Amy Parkinson

Compensatory Neural Reorganization in Tourette Syndrome

Summary Children with neurological disorders may follow unique developmental trajectories whereby they undergo compensatory neuroplastic changes in brain structure and function that help them gain control over their symptoms [1–6]. We used behavioral and brain imaging techniques to investigate this conjecture in children with Tourette syndrome (TS). Using a behavioral task that induces high levels of intermanual conflict, we show that individuals with TS exhibit enhanced control of motor output. Then, using structural (diffusion-weighted imaging) brain imaging techniques, we demonstrate widespread differences in the white matter (WM) microstructure of the TS brain that include alterations in the corpus callosum and forceps minor (FM) WM that significantly predict tic severity in TS. Most importantly, we show that task performance for the TS group (but not for controls) is strongly predicted by the WM microstructure of the FM pathways that lead to the prefrontal cortex and by the functional magnetic resonance imaging blood oxygen level-dependent response in prefrontal areas connected by these tracts. These results provide evidence for compensatory brain reorganization that may underlie the increased self-regulation mechanisms that have been hypothesized to bring about the control of tics during adolescence.

On the functional anatomy of the urge-for-action

Several common neuropsychiatric disorders (e.g., obsessive-compulsive disorder, Tourette syndrome (TS), autistic spectrum disorder) are associated with unpleasant bodily sensations that are perceived as an urge for action. Similarly, many of our everyday behaviors are also characterized by bodily sensations that we experience as urges for action. Where do these urges originate? In this paper, we consider the nature and the functional anatomy of “urges-for-action,” both in the context of everyday behaviors such as yawning, swallowing, and micturition, and in relation to clinical disorders in which the urge-for-action is considered pathological and substantially interferes with activities of daily living (e.g., TS). We review previous frameworks for thinking about behavioral urges and demonstrate that there is considerable overlap between the functional anatomy of urges associated with everyday behaviors such as swallowing, yawning, and micturition, and those urges associated with the generation of tics in TS. Specifically, we show that the limbic sensory and motor regions––insula and mid-cingulate cortex––are common to all of these behaviors, and we argue that this “motivation-for-action” network should be considered distinct from an “intentional action” network, associated with regions of premotor and parietal cortex, which may be responsible for the perception of “willed intention” during the execution of goal-directed actions.

Understanding the neural mechanisms involved in sensory control of voice production

Auditory feedback is important for the control of voice fundamental frequency (F0). In the present study we used neuroimaging to identify regions of the brain responsible for sensory control of the voice. We used a pitch-shift paradigm where subjects respond to an alteration, or shift, of voice pitch auditory feedback with a reflexive change in F0. To determine the neural substrates involved in these audio-vocal responses, subjects underwent fMRI scanning while vocalizing with or without pitch-shifted feedback. The comparison of shifted and unshifted vocalization revealed activation bilaterally in the superior temporal gyrus (STG) in response to the pitch shifted feedback. We hypothesize that the STG activity is related to error detection by auditory error cells located in the superior temporal cortex and efference copy mechanisms whereby this region is responsible for the coding of a mismatch between actual and predicted voice F0.

Cognitive control over motor output in Tourette syndrome

Tourette syndrome [TS] is a neurodevelopmental disorder characterised by chronic vocal and motor tics. TS has been associated with dysfunctional cognitive (inhibitory) control of behaviour, however the evidence for this, beyond the occurrence of tics, is scant. Furthermore, in recent studies of uncomplicated TS, it has been shown that adolescents with TS exhibit paradoxically enhanced cognitive control of motor output, consistent with the typical developmental profile of increasing control of tics during adolescence. Here we present arguments, together with new data, that run counter to the widely held view that prefrontal cortex (PFC) is the source of inhibitory task-control signals. Instead, we argue that PFC should be viewed as a source of facilitatory signals that bias competition in brain areas more directly involved in motor execution. Importantly, we argue that in TS, over-activation of PFC may contribute to the hyper-excitability of motor regions and the occurrence of tics; and that compensatory changes, leading to enhanced cognitive control in TS, may primarily be implemented by distributed changes in local cortical excitability.

Motor excitability is reduced prior to voluntary movements in children and adolescents with Tourette syndrome.

Tourette syndrome (TS) is a neuro-developmental disorder characterized by the occurrence of motor and vocal tics: involuntary, repetitive, stereotyped behaviours that occur with a limited duration, often typically many times in a single day. Previous studies suggest that children and adolescents with TS may undergo compensatory, neuroplastic changes in brain structure and function that help them gain control over their tics. In the current study we used single-pulse and dual-site paired-pulse transcranial magnetic stimulation (TMS), in conjunction with a manual choice reaction time task that induces high levels of inter-manual conflict, to investigate this conjecture in a group of children and adolescents with TS, but without co-morbid Attention Deficit Hyperactivity Disorder (ADHD). We found that performance on the behavioural response-conflict task did not differ between the adolescents with TS and a group of age-matched typically developing individuals. By contrast, our study demonstrated that cortical excitability, as measured by TMS-induced motor-evoked potentials (MEPs), was significantly reduced in the TS group in the period immediately preceding a finger movement. This effect is interpreted as consistent with previous suggestions that the cortical hyper-excitability that may give rise to tics in TS is actively suppressed by cognitive control mechanisms. Finally, we found no reliable evidence for altered patterns of functional inter-hemispheric connectivity in TS. These results provide evidence for compensatory brain reorganization that may underlie the increased self-regulation mechanisms that have been hypothesized to bring about the control of tics during adolescence.

Connectivity of the subthalamic nucleus and globus pallidus pars interna to regions within the speech network: A meta-analytic connectivity study

Cortico‐basal ganglia connections are involved in a range of behaviors within motor, cognitive, and emotional domains; however, the whole‐brain functional connections of individual nuclei are poorly understood in humans. The first aim of this study was to characterize and compare the connectivity of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) using meta‐analytic connectivity modeling. Structure‐based activation likelihood estimation meta‐analyses were performed for STN and GPi seeds using archived functional imaging coordinates from the BrainMap database. Both regions coactivated with caudate, putamen, thalamus, STN, GPi, and GPe, SMA, IFG, and insula. Contrast analyses also revealed coactivation differences within SMA, IFG, insula, and premotor cortex. The second aim of this study was to examine the degree of overlap between the connectivity maps derived for STN and GPi and a functional activation map representing the speech network. To do this, we examined the intersection of coactivation maps and their respective contrasts (STN > GPi and GPi > STN) with a coordinate‐based meta‐analysis of speech function. In conjunction with the speech map, both STN and GPi coactivation maps revealed overlap in the anterior insula with GPi map additionally showing overlap in the supplementary motor area (SMA). Among cortical regions activated by speech tasks, STN was found to have stronger connectivity than GPi with regions involved in cognitive linguistic processes (pre‐SMA, dorsal anterior insula, and inferior frontal gyrus), while GPi demonstrated stronger connectivity to regions involved in motor speech processes (middle insula, SMA, and premotor cortex). Hum Brain Mapp 35:3499–3516, 2014.

Modulation of somatosensory perception by motor intention

The intention to execute a movement can modulate our perception of sensory events; however, theoretical accounts of these effects, and also empirical data, are often contradictory. We investigated how perception of a somatosensory stimulus differed according to whether it was delivered to a limb being prepared for movement or to a nonmoving limb. Our results demonstrate that individuals perceive a somatosensory stimulus delivered to the “moving” limb as occurring significantly later than when an identical stimulus is delivered to a “nonmoving” limb. Furthermore, human brain imaging (fMRI) analyses demonstrate that this modulation is accompanied by a significant decrease in BOLD signal in the right parietal operculum (SII) for stimuli delivered to the moving limb. These results indicate that during movement preparation a network of premotor brain areas may facilitate movement execution by attenuating the processing of behaviorally irrelevant signals within higher-order secondary somatosensory (SII) areas.

Altered resting-state network connectivity in stroke patients with and without apraxia of speech

Motor speech disorders, including apraxia of speech (AOS), account for over 50% of the communication disorders following stroke. Given its prevalence and impact, and the need to understand its neural mechanisms, we used resting state functional MRI to examine functional connectivity within a network of regions previously hypothesized as being associated with AOS (bilateral anterior insula (aINS), inferior frontal gyrus (IFG), and ventral premotor cortex (PM)) in a group of 32 left hemisphere stroke patients and 18 healthy, age-matched controls. Two expert clinicians rated severity of AOS, dysarthria and nonverbal oral apraxia of the patients. Fifteen individuals were categorized as AOS and 17 were AOS-absent. Comparison of connectivity in patients with and without AOS demonstrated that AOS patients had reduced connectivity between bilateral PM, and this reduction correlated with the severity of AOS impairment. In addition, AOS patients had negative connectivity between the left PM and right aINS and this effect decreased with increasing severity of non-verbal oral apraxia. These results highlight left PM involvement in AOS, begin to differentiate its neural mechanisms from those of other motor impairments following stroke, and help inform us of the neural mechanisms driving differences in speech motor planning and programming impairment following stroke.

The intrinsic resting state voice network in Parkinson's disease

Over 90 percent of patients with Parkinsons disease experience speech‐motor impairment, namely, hypokinetic dysarthria characterized by reduced pitch and loudness. Resting‐state functional connectivity analysis of blood oxygen level‐dependent functional magnetic resonance imaging is a useful measure of intrinsic neural functioning. We utilized resting‐state functional connectivity modeling to analyze the intrinsic connectivity in patients with Parkinsons disease within a vocalization network defined by a previous meta‐analysis of speech (Brown et al., 2009). Functional connectivity of this network was assessed in 56 patients with Parkinsons disease and 56 gender‐, age‐, and movement‐matched healthy controls. We also had item 5 and 18 of the UPDRS, and the PDQ‐39 Communication subscale available for correlation with the voice network connectivity strength in patients. The within‐group analyses of connectivity patterns demonstrated a lack of subcortical–cortical connectivity in patients with Parkinsons disease. At the cortical level, we found robust (homotopic) interhemispheric connectivity but only inconsistent evidence for many intrahemispheric connections. When directly contrasted to the control group, we found a significant reduction of connections between the left thalamus and putamen, and cortical motor areas, as well as reduced right superior temporal gyrus connectivity. Furthermore, most symptom measures correlated with right putamen, left cerebellum, left superior temporal gyrus, right premotor, and left Rolandic operculum connectivity in the voice network. The results reflect the importance of (right) subcortical nodes and the superior temporal gyrus in Parkinsons disease, enhancing our understanding of the neurobiological underpinnings of vocalization impairment in Parkinsons disease. Hum Brain Mapp 36:1951–1962, 2015.

The neural changes in connectivity of the voice network during voice pitch perturbation

Voice control is critical to communication. To date, studies have used behavioral, electrophysiological and functional data to investigate the neural correlates of voice control using perturbation tasks, but have yet to examine the interactions of these neural regions. The goal of this study was to use structural equation modeling of functional neuroimaging data to examine network properties of voice with and without perturbation. Results showed that the presence of a pitch shift, which was processed as an error in vocalization, altered connections between right STG and left STG. Other regions that revealed differences in connectivity during error detection and correction included bilateral inferior frontal gyrus, and the primary and pre motor cortices. Results indicated that STG plays a critical role in voice control, specifically, during error detection and correction. Additionally, pitch perturbation elicits changes in the voice network that suggest the right hemisphere is critical to pitch modulation.