Intra- and inter-regional priming of ipsilateral human primary motor cortex with continuous theta burst stimulation does not induce consistent neuroplastic effects

Human responses to non-invasive brain stimulation (NIBS) techniques can be highly variable. Recently, priming protocols involving a conditioning round of NIBS applied to a target brain region prior to the application of a test protocol have shown promise in inducing more reliable effects. We investigated whether intra- or inter-regional priming of the left primary motor cortex (M1) using continuous theta burst stimulation (cTBS) can induce consistent, and reliable modulation of corticospinal excitability. Twenty healthy adults (six males) underwent four cTBS protocols. For intra-regional priming, cTBS was applied twice to the left M1 (M1-M1). For inter-regional M1 priming, cTBS was applied to the ipsilateral (left) dorsal premotor cortex (dPMC-M1), and ipsilateral (left) dorsolateral prefrontal cortex (DLPFC-M1). In the control condition, sham stimulation was applied to left M1, followed by active cTBS also applied to the left M1 (sham-M1). Each round of cTBS was separated by 10 min. Neuroplastic responses were indexed using motor evoked potentials (MEPs) elicited from the left M1 hand region, and measured from the contralateral first dorsal interosseous (right hand). MEP measurements were taken before the first round of cTBS priming, then immediately, 10, 20 and 30 min after the second test round of cTBS. The primary two-way repeated measures ANOVA revealed no significant differences in MEP responses across each condition (no main effects or interaction). Intra- and inter-regional priming of the left M1 using cTBS does not induce consistent neuroplastic effects. Further work is required to identify factors which contribute to such variability in human responses to NIBS

Resting state electroencephalography microstates in autism spectrum disorder: a mini-review

Atypical spatial organization and temporal characteristics, found via resting state electroencephalography (EEG) microstate analysis, have been associated with psychiatric disorders but these temporal and spatial parameters are less known in autism spectrum disorder (ASD). EEG microstates reflect a short time period of stable scalp potential topography. These canonical microstates (i.e., A, B, C, and D) and more are identified by their unique topographic map, mean duration, fraction of time covered, frequency of occurrence and global explained variance percentage; a measure of how well topographical maps represent EEG data. We reviewed the current literature for resting state microstate analysis in ASD and identified eight publications. This current review indicates there is significant alterations in microstate parameters in ASD populations as compared to typically developing (TD) populations. Microstate parameters were also found to change in relation to specific cognitive processes. However, as microstate parameters are found to be changed by cognitive states, the differently acquired data (e.g., eyes closed or open) resting state EEG are likely to produce disparate results. We also review the current understanding of EEG sources of microstates and the underlying brain networks

The influence of biological sex on neurobiological mechanisms underlying autism spectrum disorder: an investigation of neural activity and connectivity

Autism spectrum disorder (ASD) is characterised by impairment in social communication and interaction, and the presence of restricted and repetitive patterns of behaviours and interests. Though a behaviourally defined condition, a growing amount of literature provides substantial support for neurobiological abnormality underlying a vast array of impairments and characteristics associated with ASD. Of particular relevance to this thesis is the notion of abnormal or impaired neural connectivity (NC) in ASD. There is typically a differentiation between structural connectivity (SC; structural integrity of connections within and between brain regions) and functional connectivity (FC; synchronous activity between brain regions), and abnormalities in both of these have been noted among individuals with ASD compared to unaffected, neurotypical (NT) controls. Often overlooked in the literature at a neurobiological level, but also more broadly, is the role of biological sex in ASD. The limited literature investigating females with ASD is scarce and inconsistent, however some common themes do emerge. At a behavioural level, females with ASD appear to experience greater social difficulty, yet have the ability to mask or camouflage their symptoms. Structural brain imaging further supports this notion of greater abnormality among females with ASD, while accounting for expected sexual dimorphisms. To date, the functional underpinnings of these observations has not been investigated. This research examined whether biological sex influences the neurobiological abnormalities observed in ASD. Broadly, this study aimed to 1) investigate structural mechanisms (i.e., white matter [WM] pathways) involved in NC in ASD, 2) to provide insight into the functional underpinnings of key processes known to be impaired in ASD, and 3) to further understand electrophysiological processes in cortical regions known to be functionally impaired in ASD. Participants attended three experimental testing sessions. Session 1 involved clinical, behavioural and neurocognitive assessment. In session 2, participants underwent a magnetic resonance imaging (MRI) scan. Finally, session 3 involved a combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) paradigm. Broadly, it was hypothesized that individuals with ASD would have impaired SC and FC compared to unaffected NT controls. It was further hypothesized biological sex would mediate this finding in ASD beyond expected sexual dimorphisms, and that neurobiological abnormality would be more severe in females with ASD. Firstly, we present an investigation of SC of key WM tracts throughout the brain, as there is strong evidence to suggest differences in WM architecture and structure in individuals with ASD compared to NT controls. We used diffusion tensor imaging (DTI) to investigate WM aberration in adults with high-functioning ASD and age, sex and IQ matched controls. Tract-based spatial statistics (TBSS) was used to explore differences in WM in major tract bundles. The effects of biological sex were also investigated. TBSS revealed no differences in fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), or axial diffusivity (AD) between groups. There were no effects of biological sex. Next, FC was explored in a resting state paradigm, as atypical FC of the default mode network (DMN) has previously been identified in ASD. We investigated resting state FC, within the key DMN structures and also the wider resting state network, in a sample of high functioning males and females with ASD, and age, sex and IQ matched NT controls. FC within the DMN and broader resting state network did not differ between groups. Individuals with ASD did however have increased FC between a) the cingulate and primary somatosensory cortices, and b) the posterior superior temporal gyrus and primary somatosensory cortex. This effect appeared to be largely driven by affected males, who show increased FC relative to neurotypical males. Females with ASD did not differ in any regard to neurotypical females. Subsequently, the functional role of the mentalising network (primarily comprising the medial prefrontal cortex [mPFC] and the right temporo-parietal junction [rTPj]) was investigated, as this network is suggested to be highly involved in social understanding, a core impairment in ASD. Functional abnormalities have also been previously observed in this network among individuals with ASD. While observing a series of silent animations depicting social interactions between two geometric shapes, hemodynamic (blood oxygen level dependent; BOLD) response and FC were investigated. There were no differences in neural activity or connectivity in the mPFC or rTPj between groups during social processing. Sex-stratified analysis showed decreased activity in the right posterior superior temporal sulcus, and decreased functional connectivity between this site and the bilateral ventral posterior cingulate cortex in males with ASD during social processing. This pattern was not observed in the female sub-sample. Finally, electrophysiological measures of brain function were assessed using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG). TMS was applied to the right primary motor cortex, right dorsolateral prefrontal cortex and right TPj in separate blocks while EEG was concurrently recorded. Power spectra oscillations (activity) or phase-synchrony (connectivity) in the alpha, beta or gamma frequency bands did not differ statistically between groups, nor when data were stratified by sex. There are two interlinked considerations that may contribute to the overall findings of this thesis. Firstly, the sample presented in this thesis was comprised of high-functioning (i.e. IQ > 70) adults. For two reasons, chronological age may mediate the presented findings as a) it is well established that patterns of (structural) brain abnormality seen in younger individuals with ASD appear to normalise with age, and b) individuals (particularly well adapted high-functioning) with ASD may adapt their behaviours or learn to understand social cues, a process which may have an effect on brain function. A second consideration is the role of varying levels of impairment in ASD, and the extent to which this may influence the aforementioned consideration as well as the findings presented in this thesis. Future research should involve a large scale, multi-site investigation comparing males and females with ASD of various ages and levels of functioning. The findings of this thesis are, in many aspects, contradictory to our proposed hypothesis. Overall, we did not identify any neurobiological differences between high-functioning adults with ASD compared to age, sex and IQ matched neurotypical (NT) controls. Further, while it was expected that females with ASD may be more impaired neurobiological compared to affected males, the findings of our fMRI investigations suggest that in fact affected males may experience greater neurobiological impairment as high-functioning adult females with ASD displayed a functional neurobiological profile akin to their NT counterparts, while affected males did not. Moreover, from an electrophysiological perspective, our TMS-EEG investigation provides trend level suggestion that both males and females differ neurobiological from matched controls, however in seemingly opposite directions from one another. Considered together, the overall finding presented in this thesis provides support that males and females with ASD do differ neurobiologically, however the direction and function of this abnormality remains unclear, raising an imperative consideration for future research

The influence of biological sex on neurobiological mechanisms underlying autism spectrum disorder: an investigation of neural activity and connectivity

Autism spectrum disorder (ASD) is characterised by impairment in social communication and interaction, and the presence of restricted and repetitive patterns of behaviours and interests. Though a behaviourally defined condition, a growing amount of literature provides substantial support for neurobiological abnormality underlying a vast array of impairments and characteristics associated with ASD. Of particular relevance to this thesis is the notion of abnormal or impaired neural connectivity (NC) in ASD. There is typically a differentiation between structural connectivity (SC; structural integrity of connections within and between brain regions) and functional connectivity (FC; synchronous activity between brain regions), and abnormalities in both of these have been noted among individuals with ASD compared to unaffected, neurotypical (NT) controls. Often overlooked in the literature at a neurobiological level, but also more broadly, is the role of biological sex in ASD. The limited literature investigating females with ASD is scarce and inconsistent, however some common themes do emerge. At a behavioural level, females with ASD appear to experience greater social difficulty, yet have the ability to mask or camouflage their symptoms. Structural brain imaging further supports this notion of greater abnormality among females with ASD, while accounting for expected sexual dimorphisms. To date, the functional underpinnings of these observations has not been investigated. This research examined whether biological sex influences the neurobiological abnormalities observed in ASD. Broadly, this study aimed to 1) investigate structural mechanisms (i.e., white matter [WM] pathways) involved in NC in ASD, 2) to provide insight into the functional underpinnings of key processes known to be impaired in ASD, and 3) to further understand electrophysiological processes in cortical regions known to be functionally impaired in ASD. Participants attended three experimental testing sessions. Session 1 involved clinical, behavioural and neurocognitive assessment. In session 2, participants underwent a magnetic resonance imaging (MRI) scan. Finally, session 3 involved a combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) paradigm. Broadly, it was hypothesized that individuals with ASD would have impaired SC and FC compared to unaffected NT controls. It was further hypothesized biological sex would mediate this finding in ASD beyond expected sexual dimorphisms, and that neurobiological abnormality would be more severe in females with ASD. Firstly, we present an investigation of SC of key WM tracts throughout the brain, as there is strong evidence to suggest differences in WM architecture and structure in individuals with ASD compared to NT controls. We used diffusion tensor imaging (DTI) to investigate WM aberration in adults with high-functioning ASD and age, sex and IQ matched controls. Tract-based spatial statistics (TBSS) was used to explore differences in WM in major tract bundles. The effects of biological sex were also investigated. TBSS revealed no differences in fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), or axial diffusivity (AD) between groups. There were no effects of biological sex. Next, FC was explored in a resting state paradigm, as atypical FC of the default mode network (DMN) has previously been identified in ASD. We investigated resting state FC, within the key DMN structures and also the wider resting state network, in a sample of high functioning males and females with ASD, and age, sex and IQ matched NT controls. FC within the DMN and broader resting state network did not differ between groups. Individuals with ASD did however have increased FC between a) the cingulate and primary somatosensory cortices, and b) the posterior superior temporal gyrus and primary somatosensory cortex. This effect appeared to be largely driven by affected males, who show increased FC relative to neurotypical males. Females with ASD did not differ in any regard to neurotypical females. Subsequently, the functional role of the mentalising network (primarily comprising the medial prefrontal cortex [mPFC] and the right temporo-parietal junction [rTPj]) was investigated, as this network is suggested to be highly involved in social understanding, a core impairment in ASD. Functional abnormalities have also been previously observed in this network among individuals with ASD. While observing a series of silent animations depicting social interactions between two geometric shapes, hemodynamic (blood oxygen level dependent; BOLD) response and FC were investigated. There were no differences in neural activity or connectivity in the mPFC or rTPj between groups during social processing. Sex-stratified analysis showed decreased activity in the right posterior superior temporal sulcus, and decreased functional connectivity between this site and the bilateral ventral posterior cingulate cortex in males with ASD during social processing. This pattern was not observed in the female sub-sample. Finally, electrophysiological measures of brain function were assessed using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG). TMS was applied to the right primary motor cortex, right dorsolateral prefrontal cortex and right TPj in separate blocks while EEG was concurrently recorded. Power spectra oscillations (activity) or phase-synchrony (connectivity) in the alpha, beta or gamma frequency bands did not differ statistically between groups, nor when data were stratified by sex. There are two interlinked considerations that may contribute to the overall findings of this thesis. Firstly, the sample presented in this thesis was comprised of high-functioning (i.e. IQ > 70) adults. For two reasons, chronological age may mediate the presented findings as a) it is well established that patterns of (structural) brain abnormality seen in younger individuals with ASD appear to normalise with age, and b) individuals (particularly well adapted high-functioning) with ASD may adapt their behaviours or learn to understand social cues, a process which may have an effect on brain function. A second consideration is the role of varying levels of impairment in ASD, and the extent to which this may influence the aforementioned consideration as well as the findings presented in this thesis. Future research should involve a large scale, multi-site investigation comparing males and females with ASD of various ages and levels of functioning. The findings of this thesis are, in many aspects, contradictory to our proposed hypothesis. Overall, we did not identify any neurobiological differences between high-functioning adults with ASD compared to age, sex and IQ matched neurotypical (NT) controls. Further, while it was expected that females with ASD may be more impaired neurobiological compared to affected males, the findings of our fMRI investigations suggest that in fact affected males may experience greater neurobiological impairment as high-functioning adult females with ASD displayed a functional neurobiological profile akin to their NT counterparts, while affected males did not. Moreover, from an electrophysiological perspective, our TMS-EEG investigation provides trend level suggestion that both males and females differ neurobiological from matched controls, however in seemingly opposite directions from one another. Considered together, the overall finding presented in this thesis provides support that males and females with ASD do differ neurobiologically, however the direction and function of this abnormality remains unclear, raising an imperative consideration for future research

Therapeutic applications of noninvasive neuromodulation in children and adolescents

Recent advances and growing evidence supporting the safety and efficacy of noninvasive neuromodulatory techniques in adults have facilitated the study of neuromodulation applications in children and adolescents. Noninvasive brain stimulation methods such as transcranial direct current stimulation and transcranial magnetic stimulation have been considered in children with depression, autism spectrum disorder, attention-deficit hyperactivity disorder, and other neuropsychiatric disorders. However, current clinical applications of neuromodulation techniques in children and adolescents are nascent. There is a great need for developmentally informed, large, double-blinded, randomized, controlled clinical trials to demonstrate efficacy and safety of noninvasive brain stimulation in children and adolescents

Social processing in autism spectrum disorder: an fMRI investigation

BACKGROUND Females with autism spectrum disorder (ASD) may present differently to affected males. This may be due to masking or camouflaging of some of the clinical symptoms. Consequently, it may appear that, to some degree, females experience less social impairment than affected males. Further, females with ASD may experience more, or different, neurobiological impairment compared to affected males when controlling for expected sexual dimorphisms. METHODS The sample comprised 58 participants; 28 (14 male, 14 female) had a confirmed diagnosis of high functioning autism or Asperger's syndrome (based on DSM-IV criteria), and 28 (14 male, 14 female) were NT controls. Participants underwent functional magnetic resonance imaging (fMRI) while observing and judging 12 videos depicting interactions between two triangles. Participants were required to evaluate the type of interaction observed in each of the videos (no interaction, psychological interaction, physical interaction). RESULTS Whole brain analysis indicated increased BOLD responses (p=.0001) in the left middle temporal gyrus, and inferior frontal lobe in the NT group compared to the ASD group while observing psychological interactions. With respect to gender, females with ASD showed increased BOLD responses in the right medial temporal region while observing psychological interactions, a difference that was not evident in the NT group. DISCUSSION NT individuals displayed increased activity in regions commonly associated with social processing compared to individuals with ASD. This is consistent with the social impairment observed in ASD. Moreover, these results suggest that females with ASD may process social stimuli differently to affected males, and NT females. Thus, the importance of furthering our understanding of sex differences in neurobiological mechanisms underpinning symptomatology of ASD is pertinent to improve diagnostic and intervention paradigms in the future