Morphological brain differences between adult stutterers and non-stutterers

Persistent developmental stuttering (PDS) is a relatively severe disturbance characterized by involuntary, audible or silent, repetitions or prolongations of sounds or syllables. These are not readily controllable and often are accompanied by other movements and by negative emotions [1, 2]. Developmental stuttering evolves before puberty without apparent brain damage or other known cause. Several authors suppose a hereditary component of PDS because of the relatively high concordance rate in family members of PDS subjects (70% for monozygotic twins, about 30% for dizygotic twins, and 18% for siblings of the same sex) [3‐5]. Because of this hereditary component and the early onset of stuttering it has repeatedly been suggested that some kind of anatomical or neurophysiological predetermination increases the vulnerability for stuttering [for a summary of theories and findings related to stuttering research [6]].

Several experimental studies have shown that stutterers reveal prolonged manual and vocal reaction times to simple and complex verbal and nonverbal stimuli [7‐10], reduced bimanual coordination measures [11‐13], atypical functional lateralizations [14‐18], abnormalities in the auditory system [19‐21], or increased variability of time-critical speech parameters [9, 22, 23]. More recent neuroimaging studies have shown atypical hemodynamic responses in speech-related brain areas even during fluent utterances suggesting a dysfunctionally operating speech control circuit in stutterers [24‐29]. However, although much research has been invested to understand the neurophysiological mechanisms and underpinnings of this disorder, none of the aforementioned studies provide a substantial breakthrough in understanding stuttering. Several researchers have hypothesized subtle but nevertheless crucial deficiencies in the anatomical and neurophysiological underpinnings of the speech and language system. One popular hypothesis is that stutterers would show an atypical lateralisation of the speech system (reversed or reduced laterality) thought to make the system more vulnerable to speech dysfluencies [17]. Although recent neuroimaging studies have shown atypical activation and deactivation of brain regions in adults with PDS [24, 30‐32] the anatomical underpinnings of stuttering have not been examined in detail so far.

According to the present literature four anatomical studies revealed brain abnormalities in stutterers compared to controls. The earliest study examined two left-handed stuttering siblings using CT and revealed an atypical (reduced) anatomical asymmetry of the occipital poles [33]. The first high-resolution MRI study investigating stutterers revealed a reduced volumetric asymmetry of the planum temporale (a brain area which is involved in higher order auditory processing) and other anatomical peculiarities in speech-related areas [34]. A more recent paper of the same group revealed that PDS is also associated with atypical (mostly reduced) prefrontal and occipital lobe asymmetries [35]. In addition, deficits in language processing were associated with some anatomic measures in the adults who stutter. Using a new MRI technique (diffusion tensor imaging: DTI), that allows the assessment of white matter ultrastructure, Sommer et al. [36] found an area of decreased white matter tract coherence in the left Rolandic operculum. This structure is adjacent to the primary motor representation of tongue, larynx, and pharynx and the inferior arcuate fascicle linking temporal and frontal language areas, which both form a temporo-frontal language system involved in word perception and production. Thus, there are indeed first strong hints that the brain of stutterers differ from non-stuttering subjects on a macroanatomical level suggesting that morphological predispositions determine stuttering.

Although the aforementioned anatomical studies have focussed on the anatomical foundations of stuttering, several questions are not answered yet. Therefore we re-examined the hypothesis of anatomical differences between stutterers and non-stutterers using voxel-based morphometry (VBM). This approach circumvents the problem of analyzing predetermined regions of interests by analyzing stereotactically normalized brains on a voxel-by-voxels basis with respect to differences in the volume of white matter (WM) or grey matter (GM) [37, 38]. This approach has successfully been used in the last 8 years for several clinical populations and allows studying the morphology separately for GM and WM looking at the entire brain [39‐41]. A further advantage of this method is the objectivity and thus rater independence. We hypothesized that beside the previously reported atypical anatomical asymmetries in perisylvian and frontal areas there should be additional differences in further brain areas also involved in speech motor control. Because several studies report that the auditory system in stutterers is dysfunctional [19, 21, 42‐47] especially during speaking (thus, emphasizing the role of auditory feedback in the context of stuttering), we anticipated structural peculiarities in the auditory cortex (Heschl's gyrus and the planum temporale) in this group. In addition, we also anticipated anatomical peculiarities in frontal brain areas and in the somatosensory and motor system controlling the speech muscles.

Because there was no substantial difference between the results of our statistical tests for the density and volume equivalents, we only report the findings based on the analysis of the volume equivalents. We found increased WM volumes in stutterers within four clusters on the right hemisphere. The clusters are located in the superior temporal gyrus (STG) including the planum temporale, the precentral gyrus (PrCG), the inferior frontal gyrus (IFG) comprising the pars opercularis (POP), and the middle frontal gyrus (MFD) (Table 1). There was no significant difference between stutterers and non-stutterers with respect to the GM volumes.

In order to understand the differences between stutterers and non-stutterers with respect to the WM volumes in these anatomical areas more precisely, we placed regions of interest (ROI) in these anatomical areas and the homotopic areas on the left hemisphere. For the auditory cortex we used a rectangular ROI including Heschl's gyrus (HG) and the planum temporale (PT) (size of the ROI on both hemispheres: 8.4 cm³). The placement pf these ROIs were guided by anatomical landmarks and published probability atlases of the HG and PT [48, 49]. The other ROIs were defined according to the stereotactic coordinates found in the VBM analysis. For these ROIs, rectangular volumes (10 mm edge length resulting in a volume of 10 × 10 × 10 mm) were used. The mean WM measures were calculated for each ROI and subjected two-way ANOVAs with one repeated measurement factor (Hemisphere: left vs. right) and one grouping factor (Group: stutterers vs. non-stutterers). Because we found significant interaction effects for all ROIs we will only interpret these interactions. For the auditory cortex we found a strong main effect for the factor Hemisphere (F(1, 18) = 29.2, p <= 0.001, ETA² = 0.62) and a significant interaction between both factors (F(1, 18) = 31.6, p <= 0.001, ETA² = 0.64). Subsequent Scheffé contrasts and Figure 2 show that there is a strong between-hemisphere difference for non-stutterers (larger WM volume on the left hemisphere, p < 0.01) but not for stutterers (p > 0.4). For the IFG there were strong main effects (Hemisphere: F(1, 18) = 9.2, p = 0.007, ETA² = 0.34; Group: F(1, 18) = 23.6, p <= 0.001, ETA² = 0.58) and a significant interaction (F(1, 18) = 23.9, p <= 0.001, ETA² = 0.57). The strong interaction is qualified by a between-hemisphere difference found for stutterers (with larger WM volumes on the right compared to the left IFG) while there is no between-hemisphere difference in non-stutterers. For the PrCG we found a significant between-group difference (F(1, 18) = 11.1, p = 0.004, ETA² = 0.38) and a significant interaction (F(1, 18) = 31.0, p <= 0.001, ETA² = 0.64). The pattern of this interaction resembles the interaction found for the IFG with larger WM volumes on the right hemisphere for stutterers than on the left while non-stutterers show similar values for both hemispheres. For the MFG all two main effects as well as the interaction were strongly significant (Hemisphere: F(1, 18) = 23.5, p <= 0.001, ETA² = 0.56; Group: (F(1, 18) = 13.2, p = 0.002, ETA² = 0.42; interaction: (F(1, 18) = 18.4, p <= 0.001, ETA² = 0.50). The interaction is due to the fact that stutterers revealed larger WM volumes on the right compared to the left hemisphere.

In addition, we did not find any correlation between the stuttering severity measures (SSI measures) and the anatomical peculiarities neither in the context of the VBM nor the ROI analysis.

This study was motivated by the question whether stutterers reveal morphological brain anomalies compared to non-stuttering controls. In fact, we found prominent increases of WM in stutterers within a right-hemispheric network including brain structures relevant for language and speech. These areas comprise the STG (including the auditory areas PT and HG), the IFG (including the pars opercularis which is part of Broca's right-sided homologue), the somatosensory area (including the face and mouth representation, as well as the mesial part of the hand representation), and the middle frontal gyrus (MFG). Our findings of regionally increased right-hemispheric WM in stutterers might suggest an increased and possibly atypical intrahemispheric communication within these areas via association fibres [50, 51] possibly accompanying different processing strategies in the right hemisphere in stutterers.

Three of the brain areas with different WM composition in stutterers are known to be involved in different speech and language functions. For example, the right IFG (including the pars opercularis) is involved in the perception and generation of phonological or prosodic speech features [52‐55] while the ventral part of the precentral gyrus is part of the somatosensory representation of the mouth and tongue. The MFG has been shown to be involved during rhyme and tone perception [34]. The core region of this network is the auditory cortex with neurons specialized for tone, pitch, and prosody perception [56, 57]. Within this circuit the auditory cortex plays a pivotal role because speech production follows the ultimate goal to generate speech sounds others can understand. The auditory cues in speech production are either phonetic cues (such as voice onset times or formant transitions) or specific suprasegmental features like duration, intensity, linguistic or emotional stress. During speech production the auditory system controls whether the appropriate auditory cues have been generated by means of auditory feedback control of the own speech. Several studies have shown that the auditory cortex is strongly involved in the continuous control of self-generated suprasegmental speech features (duration, intensity, stress pattern) and that this auditory feedback control is detrimental in stutterers [19‐21, 45, 46, 58‐60].

The auditory cortices in the two hemispheres are relatively specialized in normal subjects [56, 57]. Thus, temporal resolution is better in left auditory cortical areas and spectral resolution as well as processing of prolonged auditory information is better in right auditory cortical areas. It is thought that this functional specialisation is based on cytoarchitectonic peculiarities (more heavily myelinated axons and greater interconnectivity) and the relative composition of WM and GM in this area. In fact, in addition to the present findings, two previous studies [61, 62] found a leftward asymmetry of WM volume in the auditory cortex in healthy subjects. However, our findings show that stutterers do not reveal the typical leftward asymmetry; they rather show symmetry with an atypically enlarged WM volume in the right auditory cortex. This atypical symmetry of WM volume in the auditory cortex in stutterers might suggest different and perhaps deficient processing of slowly changing auditory cues necessary to control suprasegmental features. In fact several studies have shown that stutterers reveal substantial peculiarities with respect to various aspects of the auditory feedback of their own speech especially when they control suprasegmental speech features [19, 60, 63].

The reported morphological features complement previous morphological studies comparing stutterers and non-stutterers. Firstly, this study shows again that stutterers reveal atypical anatomical lateralisation in speech-relevant areas. In three areas (PrCG, MFG, and IFG) stutterers reveal more WM volumes on the right than on the left. For the auditory cortex (STG) we found symmetric WM volumes while non-stutterers typically show a leftward asymmetry for this measure. Thus, some kind of hemispheric imbalance seems to be related to persistent developing stuttering. Secondly, using a different method than Foundas et al. [34], we also found an atypical anatomical lateralisation in the auditory cortex expressed as an increased symmetry of WM volume. Thus, the different "hardware" composition of the auditory cortex in stutterers is a crucial peculiarity possibly determining the processing mode of the right auditory cortex and the interaction between both auditory cortices. Taken together, the present results and findings of previous behavioural and neuroimaging studies emphasize a specific role of the auditory cortex in stuttering. Thirdly, while Foundas et al. [35] found atypical anatomical lateralisation in prefrontal areas we detected increased WM volumes in the right anterior MFG which is part of the prefrontal cortex. Thus, the atypical prefrontal lateralization may be due to atypical lateralisation of the WM volume of the right MFG. Finally, our analysis also revealed an atypical asymmetry with respect to the WM volume in vicinity of the right sensorimotor cortex (including the face and mouth representation as well as parts of the hand representation) possibly suggesting that these areas use different processing strategies as compared to non-stuttering subjects. However, although we and others found large morphological differences between stutterers and non-stuttereres we cannot rule out the possibility that the anatomical differences are the consequence of stuttering rather than the cause. Persistent developmental stuttering commences early in life forcing the affected subject to cope with this annoying and detrimental situation. Thus, some kind of adaptation or cortical reorganisation might accompany this process. Indeed, several studies indicate that intensive practise of various skills might affect the brain even on the macroanatomical level [64, 65]. Future studies, however, are clearly needed to disentangle whether the anatomical peculiarities in stutterers are the cause or the consequence of stuttering.

These results provide strong evidence that adults with PDS have anomalous anatomy not only in perisylvian speech and language areas but also in prefrontal and sensorimotor areas. These anatomical features might indicate a deficiently working speech system. Whether this atypical asymmetry of WM is the cause or the consequence of stuttering is still an unanswered question.