Altered Small-World Brain Networks in Temporal Lobe in Patients with Schizophrenia Performing an Auditory Oddball Task

The functional architecture of the human brain has been extensively described in terms of complex networks characterized by efficient small-world features. Recent functional magnetic resonance imaging (fMRI) studies have found altered small-world topological properties of brain functional networks in patients with schizophrenia (SZ) during the resting state. However, little is known about the small-world properties of brain networks in the context of a task. In this study, we investigated the topological properties of human brain functional networks derived from fMRI during an auditory oddball (AOD) task. Data were obtained from 20 healthy controls and 20 SZ; A left and a right task-related network which consisted of the top activated voxels in temporal lobe of each hemisphere were analyzed separately. All voxels were detected by group independent component analysis. Connectivity of the left and right task-related networks were estimated by partial correlation analysis and thresholded to construct a set of undirected graphs. The small-worldness values were decreased in both hemispheres in SZ. In addition, SZ showed longer shortest path length and lower global efficiency only in the left task-related networks. These results suggested small-world attributes are altered during the AOD task-related networks in SZ which provided further evidences for brain dysfunction of connectivity in SZ

Using Electrophysiology to Investigate Changes in Brain Activation in Individuals with Chronic Stroke

Many individuals who have experienced a stroke also experience persistent decrements in several domains, such as sensorimotor, language, and cognition. While rehabilitation for these deficits is helpful even decades after a stroke, there is limited information available to determine the most effective pairing of treatment with individual deficits. Further, despite decades of neuroimaging research, our understanding of optimal recovery patterns following stroke is relatively poor. In order to improve outcomes for individuals living with chronic deficits due to stroke, neurophysiological biomarkers corresponding to recovery patterns and treatment response are needed. Electroencephalography (EEG) holds great potential for identifying biomarkers as it directly measures brain activation, and is non-invasive, reliable, replicable, and portable. Further, almost all individuals post-stroke are able to tolerate EEG recording. In addition, different methods of analyzing EEG data allow multiple information streams to be gleaned from a single dataset. In this study, 27 persons with chronic stroke (PWCS) and 27 neurologically healthy controls completed speech, language, cognitive, and sensorimotor behavioral assessments. Participants also completed two EEG sessions approximately one month apart which included recording of brain activity at rest and during language, cognitive, and motor tasks. Spectral EEG and event-related potential (ERP) analyses revealed significant differences between neurologically healthy controls and PWCS both at rest and during an auditory oddball task. Test-retest reliability measured across a one-month interval varied by group, task, and electrode montages or regions of interest from poor to excellent. The spectral EEG analysis showed changes previously reported during the acute and sub-acute phase of recovery persist into the chronic phase. ERP analysis demonstrated that individuals with a wide range of post-stroke deficits perform significantly differently during a cognitive task. However, no statistically significant differences were observed between healthy controls and this mixed group during language tasks. Finally, reliability findings indicate some tasks and measures may be appropriate for use in determining treatment response. These results provide support for the use of EEG as a biomarker in the chronic phase in a general stroke population. Future research should investigate the utility of EEG in specific subgroups of persons with chronic stroke

Cortical Representation of Tympanic Membrane Movements due to Pressure Variation: An fMRI Study

Middle ear sensory information has never been localized in the homunculus of the somatosensory cortex (S1). We investigated the somatosensory representation of the middle ear in 15 normal hearing subjects. We applied small air pressure variations to the tympanic membrane while performing a 3T-fMRI study. Unilateral stimulations of the right ear triggered bilateral activations in the caudal part of the postcentral gyrus in Brodmann area 43 (BA 43) and in the auditory associative areas 42 (BA 42) and 22 (BA 22). BA 43 has been found to be involved in activities accompanying oral intake and could be more largely involved in pressure activities in the oropharynx area. The tympanic membrane is indirectly related to the pharynx area through the action of tensor tympani, which is a Eustachian tube muscle. The Eustachian tube muscles have a role in pressure equalization in the middle ear and also have a role in the pharyngeal phase of swallowing. Activation of BA 42 and BA 22 could reflect activations associated with the bilateral acoustic reflex triggered prior to self-vocalization to adjust air pressure in the oropharynx during speech. We propose that BA 43, 42, and 22 are the cortical areas associated with middle ear function. We did not find representation of tympanic membrane movements due to pressure in S1, but its representation in the postcentral gyrus in BA 43 seems to suggest that at least part of this area conveys pure somatosensory information

What computations support response inhibition? The roles of context-monitoring, selective stopping, and strategic control

Response inhibition is thought to be central to the function of the frontal lobes and intimately related to all higher cognitive functions. The effortful and controlled component to response inhibition is often assumed to be the act of motoric stopping per se, such that motoric stopping can be strategically directed either at all actions (thus taking a global form) or only a subset (thus taking a more selective form). Here we challenge these core assumptions, first by offering a more viable alternative to dominant accounts of global stopping, and second by raising both empirical and computational dilemmas for dominant accounts of selective stopping. Using behavioral, neuroimaging, electroencephalographic and computational approaches, we demonstrate that the global stopping of responses does not require control mechanisms beyond those involved in detecting contexts in which old behaviors are inappropriate - in other words, the ability to monitor context in the service of goals. A computational model is used to demonstrate that these context-monitoring processes may underlie the behavioral, neuroimaging, and pharmacological phenomena of global stopping in the absence of any controlled stopping mechanisms. This work also challenges claims that more strategically selective forms of stopping are enabled by the controlled use of a slower but more response-specific stopping mechanism. We find a developmental double dissociation between the speed of stopping and its specificity, indicating that they cannot unambiguously be taken to reflect the use of a single neural mechanism. A computational model raises further challenges for extant theories of selective stopping, raising the possibility that the control mechanisms supporting this ability are not actually directed at specific responses. Together these results challenge dominant accounts of both global and selective inhibitory control, and clarify emerging debates on the frontal substrates of response inhibition, while raising novel questions about the substrates and processes that support selective stopping. More broadly, this work provides a coherent account of prefrontal cortex function across inhibitory domains, which may in turn enable both a more precise characterization of frontal disinhibitory syndromes as well as enable more targeted diagnosis and treatment of pathologies associated with response inhibition deficits

Repetitive Transcranial Magnetic Stimulation by Theta Burst

Transcranial magnetic stimulation (TMS) is a non-invasive diagnostic and therapeutic technique used to stimulate the brain in several neurological and psychiatric diseases, even though the main bases underlying its action are not fully understood. Theta Burst Stimulation (TBS), a patterned form of repetitive TMS, has been assuming particular importance due to its faster application. Research of TBS effects on some higher cortical functions such as cognition after stimulation of the prefrontal cortex (PFC), or its possible influence in some less studied cortical regions (as the temporal cortex) has been limited and revealed inconsistent results. One of the problems assessing the cognitive TBS after-effects relates to the use of multiple evaluation methods, with different sensitivities. In this matter, the use of neurophysiology studies such as the auditory P300, a cognitive evoked potential, may be of particular importance. To date, studies addressing the association between auditory P300 and TBS are scarce, and some contradictory results were found. The study of other higher cognitive domains such as creativity is even rarer, but it may be relevant given that part of the neural networks involved in creative processing are associated with the PFC. The effect of TMS over the PFC, studying the modulation of functions mediated by the autonomic nervous system has also been reported, but there is still a significant disagreement between the rare studies performed. So far, the extent of the modulatory effects associated with TBS at the sensory level is still poorly known, and research with TBS over the auditory cortex, despite showing some positive results, remains inconclusive, with some reports of sound hypersensitivity after sessions with higher intensity stimulation. It should also be noted that a significant part of the knowledge about the effects of TBS derives from studies in patients, with dysfunctional neuronal networks or hemispheric lesions, which add challenges to the search for scientific evidence in healthy individuals. Given the uncertainties that remain regarding the extent of the neuromodulatory effects of TBS, the primary objective of this thesis focused on increasing the scientific knowledge related to the use of TBS in the healthy brain. Therefore, we intended to study the neurophysiological responses (such as auditory P300), the functional responses (such as auditory thresholds), and the physiological responses (such as cerebral oximetry and blood pressure) associated with the application of TBS in the prefrontal and temporal cortices. All studies used a target population of healthy young adults, with an average age of approximately 23 years, and similar education. TBS was performed accordingly to the 600-pulse paradigm described by Huang et al. (continuous and intermittent). Sham-controlled, double-blind intervention protocols were used, with random distribution by the respective groups. The main objective of the study in chapter III was to evaluate the effect of TBS on the dorsolateral prefrontal cortex (DLPFC) of both cerebral hemispheres in cognitive processing. The objective was to assess if the auditory P300 would be influenced by the stimulation type. Results revealed that the mean P300 peak latency after TBS decreased only after leftward iTBS. A significant delay in P300 latency was originated from both right and left cTBS. Amplitude response did not change significantly. The results covered in chapter IV derived from the use of TBS on the left DLPFC, studying the possibility of a relationship between the post-TBS auditory P300 and the post-TBS neuropsychological tests: Trail Making Test (TMT) and the Stroop Test of Words and Colours. Results revealed that cTBS led to a delay of the P300, also significantly influencing the expected performance on Stroop C and Stroop Interference when compared to the groups submitted to iTBS and sham stimulation. No significant results were found in the TMT tests for any type of TBS stimulation. In Chapter V, we studied the cerebral oximetry using Near Infra-Red Spectroscopy, blood pressure, and heart rate, after applying TBS to the right and left DLPFC. We found a significant reduction in oximetry in the left frontal region after ipsilateral cTBS and a significant decrease in systolic blood pressure after cTBS to the right DLPFC. Chapter VI covered the evaluation of the effects of TBS over the left temporal cortex, specifically studying the auditory thresholds in the ear closest to the coil. Results showed no major side effects after iTBS, cTBS, or sham stimulation. It was also found that iTBS led to lower hearing thresholds, especially when comparing the iTBS and sham groups at 500Hz and between the iTBS and cTBS groups at 4000Hz. Chapter VII addresses a patent concerning the technique and possible use of iTBS as a method to influence creative processing. After iTBS over the right DLPFC, results of an adapted selection of the Torrance Tests of Creative Thinking suggest that divergent thinking, originality and fluency improved significantly compared to the sham group. An integrative analysis of the results shows that TBS seems to effectively influence the underlying cortical neurons and cortico-subcortical networks. The findings thus support the existence of a trans-synaptic effect advocated initially for the classic repetitive TMS, which after the publication of our research can continue to be extended with greater confidence to TBS protocols. Our results also support the most consensual theory about the modulatory effects of the two main forms of TBS – intermittent (excitatory) and continuous (inhibitory) – particularly on the prefrontal and temporal cortices. The effects of TBS seem to be intrinsically correlated with the hemispheric lateralization and this may be related to the specific functions or dominance of each hemisphere and the specific stimulated cortical regions. The combined results of this investigation also seem to suggest that the inhibition induced by cTBS seems more effective when compared to the excitatory effect of iTBS, which seemed stronger in the left hemisphere. After all our research with TBS in more than one cortical region, we can infer that this is a safe technique, with rare and incipient side effects. The encouraging results after using iTBS in the auditory cortex opens new perspectives regarding future implementations of the technique and should be replicated in patients, particularly with mild sensorineural hearing loss, in order to assess whether this stimulation protocol can be a valid therapeutic technique in these cases. We also conclude that the techniques used to study TBS-related effects, as the P300 or the NIRS, can be very useful in the future, as an attempt to identify the effectiveness of the therapeutic use of TBS protocols, possibly allowing to adapt and modify the idealized interventions, leading to a personalized patient intervention. Our findings provide relevant information, necessary to increase the technical and scientific credibility required for achieving a more comprehensive and reliable clinical use of TBS. This is crucial at a time when transcranial magnetic stimulation use as an off-label therapy for numerous neurological and psychiatric diseases grows unregulated, and the patient best interests must be defended.A estimulação magnética transcraniana (EMT) é uma técnica de diagnóstico e terapêutica não invasiva, que tem vindo a evoluir nos últimos 35 anos. A aplicação terapêutica da forma repetitiva da EMT (EMTr), tem vindo a demonstrar a sua utilidade científica e clínica, com aplicação em várias doenças neurológicas e psiquiátricas como a depressão major, a perturbação obsessivo-compulsiva, dor e reabilitação em doentes com acidentes vasculares cerebrais, ainda que as principais bases subjacentes à sua acção não sejam totalmente compreendidas. A EMT baseia-se no princípio da indução magnética e na sua capacidade de induzir correntes elétricas no tecido cortical. Esses campos magnéticos (pulsos) originados por uma bobina adjacente ao couro cabeludo originam um fluxo iónico intracraniano que irá provocar a despolarização da membrana neuronal, desencadeando assim um potencial de ação. Embora a EMT exerça os seus efeitos predominantemente na área cortical adjacente à bobina, os potenciais de ação induzidos espalham-se trans-sinapticamente, originando a propagação da ativação para regiões corticais e subcorticais vizinhas pertencentes à rede neuronal em questão. Parece ocorrer ainda a aparente capacidade de influenciar a função do hemisfério contralateral à estimulação possivelmente por mediação calossal. Os efeitos da EMTr ao nível da modulação da excitabilidade neuronal estão intrinsecamente dependentes das características da estimulação, nomeadamente ao nível da frequência e padronização dos estímulos. A aplicação de frequências inferiores ou iguais a 1 Hz (EMTr de baixa frequência) são associadas à indução de um efeito inibitório neuronal, enquanto que a aplicação de frequências acima de 1 Hz, normalmente acima dos 5 Hz (EMTr de alta frequência), podem induzir um efeito excitatório. Em 2005 surgiu uma forma padronizada de aplicação dos pulsos magnéticos, denominada Theta Burst Stimulation (TBS), na qual grupos de 3 pulsos com alta frequência (bursts de 50Hz) são enviados a cada 200 milissegundos (5 Hz – frequência teta), implicando normalmente a aplicação de 600 pulsos por cada sessão de estimulação. Este é um protocolo que assume particular importância pela sua rápida aplicação, levando menos de 3 minutos a executar, sendo significativamente mais célere do que os protocolos clássicos de EMTr (que podem exceder 30 minutos). Efeitos neuromodulatórios opostos podem ser igualmente induzidos com TBS, sendo que a aplicação ininterrupta da estimulação durante 40 segundos – TBS contínua (cTBS) – parece originar uma diminuição na excitabilidade cortical com uma duração de até 50 minutos pós-estimulação, enquanto que a aplicação de apenas 2 segundos de TBS intervalada por 8 segundos de pausa – TBS intermitente (iTBS) – durante 190 segundos, terá a capacidade de induzir aumento na excitabilidade cortical até cerca de 60 minutos pós-estimulação. Apesar do volume significativo de investigação acumulada na estimulação com EMTr e TBS, demonstrando a sua capacidade modulatória e a sua aplicabilidade na prática clínica, a investigação dos seus efeitos sobre algumas funções corticais superiores como a cognição ou os efeitos da aplicação em algumas regiões corticais menos estudadas como a região temporal tem sido mais limitada (principalmente com a TBS) e apresentado alguns resultados contraditórios. O córtex pré-frontal assume particular importância associado à aplicação da EMTr/TBS dada a extensa rede de conexões com outras regiões corticais (como o córtex motor, o córtex sensitivo, a amígdala, o tálamo e o hipocampo), importantes em doenças como a depressão (desequilíbrio inter-hemisférico pré-frontal verificado por neuroimagem), e ainda pela sua aparente capacidade de influenciar funções autonómicas e cardiovasculares. Meta-análises como a de Lowe et al. 2018, avaliando os efeitos da TBS sobre o córtex pré-frontal, revelam que parece existir um efeito negativo no desempenho das tarefas de função executiva após estimulação com cTBS e um efeito positivo mas em menor grau após estimulação com iTBS. No entanto, o efeito mais definido da estimulação sobre as várias dimensões cognitivas permanece envolto em alguma dúvida, dado que por um lado têm surgido alguns resultados negativos e por outro lado a maioria dos estudos tem usado populações relativamente pequenas, com infrequente recurso a grupos sham. Um dos principais problemas na avaliação dos possíveis efeitos da estimulação magnética repetitiva prende-se com o uso de diversos métodos de avaliação, com diferentes sensibilidades para o estudo das várias dimensões cognitivas, ou ainda com técnicas com menor resolução temporal (como os estudos de imagem cerebral funcional) comparativamente a técnicas neurofisiológicas. Neste ponto, a utilização de estudos no âmbito da neurofisiologia, como os potenciais de longa latência, pode assumir particular importância. O P300 auditivo, é um potencial evocado cognitivo, dependente da atenção e capacidade de discriminação do sujeito, traduzindo estadios mais superiores ou avançados de processamento associado a uma tarefa. As origens neuronais do P300 são múltiplas e bi-hemisféricas, associando-se a regiões como o hipocampo, o córtex pré-frontal ventrolateral e o córtex cingulado posterior. Até à data, são raros os estudos que abordaram a associação entre o P300 auditivo e a EMTr e ainda mais raros combinando a estimulação com TBS e o P300. A avaliação dos resultados prévios sugere que a estimulação magnética pode ser capaz de influenciar o processamento cognitivo e que as alterações podem ser monitorizadas pelo P300, mas são encontrados alguns resultados contraditórios, existindo significativas discrepâncias na metodologia usada. […

Applications of functional near-infrared spectroscopy (fNIRS) in studying cognitive development: the case of mathematics and language

We discuss how technical limitations of common neuroimaging techniques such as functional magnetic resonance imaging (fMRI) have resulted in our limited understanding of neural changes during development, while fNIRS would be a suitable and child-friendly method to examine cognitive development. We suggest fNIRS as an additional technique to track brain activation changes in the field of educational neuroscienc