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OBJECTIVES: Many chronic pain conditions show evidence of dysregulated synaptic plasticity, including the development and maintenance of central sensitization. This provides a strong rationale for neuromodulation therapies for the relief of chronic pain. However, variability in responses and low fidelity across studies remain an issue for both clinical trials and pain management, demonstrating insufficient mechanistic understanding of effective treatment protocols. MATERIALS AND METHODS: In a randomized counterbalanced crossover designed study, we evaluated two forms of patterned repetitive transcranial magnetic stimulation, known as continuous theta burst stimulation (TBS) and intermittent TBS, during normal and central sensitization states. Secondary hyperalgesia (a form of use-dependent central sensitization) was induced using a well-established injury-free pain model and assessed by standardized quantitative sensory testing involving light touch and pinprick pain thresholds in addition to stimulus-response functions. RESULTS: We found that continuous TBS of the human motor cortex has a facilitatory (pronociceptive) effect on the magnitude of perceived pain to secondary hyperalgesia, which may rely on induction and expression of neural plasticity through heterosynaptic long-term potentiation-like mechanisms. CONCLUSIONS: By defining the underlying mechanisms of TBS-driven synaptic plasticity in the nociceptive system, we offer new insight into disease mechanisms and provide targets for promoting functional recovery and repair in chronic pain. For clinical applications, this knowledge is critical for development of more efficacious and mechanisms-based neuromodulation protocols, which are urgently needed to address the chronic pain and opioid epidemics.
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Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.
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Córtex Cerebral/fisiologia , Córtex Pré-Frontal/fisiologia , Estimulação Magnética Transcraniana , Ácido gama-Aminobutírico/metabolismo , Adulto , Córtex Cerebral/metabolismo , Neurônios GABAérgicos/fisiologia , Glutamina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Inibição Neural , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Córtex Pré-Frontal/metabolismo , Método Simples-Cego , Adulto JovemRESUMO
BACKGROUND: A recently emergent functional neuroimaging literature has described the functional anatomical correlates of deception among healthy volunteers, most often implicating the ventrolateral prefrontal and anterior cingulate cortices. To date, there have been no such imaging studies of people with severe mental illness. AIMS: To discover whether the brains of people with schizophrenia would manifest a similar functional anatomical distinction between the states of truthfulness and deceit. It is hypothesised that, as with healthy people, persons with schizophrenia will show activation in the ventrolateral prefrontal and anterior cingulate cortices when lying. METHOD: Fifty-two people satisfying Diagnostic and Statistical Manual of Mental Disorder-IV criteria for schizophrenia or schizoaffective disorder underwent functional magnetic resonance imaging at 3 T while responding truthfully or with lies to questions concerning their recent actions. Half the sample was concurrently experiencing delusions. RESULTS: As hypothesised, patients exhibited greater activity in ventrolateral prefrontal cortices while lying. Truthful responses were not associated with any areas of relatively increased activation. The presence or absence of delusions did not substantially affect these findings, although subtle laterality effects were discernible upon post hoc analyses. CONCLUSIONS: As in healthy cohorts, the brains of people with schizophrenia exhibit a functional anatomical distinction between the states of truthfulness and deceit. Furthermore, this distinction pertains even in the presence of delusions.
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Enganação , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Adulto , Imagem Ecoplanar , Feminino , Humanos , Detecção de Mentiras/psicologia , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Radiografia , Esquizofrenia/diagnóstico , Inquéritos e Questionários , Adulto JovemRESUMO
Recent neuroimaging studies investigating the neural correlates of deception among healthy people, have raised the possibility that such methods may eventually be applied during legal proceedings. Were this so, who would volunteer to be scanned? We report a "natural experiment" casting some light upon this question. Following broadcast of a television series describing our team's investigative neuroimaging of deception in 2007, we received unsolicited (public) correspondence for 12 months. Using a customized template to examine this material, three independent assessors unanimously rated 30 of an initial 56 communications as unequivocally constituting requests for a "scan" (to demonstrate their author's "innocence"). Compared with the rest, these index communications were more likely to originate from incarcerated males, who were also more likely to engage in further correspondence. Hence, in conclusion, if neuroimaging were to become an acceptable means of demonstrating innocence then incarcerated males may well constitute those volunteering for such investigation.
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Mapeamento Encefálico , Encéfalo/fisiologia , Enganação , Correspondência como Assunto , Feminino , Psiquiatria Legal , Humanos , Imageamento por Ressonância Magnética , Masculino , Prisioneiros , Televisão , Reino UnidoRESUMO
'Munchausen's syndrome by proxy' characteristically describes women alleged to have fabricated or induced illnesses in children under their care, purportedly to attract attention. Where conclusive evidence exists the condition's aetiology remains speculative, where such evidence is lacking diagnosis hinges upon denial of wrong-doing (conduct also compatible with innocence). How might investigators obtain objective evidence of guilt or innocence? Here, we examine the case of a woman convicted of poisoning a child. She served a prison sentence but continues to profess her innocence. Using a modified fMRI protocol (previously published in 2001) we scanned the subject while she affirmed her account of events and that of her accusers. We hypothesized that she would exhibit longer response times in association with greater activation of ventrolateral prefrontal and anterior cingulate cortices when endorsing those statements she believed to be false (i.e., when she 'lied'). The subject was scanned 4 times at 3 Tesla. Results revealed significantly longer response times and relatively greater activation of ventrolateral prefrontal and anterior cingulate cortices when she endorsed her accusers' version of events. Hence, while we have not 'proven' that this subject is innocent, we demonstrate that her behavioural and functional anatomical parameters behave as if she were.