 3 ms) covering the whole brain. The images were acquired with an acceleration factor = 2.

Quantitative evaluation of the Phenomenology Questionnaire

Attention strength towards each thumb was assessed with a Likert scale ranging from weak attention (1) to strong attention (5). Subject's subjective sensations scores for attention strength were used as covariates to model the attention regressor. A pilot study performed where volunteers were instructed to focus their attention on either thumb and generate an unrestricted phenomenological description revealed that the most frequently used adjectives were: pulsation, vibration, enlargement, heat, cold, shrinkage, itching, stinging, and numbness. Thus, these were the adjectives used in the subjective sensations Likert scale assessment ranging from no sensation (1) to intense sensation (5). The mean subjective sensation for all these nine somatosensory sensations was used as the covariate to model the qualia regressor (see row in Table 1 in Results section for details).

Image processing and statistical analyses

Functional image datasets were processed and analyzed with FSL 4.1.5 (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl) [27].

Preprocessing.

The skull and other non-brain areas were extracted from the anatomical and functional scans using the script brain extraction tool (BET) of FSL, motion correction using MCFLIRT [28], spatial smoothing using a Gaussian kernel of FWHM 6 mm, mean-based intensity normalization, and nonlinear highpass temporal filtering. Extracted brains of all participants were linearly registered into the brain-extracted MNI152template using a linear spatial transformation function.

First-level fMRI analysis.

Statistical analysis was performed with FMRI Expert Analysis Tool using FMRIB's Improved Linear Model (FEAT FILM) Version 5.98 with local autocorrelation correction contrasts with a significance threshold criterion of Z>2.3 with a cluster significance threshold of P<0.05 corrected for multiple comparisons [29] and using the canonical hemodynamic response function (HRF) convolved with a function longer in duration to model the entire blocks and its time derivative as basic functions. The model included the following regressors with their corresponding HRF and their temporal derivatives: Touch-Stimulus and Spontaneous-Sensation as well as stimulation-aftereffect per thumb, with motion parameters controlled for in the model. The Touch-Stimulus regressor was modeled to fit a transient response curve in accord with previous somatosensory habituation reports [30], [31] where somatosensory cortex activation peaked around 6 sec after the onset of the stimulation and then exponentially returned to baseline for the rest of the block. In this manner it was ensured that only the touch-related processes were identified and measured. The Spontaneous-Sensation regressor was modeled to fit the last 30 sec of the block, as this would have stronger correspondence to the subjective ratings (see Experimental design), and the first 30 sec were modeled as dummy condition and discarded. Although all four conditions were considered in the GLM, only the response obtained for the Spontaneous-Sensation Condition of the last thumb of each participant was assessed and correlated with the subject's Subjective Sensation scores obtained from the Phenomenology Questionnaire. The rationale is that, although two functional runs were conducted (one for each thumb), the Phenomenology Questionnaire was only conducted once at the end of the session. Due to the recency effect, responses to this Questionnaire are more applicable to the last thumb stimulated, so only data acquired from the last functional run were analyzed with the Questionnaire data.

Group-level Subjective-Sensation analysis.

To identify activations at the group-level related to attention strength and subjective-sensation for somatosensory experiences, a subjective-sensation analysis using FLAME (FMRIB's Local Analysis of Mixed Effects) was conducted using subject's subjective sensations scores as covariates to model both attention and somatosensory experience regressors (see the Quantitative evaluation of the phenomenology questionnaire and rows A and of Table 1). All group Z statistical images were thresholded at Z>2.3 (p<0 .05) to define contiguous voxel clusters. The FSL cluster correction for multiple comparisons (Gaussian-random field theory based) was set at p<0.05, whole brain correction (http://www.fmrib.ox.ac.uk/fsl) [29]. Because we did not find any frontal activation at this threshold as previously hypothesized (see Introduction), we additionally performed an exploratory whole-brain group-level analyses using an uncorrected p-value of p<0.001 with a minimum cluster size threshold (k) of 15 voxels [32], [33]. This statistical threshold is in line with the recommendations for such complex and subtle cognitive processes, as used in previous social and affective neuroscience studies [33]. Subsequently, except where indicated, and due to the documented importance of the frontopolar prefrontal cortex in the integration of multiple separate cognitive processes in the service of higher-order behavioral goals like self referential processes (i.e. mentalizing) and attention [11], we specifically explored this region using a small-volume-correction through a region of interest (ROI) approach. The frontopolar prefrontal ROIs were based on the peak activation of this exploratory whole-brain group-level analyses and the results reported in the meta-analysis in Gilbert et all 2006 that specifically relate to left frontopolar cortex activation either during attention [34]–[37] or during self referential processes (i.e. metalizing) [11]–[13]. The ROIs were defined by merging individually created ROIs of 5 voxel (10 mm) diameter spheres (~131 mm³) around each of the documented peak coordinates and our own results in order to obtain oblong ROI volumes for a) Attention of k = 725 voxels (1450 mm³) and b) Subjective Sensation of k = 500 voxels (1000 mm³) covering the left frontopolar prefrontal cortex associated with these processes (ROIs were constructed in the 2 mm MNI-152 template). The statistical significance for the ROI analysis were corrected for multiple comparisons using the false discovery rate (FDR) correction as implemented in FSL [38]. The FDR procedure ensures that on average no more than 5% of activated voxels for each contrast are expected to be false positives. The resulting peak voxel activation for either regressor was used to calculate the percent changes of BOLD signal in each subject using Featquery (part of FSL 4.1.5). These signal changes were then correlated with the subject's individual specific subjective attention strength or mean somoatosensory qualia scores of the Lickert scale using Spearman's rank correlation coefficient (see rows A and of Table 1). Results were projected onto the surface representation of the MNI-152 template with the Freesurfer suite (http://surfer.nmr.mgh.harvard.edu/) [39] for visualization purposes.

Results

Qualitative evaluation of the phenomenology questionnaire

Subject's answers for the Phenomenology Questionnaire during the Spontaneous-Sensation Condition are shown in Table 1. All subjects experienced and spontaneously expressed their subjective sensations.

Spontaneous-Sensation analysis

Sixty-eight runs (34 right thumb and 34 left thumb) from 34 subjects were included in the analysis. Figure 2 shows that, compared with the resting task-free condition (neither external touch-stimuli nor spontaneous sensations), focusing of attention to Spontaneous-Sensation showed a group activation where the peak MNI coordinates for the right thumb (Figure 2B) were found in the left primary somatosensory cortex (BA 3b: X = −58 mm, Y = 6 mm, Z = 14 mm), bilateral secondary somatosensory cortices (SII: 34, 2, 20 and −42, −2, 12), left premotor cortex (BA 6: −2, 6, 52), left parietal lobe (PL: −26, −48, 26), left Broca's area (BA 44: −48, 4, −2), anterior cingulate cortex (BA 32: −18, 14, 28) and right insula (BA 13: 38, 10, 2). Focusing attention on Spontaneous-Sensation of the left thumb (Figure 2A), showed activations in the left primary somatosensory cortex (BA 3a: −46, 4, 16), left premotor cortex (BA 6: −56, 10, 42), and left Broca's area (BA 44: −50, 6, 8). Coordinates of peak activation, cluster size and z-values for this and all subsequent contrasts are shown in Table 2.

Figure 2. Spontaneous-Sensation analysis: Overall activations associated with focusing of attention during the different phases of the experimental paradigm. A) Focusing attention on Spontaneous-Sensation of the left thumb. B) Focusing of attention on Spontaneous-Sensation of the right thumb. All statistical maps had a significance threshold of Z>2.3, with a cluster significance threshold of p<0.05 (corrected for multiple comparisons). Images are presented in radiological convention and mapped to the MNI-152 template. doi:10.1371/journal.pone.0104721.g002

Table 2. Peak voxel activation for all experiments. doi:10.1371/journal.pone.0104721.t002

The activations found during the Touch-Stimulus Condition and their relation to the activations during the Spontaneous-Sensation Condition are detailed in a separate communication [21]. It is relevant to mention here that the contralateral activation of the somatosensory cortex (BA 3a/b corresponding to the hand area) obtained during the Touch-Stimulus Condition was also observed during the Spontaneous-Sensation Condition. Additionally, a left parieto-frontal activation was detected in the first-level analysis in the right-handed subjects during the Spontaneous-Sensation Condition. This prompted us to include a sample of 14 left-handed individuals for a statistically suitable comparison, but no differences between right and left-handed subjects were found after analyzing right and left thumbs separately and between groups for details please refer to [21]. Thus, we considered both hand-dominance groups as statistically similar and the left parieto-frontal activation as a result of top-down attentional mechanisms for a discussion on this please see [21].

Subjective-Sensation analysis

Attention.

left frontopolar prefrontal cortex (ventral portion) (BA 10: −4, 66, −4; Z = 3.78, p<0.05, small-volume-FDR-corrected; red cluster in Figure 3A) was active for attention as covariate and the percentage BOLD signal change correlated positively with the subjects' subjective attention strength reports (r(32) = 0.54, p = 0.0013, Figure 3B.1) but not for subjects' subjective somatosensory experience reports (r(32) = −0.1, p = 0.563, Figure 3B.4).

Figure 3. Subjective-Sensation analysis: Significant activations and correlations for the covariates from the Phenomenology Questionnaire.
A) Attention as a covariate revealed left ventral frontopolar prefrontal cortex (BA10 in red); Subjective somatosensory experience mean as a covariate revealed (in green) left dorsal frontopolar prefrontal cortex (BA10 in green), right primary somatosensory cortex (BA2), right premotor cortex (BA 6), precuneus (BA 7), left temporopolar cortex (BA 38), right inferior parietal lober (BA 39), right hippocampus, right insula and right amygdala, and. B) Spearman's rank correlations of subjective sensation scores with % BOLD signal change of peak voxels for 1) Subjective Attention score vs. ventral BA10 L, 2) Subjective Somatosensory Experiences vs. ventral BA 10 L, 3) Subjective Attention score vs. dorsal BA10 L, 4) Subjective Somatosensory Experiences vs. dorsal BA 10 L, 5) Subjective Somatosensory Experiences vs. BA 2 R, 6) Subjective Somatosensory Experiences vs. BA 6 L, 7) Subjective Somatosensory Experiences vs.BA 7 R, 8) 6) Subjective Somatosensory Experiences vs. BA 38 L, 9) Subjective Somatosensory Experiences vs. BA 39 R, 10) Subjective Somatosensory Experiences vs. Hippocampus R, 11) Subjective Somatosensory Experiences vs. Insula R, 12) Subjective Somatosensory Experiences vs. Amygdala R. Coordinates shown are X, Y, Z in mm for the MNI152 template. Activations have a significance threshold of Z>2.3, with a cluster significance threshold of p<0.05 (corrected for multiple comparisons) except for *BA10 = small-volume-FDR-correction with p<0.05. All correlations were assessed with the Pearson product-moment correlation and assessed for outliers using Spearman's rank-order correlation. Dashed lines indicate 95% confidence intervals. doi:10.1371/journal.pone.0104721.g003

Subjective Somatosensory Experiences.

Activity in several regions covaried with subjective somatosensory experiences (Figure 3A, green clusters, all clusters corrected p<0.05). These regions include the left frontopolar prefrontal cortex (dorsal portion) (BA10: −20, 72, 8), right primary somatosensory cortex (BA 2: 28, −42), right premotor cortex (BA 6: 50, 0, 28), right precuneus (BA 7: 8, −64, 52), left temporopolar cortex (BA 38: −32, 2, −18), right inferior parietal lobe (BA 39: 46, −70, 32), right hippocampus (30, −26, −14), right insula (38, −8, 4), and right amygdala (26, −8, −18). Additionally, the percentage BOLD signal change correlated positively with the subjects' subjective somatosensory experience reports (i.e. BA10: r(32) = 0.46, p = 0.007, Figure 3B.2; BA 2: r(32) = 0.36, p = 0.039, Figure 3B.5; BA 6: r(32) = 0.38, p = 0.029, Figure 3B.6; Precuneus: r(32) = 0.37, p = 0.034, Figure 3B.7; BA 38: r(32) = 0.33, p = 0.57, ρ = 0.4, p = 0.21, Figure 3B.8; BA 39: r(32) = 0.4, p = 0.02, Figure 3B.9; Hippocampus: r(32) = 0.51, p = 0.002, Figure 3B.10; Insula: r(32) = 0.38, p = 0.028, Figure 3B.11; Amygdala: r(32) = 0.36, p = 0.039, Figure 3B.12). Additionally, ventral BA 10 (−20, 72, 8) did not correlate with subjects' subjective attention strength reports (r = −0.07, p = 0.719, Figure 3B.3). To check for outliers we ran a non-parametric correlation test for all the brain areas, i.e. Spearman's rank-order correlation, which only showed a significant change for BA 38 (see above and Figure 3B.8).

Discussion

After verifying in 34 healthy volunteers that sustained attention directed to the spontaneous sensations of either thumb in the absence of any external stimuli effectively activates brain somatosensory areas, the present results show that corresponding subjective somatosensory experiences correlate with left dorsal frontopolar prefrontal cortex, right primary somatosensory cortex, left temporopolar cortex, right inferior parietal lobe, right hippocampus, right insula and right amygdala activations. Therefore, the main hypothesis of this work was largely corroborated with the additional finding that the left frontopolar prefrontal cortex (BA 10) and the temporopolar cortex (BA 38), in conjunction with primary somatosensory (BA 2), cortex, premotor cortex (BA 6), precuneus (BA 7), inferior parietal lobe (BA 39), hippocampus, insula and amygdala are involved in general spontaneous subjective somatosensory experiences.

The results show that the frontopolar prefrontal cortex has functional subdivisions, updating previous theories [11]. In particular, we show that the dorsal part of the frontopolar prefrontal cortex is involved during subjective sensory experiences known as qualia [6]–[8] and that it is coupled with other brain areas during this process. Hence, contributing to narrow down the individual brain structures involved [9], [10], [40]. In particular, our results agree with Feinstein et al. [6] in terms that the magnitude and time course of activation within the frontopolar prefrontal cortex, medial prefrontal cortex, and the anterior cingulate predict whether information is consciously perceived or slips away unnoticed. Other studies also report signal increases in frontopolar prefrontal cortex during different self-referential processing tasks [11]–[13]. It has also been shown that synchronic frontal gamma patterns (around 40 Hz) emerge with the recognition of a 3D object from an auto-stereogram and this pattern occurred only when subjects were readily expecting the arrival of the concealed visual object (26).

We also found that the left temporopolar cortex (BA38), together with the frontopolar cortex, becomes active during both attention mechanisms and subjective experience. Since the temporopolar cortex is a convergence zone where information from sensory, association, and limbic systems is integrated [41], [42]; this activation may relate to the awareness and conscious processing of the affective component of somatosensory experiences. In agreement with this interpretation, Ramsøy et al. [14] found that object encoding evokes bilateral activations of temporopolar, perirhinal, parahippocampal cortices, hippocampus and amygdala, while D'Argembeau et al. [43] found that the temporopolar cortex along with dorsomedial prefrontal cortex, left anterior middle temporal gyrus, and right cerebellum is implicated in reflective tasks pertaining to self, another person, and social issues.

Besides frontopolar and temporopolar activation, in the present study other areas appeared to be involved in the retrieval and processing of somatosensory experiences, i.e., primary somatosensory cortex, premotor cortex, precuneus, inferior parietal lobe, hippocampus, insula and amygdala. The combined activity of these areas probably supports conscious perceptual and phenomenological awareness [44], [45]. Consequently, pimary somatosensory cortex activation suggests its causal involvement due to the nature of the attended somatosensory experiences [21], [45]. Parietal and premotor cortices have been implicated in multisensory integration, embodiment, localization and self-attribution of body parts [46]–[49] and insula activation has been implicated in the integration of interoceptive and exteroceptive signals to construct the mental self [49], [50] and amygdala activation has been found coupled to frontal brain regions when subjects involve in self-related processing [43] and is probably a key node involved in self-referential emotion processing [51]–[53]. Finally, autobiographical memory and past experiences relate to consciousness of one self, which requires hippocampal processing [54]–[57]. Even though the instructions in our study focus on actual somatosensory experiences, the activations detected in these brain areas suggests an underlying neurocognitive requirement of body-ownership and self-consciousness. Finally, the noteworthy finding that primary somatosensory cortex is activated in the absence of external stimulation by the focusing of attention on spontaneous sensory qualia verifies that selective attention controlled by top-down cognitive processes enhance bottom-up qualitative processes of somatosensory/external and proprioceptive/internal nature that normally do not elicit primary somatosensory cortex activity in absence of stimuli [17]–[20]. This spontaneously-elicited somatosensory activity is accompanied by phenomenological somatosensory qualitative experiences or qualia, some of the most characteristic and enigmatic subjective phenomena [58], but suitable to be correlated with objective measures of brain activity [59].

Within a broader perspective, the study of sensory qualia intending to match third-person fMRI brain imaging with standardized first-person somatosensory reports constitutes a particular neurophenomenological endeavor to study the neural correlates of qualitative subjective experience. In the light of the present results, the precise mechanism for the production or correspondence of subjective sensory experiences in the detected neural networks remains a challenging, but perhaps a more delimited research question.

Supporting Information

Data_S1.docx

figshare

download

Data S1.

doi:10.1371/journal.pone.0104721.s001

(DOCX)

Acknowledgments

We are grateful to Dr. Luis Concha for his relevant comments and to Dr. G. Andrew James for his thorough and insightful review of the paper and wonderful suggestions to improve it. Also to M.Sc. Leopoldo González-Santos, M.Sc. Juan J. Ortiz, Dr. Sarael Alcauter, and Dr. Erick Pasaye for technical support.

Author Contributions

Conceived and designed the experiments: CCCB FAB JLD. Performed the experiments: CCCB FAB. Analyzed the data: CCCB FAB. Contributed reagents/materials/analysis tools: FAB. Contributed to the writing of the manuscript: CCCB FAB JLD.

References are available at the PLoS ONE site.

Sharon K. Farber - Cults and the Mind-Body Connection

We tend to think of cults as exerting mind control over their members, a kind of psychological enslavement, and this is partially true. However, as Dr. Farber argues, the way to obtain control of the mind is through the senses - music, incense, chanting, drumming, dancing, touch. Mind control, as she shows below, can often begin with the body.

This comes from Sharon K. Farber, PhD and her Psychology Today blog, The Mind-Body Connection. The one place where I think she is off the rails is on meditation - her experience with her brother has seriously biased her objectivity.

Cults and the Mind-Body Connection

A Form of Soul Murder

Published on July 19, 2014 by Sharon K. Farber, Ph.D. in The Mind-Body Connection

I just returned from the International Cultic Studies Association‘s (ICSA) annual conference and wanted to tell you about soul murder, the term coined by psychoanalyst Leonard Shengold to describe the intentional attempt to stamp out or compromise the separate identity of another person. That is what destructive cults do. My interest in cults grew out of my shock many years ago upon discovering how deeply my brother was involved in Transcendental Meditation (TM), so deeply that he lost the ability to think for himself. Since then I have treated a number of patients who had been profoundly damaged by cults, and when I heard about the International Cultic Studies Association (ICSA) some years ago, I joined and have attended and presented on topics related to cult involvement, something that the mental health field tends to know little about. At these conferences I have met so many intelligent people who have been victims of cults, their families, researchers, and mental health professionals in the U.S. and abroad with expertise in treatment of those who had been involved in a cult. I also met what are today known as exit counselors, usually former cult members themselves who left their cult, who will talk with individuals who agree to speak with them. (No kidnapping, as in the deprogramming of years ago.) ICSA even has a number of members who were born into a cult. Having high intelligence is no protection from becoming victimized by a cult.

My practice is two or three miles from Irvington and Tarrytown, in Westchester County, where the Rev. Sun Myung Moon, founder of the Unification Church (aka the Moonies) owned hundreds of acres. At least a few times a week I pass by Belvedere, a large estate where many followers live. Years ago, I imagined myself infiltrating the group but after reading accounts of how people can succumb to mind control, I decided against it. At the conference, I met a young man who discovered when he was around twelve that the Rev. Moon was his father.

The  (ICSA) is a global network of people concerned about psychological manipulation and abuse in cultic or high-demand groups, alternative movements, and other environments. ICSA is not affiliated with any religious or commercial organizations.Its mission, as stated at their website icsahome.org, is to apply research and professional perspectives to help those who have been spiritually abused or otherwise harmed by psychological manipulation and high-demand groups, educate the public, promote and conduct research, and support helping professionals interested in cults, related groups, and psychological manipulation. Hearing parents speak at the conference of their anguish after losing a child to a cult was heart-wrenching. And yet they gained some comfort and lessened their feeling of isolation by sharing their stories with others who understood.

Cult activity is far more common than you might imagine. Our attention was drawn to cults in the sixties and seventies, when Allen Ginsberg said that life should be ecstasy and went to India and Hindu culture in search of it. Many young people followed suit, questioning western values and embracing eastern thought. Indian clothing and Hindu practices became the rage, and we became accustomed to seeing young men in orange robes chanting their Hare Krishna mantra in airports and bus stations, where they sought recruits.

hare kṛiṣhṇa hare kṛiṣhṇa
kṛiṣhṇa kṛiṣhṇa hare hare
hare rāma hare rāma
rāma rāma hare hare

Their heads were shaved except for a small lock of hair in the back, and they had paint marks on their foreheads. These representatives of the International Society for Krishna Consciousness (ISKON) became known as the hare krishnas. If anyone had told me years ago that I would develop a friendship with a man who had been deeply involved with this cult, I would not have believed it.

The first generation of cult members were young people who left home and school looking for meaning at a vulnerable period in their life. They were seduced into thinking they had found what they were looking for in such groups as the Unification Church, Children of God, The International Society for Krishna Consciousness, Scientology and others. As their numbers increased, the different groups and practices began to blur in the public eye.

When we think of cults today, we tend to think of the Hare Krishnas or other eastern meditation groups. But many Christian cults have evolved, such as the Jesus freaks, Children of God, The Way International, the Unification Church, and the Mormon Church. And today cults are not limited to religious groups but include EST, Scientology, yoga cults, psychotherapy cults, and philosophy cults such as Aesthetic Realism.

Just what is a cult? The word itself is controversial, because it used to be used to mean any religious group with unusual beliefs that deviated from the norm, what we might today consider a sect. Today, the term destructive cult is used to describe groups that use manipulative techniques and mind control to heighten suggestibility and subservience. They tend to isolate recruits from former friends and family in order to promote total dependence on the group. The aim is to advance the goals of the group’s leaders, which is to have total control over members.

Gaining total control of members is done by assaulting the minds of recruits, an assault meant to control their minds. The mind is located in the brain and in certain hormones and enzymes that travel through the body, affecting our senses. It is through the senses. through seeing, hearing, tasting, smelling and touching. that we know about the world. Think of the body as a giant pharmaceutical factory that manufactures powerful, mind-altering chemicals which we can release by immersing ourselves in mood altering activities or ingesting mood altering substances. The medieval Christian mystics who starved and flagellated themselves knew this well. So do Turkey’s Whirling Dervishes who once a year, put on long white robes with full skirts, black cloaks, and tall conical red hats and twirl in unison to the sound of drums and flutes, faster and faster, whirling their way toward God and ecstasy.

Cults start seducing people with love-bombing, paying a great deal of attention to and being very affectionate with potential recruits, a very effective way of connecting with someone who is feeling lonely and isolated. Then they assault and overwhelm their senses by using various various techniques to induce a dissociated state, an altered state of consciousness, a trance state, in which mind and body are disconnected from each other. These techniques include sleep and food deprivation, drumming, chanting, lecturing on and on for hours, flashing lights, spinning around in circles, all of which assault the senses and break down a person’s ability to think. The cult uses mind control to fill the dissociated mind with their beliefs and magical thinking. A moment comes when the mind shuts down and seems to snap from this assault to the nervous system. Snapping may happen suddenly and abruptly, or it may be a slower, more gradual process of subtle changes, resulting in personality change.

Many cults promote meditation, at times for many hours a day. When TM first came on the scene in the sixties, most people thought of it as a benign practice occurring twenty minutes in the morning and evening, but many advanced TMers devote many hours a day to meditating. In fact, they may go into the dissociated meditational state without intending to do so, and may live largely in a dissociated state of consciousness.

Meditation is generally promoted as having many health benefits, and mindfulness meditation has been actively promoted in the past two decades. It is a western, non-sectarian, research-based form of meditation derived from a 2,500 year old Buddhist practice called Vipassana. However, it is important to know that meditation of any kind is not for everyone.There are several studies indicating that up to as many as 55% of long-term meditators showed adverse effects, including partial epileptic-type seizures, with adverse effects increasing with the length of practice. Meditation can produce anxiety, panic, confusion, depression, agitation, ongoing dissociation, hallucinations, tics, sweating, trembling, shivering, worsened interpersonal relations, psychotic breakdowns and suicidal tendencies in some people. Meditation is particularly dangerous for those with a history of schizophrenia.

The TM movement is known for ascribing positive qualities to all kinds of cult-induced psychopathology. A psychotic breakdown may be regarded as achieving cosmic consciousness, the key to enlightenment. TMers are indoctrinated to believe that if they spend thousands of dollars for a higher level of training, they would be able to levitate, also known as yogic flying. David Wants to Fly, a recently released film about a young man’s interest in levitation, has scenes of levitation, some of which can be viewed on Youtube.com. What you see is not people flying, but sitting in the lotus position within a dome-shaped structure known as a levitation

dome, on a thick layer of foam rubber padding, and bouncing and hopping around on their behinds. I have also heard that they strap on foam rubber “butt pad”, which happen to be the number one bestselling accessory at Maharishi International University in Fairfield, Iowa. Apparently, they help someone bouncing around on his behind to bounce higher.

Radiance, the TM Ideal community where my brother lives has, in addition to a community swimming pool, its own levitation dome. My brother said he banged into a wall while levitating and broke his good watch, making him decide to switch to a cheaper Timex. I tried it myself. I just bounced around. You too can bounce around on your behind without spending lots of money to learn how to do it. You don’t need to meditate. Just don’t call it levitation. Although TM purported that members could levitate, they never allowed photographers or film makers to witness it, and for good reason.

The cult preys upon the tendency of many to rely on magical thinking, which reinforces the tendency to endow the leader with omnipotent and magical powers, much like the child’s early mental representations of the parent who at that time, did control his universe. The member can readily come to believe that the leader can read his mind or hear conversations at a distance. Slowly, greater and greater irrational power is attributed to the leader. Because the cult leader tends to be a person with a sense of self-esteem so damaged that he requires the adoration, obedience, and subjugation of others to gain a sense of self-esteem and power, he cannot get enough of this. This is very much the same dynamic as is found in cases of domestic violence, when one spouse, usually the husband, Tries to assert total control over the other, seemingly a cult of one.

Some in cults who cannot verbally express what they feel about what has been done to them express it through their bodies, harming themselves through cutting and burning themselves, starving their bodies or stuffing themselves with food when they can get their hands on it, or purging through vomiting. When they get so sick in the cult, this is when the cult will eject them because they feel no responsibility for getting them the help they need. It should not be a surprise to hear that many cults are openly against psychotherapy.

I hope this helps you understand a bit more about soul murder. The victims of soul murder remain in large part possessed by another, their souls in bondage to another. Shengold cites George Orwell ‘s 1984, in which O’Brien says to Winston Smith: “You will be hollow. We will squeeze you empty, and then we shall fill you with ourselves .. .Power is in tearing human minds to pieces and putting them together again in new shapes of your own choosing.”

There is help available to those who have been victimized by a cult.

There is a chapter about the cults, “Cult-Induced Ecstasies and Psychosis” in my new book, Hungry for Ecstasy: Trauma, the Brain, and the Influence of the Sixties (2013). It is an expensive book but available with a 30% discount if you email me at Sharonkfarber@gmail.com. Or you can request your library obtain a copy.

Also, if you go to the ICSA website (icsahome.orgicsahome.org) there is much valuable information there. If you join you will receive their magazine and the Cultic Studies Journal and more.

In NY, there is the Cult Hotline and Clinic at the -Jewish Board of Family and Children’s Services,telephone 212 632-4640. Arnold Markowitz is the director. There are local ICSA support meetings in NYC, Philadelphia and Boston. Bill and Lorna Goldberg, both licensed clinical social workers, run a monthly free support group for people whose lives have been affected by cults, victims and families, in Englewood NJ. See http://www.blgoldberg.com/

Or call 201.894.8515. There is also help available in other areas of the country and Europe.

Lisa Wade - The Mind-Body-Metaphor Connection (Pacific Standard)

The depths to which the mind and body are connected are staggering, even for someone like me, a person who believes that the mind IS the body. The brief article below, from Pacific Standard, presents some very cool research findings.

On the specific topic of metaphors and embodied mind, George Lakoff's Philosophy in the Flesh: the Embodied Mind & its Challenge to Western Thought (1999) is the definitive book.

The Mind-Body-Metaphor Connection

By Lisa Wade • February 20, 2014 • Pacific Standard



(Photo: Aaron Amat/Shutterstock)  

New research shows that if you’re holding something heavy, you’ll take things more seriously. Why?
•
Last year I was tickled to write about a cool study showing that, if a person grows up with a language that writes from left to right, then numerical estimates of things like weight or height will, on average, be smaller when a person is imperceptibly and unknowingly leaning to the left. Seriously, it’s awesomely fun research and you can read about it here.

Today I have the equally fun pleasure of sharing a research study on weight and importance. It turns out that, when people are holding something heavy, they will report an issue to be more serious, compared to when they are holding something lighter.

Some examples come from a set of studies by psychologist Nils Jostmann and colleagues:

• In the first study, European participants were asked to guess the value of various foreign currency in euros. Some were given a heavy clipboard on which to mark their estimates, and others a light clipboard. Those who held the light clipboard estimated, on average, lesser values.
• In a second study, subjects were asked to estimate the importance of college students having a voice in a decision-making process involving grants to study abroad. Participants with the heavy clipboard felt that it was more important for students to have a voice.
• In a third, subjects were asked to report whether they liked their city after reading a biography of the mayor and indicating how they felt about him. If they carried the heavy clipboard, there was a relationship between their estimation of the mayor and that of the city, but not if they carried a light clipboard. In this case, the importance of their feelings about the mayor weighed heavier on their evaluation of the city if the clipboard was heavy.

What is driving these findings?

In English, and several other languages as well, weight is used as metaphor to signify importance. The authors hypothesized that this abstraction can be triggered by concrete experiences of weight, like holding something heavy. They call this “embodied cognition.” Our thinking is affected by the connection between our bodies, their relationship with objects, and metaphors in our minds.

Another nail in the Descartian mind-body dualism coffin.

This post originally appeared on Sociological Images, a Pacific Standard partner site.

Sharon K Farber - Why We All Need to be Touched

Sharon Farber, PhD, is the author of When the Body Is the Target: Self-Harm, Pain, and Traumatic Attachments (2002), an excellent book that I have found to be very useful with some of the clients with whom I work. In this post from her Psychology Today blog, The Mind-Body Connection, looks at the importance of touch for emotional and psychological health.

I tend to agree - and I think it's important for therapists to have a list of bodywork practitioners they know and trust (male and female) to whom they can refer clients.

The Mind-Body Connection

Why We All Need to be Touched

Published on December 25, 2013 by Sharon K. Farber, Ph.D. in The Mind-Body Connection

Being touched and touching someone else are fundamental modes of human interaction, and increasingly, many people are seeking out their own "professional touchers" and body arts teachers-- chiropractors, physical therapists, Gestalt therapists, Rolfers, the Alexander-technique and Feldenkrais people, massage therapists, martial arts and T'ai Chi Ch'uan instructors. And some even wait in physicians’ offices for a physical examination for ailments that have no organic cause—they wait to be touched.

The body-oriented approaches are based on a principle that is becoming more obvious to researchers: Ken Wilbur wrote in The Spectrum of Consciousness,

"For every mental 'problem' or 'knot', there is a corresponding bodily 'knot', and vice versa since, in fact, the body and the mind are not two. That is, psychic conflict, guilt, shame, unresolved grief all can be lodged in the body as body memories, and when the site of the psychic difficulty is deeply touched through massage or other manipulation, it can not only release the physical pain but may make the psychic pain accessible."

I remember that soon after my mother died I developed a case of frozen shoulder, technically called adhesive capsulitis, in my left shoulder. It causes stiffness and pain in the shoulder joint and often occurs for no known reason. My doctor had told me that because my shoulder was "frozen", there must be adhesions, or scar tissue that were freezing up my shoulder joint. And probably my body lacked something called synovial fluid, needed to lubricate the shoulder joint. I asked him what caused this to happen. He could not say, because medicine does not really understand why it happens. He referred me for physical therapy.

I like to understand why things happen the way they do and he could not tell me. But I was in pain. I could not sleep in the usual position I sleep in, I couldn’t reach for something on a shelf without feeling pain. So I made an appointment for a physical therapy evaluation for treatment. As I lay on the examining table, the physical therapist came in, smiled, introduced herself and explained what she was going to do. As soon as she put her warm hands on my shoulder, tears welled up in my eyes. I was surprised and embarrassed and turned my head away from her gaze so that she would not see. I suspect she noticed. She continued examining me and I found that I enjoyed it. It felt like a massage, something I am not used to having. She recommended that I come in three times a week and I had to arrange my schedule to do that. She did various exercises with me that I was advised to do at home. As I followed her instructions, I thought and felt a great deal about my mother, with whom I had a complex and ambivalent relationship. I stretched and cried, cried and stretched, wrote about what I was feeling, and after a few months I was better. The pain of my loss had lodged itself in my body, and a woman’s warm touch started to release it. It also probably released some oxytocin in me, the hormone of love and attachment. As I mourned her loss over several months, I realized something. I had had a hard time crying for my mother, whom I loved very much but whom I was angry with too. When there are difficulties in mourning a loss, somatic or psychological difficulties may present themselves. The therapist’s warm touch on my shoulder was lubrication for my soul, needed for me to let go and feel the loss, complicated and ambivalent as it was.

Treatment that uses direct touch can have a depth and potency that can have a great therapeutic impact, which provides some explanation for why so many people are seeking out their own "professional touchers" or are filling the waiting rooms of physicians, waiting for the doctor to find the cause of the pain and make them better. In the process, they are touched. When the patient is assured that the work of the professional toucher is free from infringement, that sexual contact is clearly out of bounds, and that the patient can say "no" to any intervention the body-work practioner proposes, then the patient can have the experience of trust and physical touch in the context of a controlled respectful relationship.

Nature is so intelligent for creating oxytocin. Kerstin Uvnas Moberg became a world authority on ocytocin through her personal experience. When she, was pregnant, delivered, and nursed her four children, she was struck by feeling a state of mind so different from the stress she was used to in connection with life’s other challenges—challenge, performance, and competition. Wanting to understand this scientifically, she learned that there is a key biological marker—oxytocin—that can explain this sense of calm and connectedness in pregnancy, childbirth, and nursing, and through this research, discovered hat oxytocin is able to influence many vital operations in the body. Her research showed that the level of oxytocin in the blood during nursing was correlated with the mothers’ subjective experiences of calmness, and ability to interact with their babies. Oxytocin stimulates growth during pregnancy and stimulates the uterus to expel the newborn It restores the balance between stress and calm It stimulates the muscle activity of orgasm (in both men and women) and can, when conditions are good, strengthen the attachment bond. We are told that “oxytocin is with us throughout our lives.” She wrote that, with a natural delivery to loving parents,

When you were born, oxytocin helped expel you from your mother’s womb and made it possible for her to nurse you. As a small child, you enjoyed your mother’s and father’s loving touch because it released oxytocin in your body. As an adult, you experience the effects of oxytocin when you enjoy good food, or a massage, or an intimate interlude with your romantic partner (Uvnas Moberg 2003, p. 65).

If you’d like to learn more about oxytocin, read Uvnas Moberg’s book The Oxytocin Factor: Tapping the Hormone of Calm, Love, and Healing.

If you’d like to learn more about how, when people lack love and touch in their lives, they may turn to “professional touchers, read my book, When the Body Is the Target: Self-Harm, Pain, and Traumatic Attachments. It will also tell you about how when people lack love and touch in their lives this can result in bodily self harm.

Neuron-Glia Interaction as a Possible Glue to Translate the Mind-Brain Gap

Hmmmm . . . . I'm not sure what I think of this article. The mere fact that they use the terms Id, Ego, and Super Ego lead me to suspect that the authors are very poorly trained in contemporary psychology models, especially post-Freudian psychoanalysis.

Still, looking at the interactions between glia and neurons may be a worthy path to a better understanding of how the body-brain generates the emergence of mind.

Neuron-glia interaction as a possible glue to translate the mind-brain gap: a novel multi-dimensional approach toward psychology and psychiatry

Takahiro A. Kato [1,2], Motoki Watabe [3] and Shigenobu Kanba [1]

1. Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2. Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan
3. Department of Management, School of Business, Monash University, Sunway, Malaysia

Neurons and synapses have long been the dominant focus of neuroscience, thus the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine. However, the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes, and microglia. Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored. Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. We briefly review the current situation of glial research in the field, and propose a novel translational research with a multi-dimensional model, combining various experimental approaches such as animal studies, in vitro & in vivo neuron-glia studies, a variety of human brain imaging investigations, and psychometric assessments.

Full Citation: 
Kato TA, Watabe M and Kanba S (2013) Neuron-glia interaction as a possible glue to translate the mind-brain gap: a novel multi-dimensional approach toward psychology and psychiatry. Frontiers in Psychiatry: Neuropsychiatric Imaging and Stimulation; 4:139. doi: 10.3389/fpsyt.2013.00139

Introduction

Neurons and synapses have long been the dominant focus of neuroscience, thus the pathophysiology of psychiatric disorders has come to be understood within the neuronal doctrine. However, the majority of cells in the brain are not neurons but glial cells including astrocytes, oligodendrocytes, and microglia. Traditionally, neuroscientists regarded glial functions as simply providing physical support and maintenance for neurons. Thus, in this limited role glia had been long ignored (1). Recently, glial functions have been gradually investigated, and increasing evidence has suggested that glial cells perform important roles in various brain functions. Digging up the glial functions and further understanding of these crucial cells, and the interaction between neurons and glia may shed new light on clarifying many unknown aspects including the mind-brain gap, and conscious-unconscious relationships. In addition, glial pathophysiology may explain the possible implications for the pathogenesis of major psychiatric disorders. The complexity of these aspects has yet to be well investigated. To explore these physiological and pathological aspects, novel translational methods should be applied with a multi-dimensional approach. Herein, we will briefly review the current situation of glial research in the field, and propose a novel translational research with a multi-dimensional model, combining various experimental approaches such as animal studies, in vitro & in vivo neuron-glia studies, a variety of human brain imaging investigations, and psychological/psychiatric assessments.

Glial Roles and Pathology in Psychiatric Disorders

Recent biological studies have been revealing the important roles of glial cells in the process of neuropsychiatric disorders. 

Astrocytes

Astrocytes are the most prevalent cell type in human brain and contribute to the homeostasis of the brain by regulation of neuronal metabolism, modulation of CNS inflammation, and direct/indirect synaptic transmission such as MNDA receptors (2, 3). Astrocyte dysfunction has been critical for various neurological disorders (4). Recent studies have shown abnormal expression of glial fibrillary acid protein (GFAP) – a prototypical marker of astrocyte – in postmortem brain of patients with schizophrenia and major affective disorders (5–7). In addition, recent rodent studies have suggested that astrocytes modulate anxious and depressive behaviors (8, 9). On the other hand, direct modulating effects of antidepressants have also been revealed (10–13). Thus, astrocytes have been supposed to be a novel therapeutic target against various psychiatric disorders such as major affective disorders and bipolar disorders (14, 15).

Oligodendrocytes

Oligodendrocytes contribute to brain development and homeostasis in the brain by formulating myelin around axons, supporting neuronal networks in the brain. Recently, novel oligodendrocyte functions have been revealed such as monitoring neuronal activities via myelin-forming oligodendrocytes (16) and modulating the conduction velocity of action potentials along axons in the rat hippocampus (17). Dysfunctions of oligodendrocytes have been indicated in psychiatric disorders, especially schizophrenia and major affective disorders, from a series of genetic studies (18, 19), postmortem studies (20–22), and diffusion tensor imaging (DTI) studies (23–27). A novel animal model of schizophrenia has been developed by treating a copper chelator, which induces oligodendrocyte dysfunction and white matter abnormality as demyelination and schizophrenia-related behaviors (28, 29). Cuprizone caused marked behavioral changes (working memory deficit) indicated by the results of Y-maze task, which showed an increase in the number of arm entries and a decrease in alternation behavior. These cuprizone-induced behavioral changes were effectively prevented by chronic administration of quetiapine, an atypical antipsychotic, which also diminished demyelination (28). On the other hand, recent rodent studies have revealed the interaction between oligodendrocyte dysfunction and social behaviors. Makinodan et al. reported that oligodendrocyte dysfunction is formed by early-period social isolation and this maladaptive environment induces working memory deficit associated with prefrontal cortex (PFC) function in later life (30). Liu et al. reported that protracted social isolation of adult mice induces behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the PFC and impairs adult myelination (31).

Microglia

Microglia are unique glial cells of mesodermal origin in the brain that act as “brain macrophage”; immunological/inflammatory players by moving around and releasing cytokines and free radicals (32, 33). Thus, microglia have proved to play important roles in various brain pathologies such as neurodegenerative diseases and neuropathic pain via inducing inflammation and oxidative stress (34–36). Recently, microglia have been revealed to have direct contact with synapses and have proved to play crucial roles in neuronal development through synaptic pruning (37–39). Postmortem studies have shown microglial activation in the brain of patients with schizophrenia and major affective disorders, especially suicide victims (40–42). In addition, positron emission tomography (PET) imaging studies using the peripheral benzodiazepine receptor bindings has shown that microglia are activated in patients with schizophrenia (43–45) and autism (46). On the other hand, minocycline, an antibiotic with inhibitory effects on microglial cells, has been reported to have therapeutic effects on schizophrenia and unipolar psychotic depression (47–49). In addition, rodent in vitro studies have proved the novel effect of psychotropic drugs (atypical antipsychotics such as risperidone and aripiprazole, and antidepressants such as paroxetine and sertraline, both selective serotonin reuptake inhibitors) directly on microglia by suppressing release of inflammatory cytokines and free radicals (50–54). Thus, microglia are suggested to play key roles in psychiatric disorders (53, 55, 56).

In the brain, neurons, astrocytes, oligodendrocytes, and microglia are mutually communicating with each other, by direct-contacting or via neurotransmitters and other various small molecules (57), and dysfunction of neuron-glia communication may induce pathological conditions not only in neurodegenerative diseases (58) but also in psychiatric conditions such as psychosis, depression, and anxiety. The above-mentioned recent findings strongly suggest that glial cells contribute to psychiatric disorders, while the underlying mechanisms have not been clarified.

Possible Glial Roles in Human Mental Functions

Until recently, the actual roles of glia in mental activities, especially for healthy humans, have not been investigated. As the first step to clarify this unexplored field, we have started to conduct a series of social decision-making experiments with healthy human subjects using minocycline, a microglial inhibitor (59–61). Healthy Japanese adult males made a monetary decision about whether or not to trust an anonymous partner after a 4-day oral administration of minocycline. Our first trial revealed that the minocycline group showed a positive correlation between their monetary score in trust game and their evaluation scores of others’ trustworthiness in a questionnaire (Yamagishi’s General Trust Scale), but surprisingly the placebo group did not (60). It would be rational to consider the monetary and questionnaire score to be positively correlated because both scores measure the other’s trustworthiness, but there was no positive correlation with the placebo group. The questionnaire is measuring only conscious-level decision-making, on the other hand the monetary score is measuring the final decision-making affected by not only the conscious but also the unconscious; suggesting that some unconscious noisy factors seem to be affecting the placebo group. Treatment with minocycline, a microglial inhibitor, has shown the positive correlation. Therefore, this first trial has indicated that microglial activation may cause “unconscious noises” against appropriate social decision-making, and inhibiting microglial activity may reduce such noise (60). In a next trial with larger samples, we additionally measured the effects of anxiety and personality as candidates for “noise” factors, by using Temperament and Character Inventory (TCI) and State-Trait Anxiety Inventory (STAI) (59). The monetary score in trust game was significantly lower in the minocycline group. Interestingly, participants’ ways of decision-making were significantly shifted; certain personality traits (cooperativeness, reward dependence, and self-directedness) proved to be the main modulating factors of decision-making in the placebo group, on the other hand the minocycline group was mainly modulated by state anxiety and trustworthiness. Our results of the second trial suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Interestingly, cooperativeness has proved to be the most influential factor in the process of decision-making in the placebo group of Japanese participants (59). It is widely known that cooperativeness and cooperative behaviors have been highly respected and emphasized aspects in Japanese society. Thus, of course, these aspects are ingrained during childhood by various sociocultural experiences within family relationships, schools, and other areas of society in Japan. Early-life events may activate human microglia, establish a certain neurosynaptic connection, and this formation may determine personality and personality-oriented social behaviors in later life (59, 62). If these experiments are conducted in other countries with different sociocultural backgrounds, other personality traits may be identified.

In addition, we have recently reported a possible outcome that minocycline, a microglial inhibitor, also reduces the risk of the “honey trap” during economic exchanges between males × females (61). Males tend to cooperate with physically attractive females without careful evaluation of their trustworthiness. In our experiment, young healthy male participants made risky choices (whether or not to trust female partners, identified only by photograph, who had decided in advance to exploit the male participants). The results show that trusting behavior in male participants significantly increased in relation to the perceived attractiveness of the female partner, but attractiveness did not impact trusting behavior in the minocycline group (61). These novel effects of minocycline may highlight the unknown roles microglia play in deeper human mental activities; microglia may modulate our unconscious drives in various social settings. The above-mentioned findings shed new light on the dark side of microglial social/mental functions in humans, especially highlighting the role of microglia for the unconscious. In the same way that Sigmund Freud, the founder of psychoanalysis, proposed that our behaviors must be controlled by the unconscious world, microglia may unconsciously control our behaviors. How do microglia act as fundamental mediators between the conscious and the unconscious world? What do neurobiological mechanisms justify their eventual role in bridging the gap between neuroscience and psychoanalysis? Answers to the above questions are not yet clear, but we have recently proposed a hypothesis creating a link between Freud’s unconscious drives such as the death drive and microglial activation (62). For example, microglial maladaptive over-activation in a certain brain region may activate human aggressive behaviors as a result of destructive drives [For the details, please see our recent article; Ref. (62)]. In the brain, not only microglia but also other glia such as astrocytes and oligodendrocytes exist, thus complicated neuron-glia interactions may modulate our mental activities including the unconscious (Figure 1). Further research should be applied to clarify these unresolved questions.

FIGURE 1  

Figure 1. The mind-brain gap from a novel glial neuropsychoanalytic perspective. The interaction between the mind and the brain has not been well understood. Freud, the founder of psychoanalysis, proposed the conception of mind structure models consisting of the following three components: the ID (unconscious/instinctual drives), the EGO (the exclusive apparatus of the conscious mind), and the SUPER-EGO (which represses the id in order to avoid any disruptions of rational thought). The existence and the significances of these mental components may be explained by future understandings of the neuron-glia interactions. The hypothetical interaction between the ID (unconscious drives) and microglia has already been proposed in our recent theoretical paper (62).

After Freud’s theory of unconscious roles in behaviors which was initially identified in the 1980s (63), Pribram and his colleagues have developed this theory in terms of a better articulated model of neural computation (64, 65). In addition, recent neuropsychoanalytic movements have been updating Freud’s theory with modern sophisticated methods of cognitive neuroscience (66–72). Thus, these recent approaches have been revealing the underlying mechanisms of implicit processing in a variety of information-processes including the social processes using rodent experiments. At present, the link underlying mechanisms between neuron-glia interactions and the conscious-unconscious relationship is largely unsolved, and few experimental methods have been developed to test these unknown brain mechanisms at either the microscopic or macroscopic level. Unconscious processing needs to be given a greater focus in terms of brain mechanisms. One possible solution is the novel ontogenetic approach; called “optogenetics” (73–76). Optogenetics is a revolutionary technique involving taking a light-activated gene (called a channel rhodopsin) targeted into a single neuron type. This technique enables to clarify direct interaction between activation of specific neuron in specific region by light and the resulting outcomes such as behaviors and emotional reactions at rodent level. A recent study has interestingly shown that activation of specific neurons in hippocampus produce a false memory in mice (77). Further technological developments in modulating glial cells by light and in activating both neurons and glial cells at the same time, by multiple fluorescent lights, may shed new light on resolving unknown roles of glia and neuron-glia interaction in behaviors and the conscious-unconscious. Functional roles and pathological contributions of astrocyte, oligodendrocyte, and/or microglia in conscious or unconscious processes have not been well understood, and we hypothesize that each cell may differently contribute to these physical and/or pathological processes in different brain regions such at the brainstem, limbic, or thalamocortical region, respectively. Future developments in optogenetics may clarify these unknown aspects.

Limitation and Future Perspectives of Neuro-Glia Research on Psychology and Psychiatry

To explore the above-mentioned hypothesis, further translational research is needed. Several limitations should be made note of at the present stage. At first, rodent studies focusing on the unconscious are limiting. Even if the unconscious exists in rodents, it seems to be impossible to measure the unconscious in rodents devoid of human language capabilities. Therefore, to uncover the unconscious mechanisms, we have no alternative method except examining actual human subjects. We have no specific drugs to modulate glial cells utilized in human, and minocycline is reported to have other brain functions in addition to microglial inhibition (78, 79). On the other hand, some brain imaging techniques enable us to explore the unknown roles of glial cells such as DTI technique and PET imaging using the peripheral benzodiazepine receptor bindings, while the specificities of these imaging methods are not at satisfactory levels (80). On the other hand, we can reconsider previous findings of brain imaging experiments. Functional MRI (fMRI) is a brain imaging procedure measuring brain activity by detecting associated changes in blood flow (81, 82). Outcomes of fMRI have long been believed to monitor solely neuronal activities, because cerebral blood flow and neuronal activation have been thought to be almost equivalent. However, not only neuronal activities but also glial activities, especially astrocyte activities, rely on cerebral blood flow. Therefore, at least to some extent, brain activities expressed by fMRI may be showing a part of glial activation. In addition, MR spectroscopy (MRS) is one of the novel imaging approaches to measure dynamic brain functions focusing on metabolomics including glia-related molecules. For example, myo-inositol, which can be measured by MRS, is regarded as a marker of astrocyte activity (83). These imaging methods and combination of these imaging techniques may shed new light on clarifying unknown roles of glia in psychiatric disorders (84, 85). For example, activated microglia-derived myelin damage has been indicated in the pathophysiology of schizophrenia by rodent experimental models (28, 29, 86, 87), while it is not confirmed in human subjects. Combination of human DTI and PET may clarify the mutual interaction between microglial activation and myelin damage in schizophrenia patients. On the other hand, connectivity of each brain region has been important in the understanding of the roles of brain functions from the era of Hughlings Jackson. fMRI studies have revealed the importance of these aspects (88, 89), and the recent development of DTI is showing us the significance of more complicated brain networks focusing on not only neurons but also glial cells such as oligodendrocytes (90, 91).

Finally, we propose the multi-dimensional approach to clarify the underlying brain mechanisms of mental functions including the unconscious (Figure 2). Based on our discussion, we believe that not only neurons but also glial cells have a vital role in the process of mental activities, a novel approach focusing on neuron-glia interactions should be applied. Combination of brain imaging techniques focusing on both neurons and glial cells should be applied (24, 26, 27, 43–46, 92–94). The most significant limitation in human brain research is that we cannot obtain living brain cells, including glial cells, from living human subjects from an ethical perspective. Presently, we can apply an alternative method; human brain cells such as neuronal cells can be established from somatic cells (not from the brain) such as skin fibroblasts by utilizing the gene-modification technique of induced pluripotent stem (iPS) cells. In addition, recently, neuronal cells are more easily established from directly conversion of human skin fibroblasts, called induced neuronal (iN) cells (95–99). Novel methods of establishing glial cells are strongly warranted based on iPS or direct conversion techniques in the near future. Multi-dimensional aspects of same human subjects, from genes, blood, brain imaging, psychometrics, social function, unconscious functions, psychodynamic assessments to molecular functions of somatic tissue-derived neuronal and glial cells, should be investigated and analyzed together (Figure 2). This approach may explore the novel roles of glial cells in various human mental activities including the unconscious. The application of this method for psychiatric patients should also be encouraged in the establishment of novel diagnostic methods and novel therapies.

FIGURE 2

Figure 2. A novel multi-dimensional approach toward psychology & psychiatry.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research on (1) Innovative Areas “Glia Assembly” (No. 25117011) of The Ministry of Education, Culture, Sports, Science, and Technology, Japan, (2) the Japan Society for the Promotion of Science (No. 24650227), and (3) the Health and Labor Sciences Research Grant No. [H 24-Seishin-Jitsuyouka (Seishin)-Ippan-001].

References available at the Frontiers site.