Functional connectivity of the substantia nigra in a continuous performance test in persistent developmental stuttering – a clinical study using functional magnetic resonance tomography

Speaking is a unique human ability. Fluency in speaking requires the interaction of motoric and sensory processes and is based on complex neural processes. The ability to speak freely is taken for granted to most people. One of the most common speech disorders is idiopathic stuttering. Stuttering affects more than 5% of all children. It occurs in early childhood for no apparent cause and persists in around 1% of the total population, preferably male adults. Idiopathic stuttering is a flow disorder. Stuttering is characterized by involuntary repetitions of sounds and syllables, sound expansions and speech blocks. To date, the exact cause of stuttering remains unclear. In idiopathic stuttering, the ability to initiate or end fluent speech movements appears to be sporadically impaired. Imaging studies associate stuttering with irregular neural dynamics of speech relevant cortical regions, especially the movement-controlling signals of the basal ganglia and the cerebellum seem to be affected. The basal ganglia as subcortical core areas make a significant contribution to the structuring and organization of motion sequences. My studies focused on the organization of functional cortical and subcortical networks while planning a simple motor response. I wanted to investigate, how the substantia nigra (SN) as the central modulator of the basal ganglia and the motor network interacts with other speech-relevant cortical structures and whether the activation dynamics during the preparatory phase of a motor reaction differ from those who stutter to those with healthy speech. In 2008, Lütcke and colleagues used a continuous performance test to demonstrate that attention signals activate the motor cortex and the supplementary motor area (SMA). At the same time, the signals led to reliable activations in the basal ganglia, especially in the substantia nigra (SN). The interaction of the basal ganglia with the cortex is controlled, among other things, by the transmitter dopamine. Apparently, impaired dopamine regulation also plays a role in fluent speech. Dopamine antagonists can help to speak fluently. On the other hand, dopamine can be used e.g. in Parkinson's therapy will worsen stuttering. In this study, 13 adults with stuttering and 15 fluently speaker adults were examined in the magnetic resonance tomographic machine. With the help of a functional measuring sequence [EPI, gradient-echo planar imaging (EPI) sequence], the brain activity was measured. The oxygenation level, the hemodynamic response (blood oxygenation level-dependent - BOLD) determines the measured activity. During the measurement, the test participants completed a continuous performance test (CPT). In this test, three letters are presented. A cue, a target and a calm stimulus. The purpose of this stimulation is to trigger or suppress a finger movement as a motor reaction. The target parameters of my study were hemodynamic response on the physiological level as well as reaction time and accuracy on the behavioral level. At the behavioral level, stutter test subjects showed significantly slower reaction times than the healthy speaking control group. At the physiological level, the functional MRI data were initially analyzed using the general linear model (GLM). The expected motor network has been confirmed. Robust activation of cortical and subcortical structures of the movement planning has been showed in this studie. Subcortical activations have been found in the region of the basal ganglia, especially the substantia nigra, the nucleus ruber, the globus pallidus, and the putamen. Cortical activations are mainly in areas of the precentral gyrus, in the anterior cingulum, the inferior frontal gyrus (IFG), the superior frontal gyrus, the SMA and in the somatosensory cortex. Differences in the groups in the GLM could not be shown. In order to answer the question of network organization, connectivity analyzes were carried out in a further analysis step. So called psychophysiological interaction analyses, e.g. the task-specific interaction in the SN with the signal processes in the entire brain were tested. For this purpose, the SN was segmented manually. The connectivity analysis (the PPI) showed significant group differences. In the case of stuttering, increased connectivity was observed. This can be explained as increased interaction between the SN and left-inferior-frontal and also ventro-frontal regions. In particular, increased connectivity in the left IFG pars opercularis was detected as well and in addition in the left premotor cortex and in the left thalamus. These results have been published (see Metzger FL, Auer T, Helms G, Paulus W, Frahm J, Sommer M, Neef NE (2018): Shifted dynamic interactions between subcortical nuclei and inferior frontal gyri during response preparation in persistent developmental stuttering. Brain Struct Funct 223, 165–182). A key result of this publication was the demonstration of a correlation between SN activity and stuttering severity. With increasing severity of stuttering, the activity in the SN increases as part of movement planning. The physiological results support the assumption that stuttering could be seen as a dysregulation of the substantia nigra as an expression of a disturbed network organization which could lead to incorrect control of movement sequences. Earlier findings showed that the activity in the substantia nigra increases accordingly to an increased stutter severity in anticipation of a motor reaction, while at the same time activity in areas of the motor cortex decreases. The SN serves as a modulator that drives or inhibits cortical regions relevant to speech planning. Normally the striatum which act as entrance gate to the basal ganglia receives signals from the motor cortex. If activity in the striatum is reduced, the consequence could be reduced disinhibition to the thalamus and thus reduced activity in areas of the motor cortex. For example, the increased connectivity could be necessary, among other things, for sufficient activation of the striatal neurons. This could guarantee a functioning sequence of movements for stuttering people. All of this confirms that the SN influences the left hemispherical areas of speech processing differently than in control subjects with healthy speech. During speech production and articulation, activity in the substantia nigra and the motor cortex is synchronized. That could affect a controlled flow of speech. The obtained results are based on motoric experiments. The subjects did not speak throughout the experiments. Thus, the results indicate a general deficit in motoric activities planning. It is not clear whether a malfunction of the substantia nigra itself could be a cause of stuttering or whether the substantia nigra may compensate for other malfunctions.2020-11-1