日本語における長母音の短母音化

博士（学術）神戸大

Neuroprotection in traumatic brain injury

Der endogene adaptive Mechanismus der Hypoxietoleranzentwicklung, als ischemic tolerance bezeichnet, wurde sowohl für Angina-pectoris-Anfälle vor einem folgenden Myokardinfarkt als auch für eine TIA vor einem ischämischen Hirninfarkt beschrieben. Da es Anhalte für eine Minderperfusion des Hirngewebes nach einem Schädelhirntrauma (SHT) gibt, wurde hier untersucht, welche Auswirkung eine cerebrale, ischämische Präkonditionierung (IPC) in Form einer TIA vor dem Trauma oder mikroangiopathische Veränderungen des Hirnparenchyms im CT oder die als neuroprotektiv beschriebene Acetylsalicylsäure auf die Nachblutungsrate bei SHT-Patienten haben. Die Nachblutungsrate in der Gruppe der ischämisch präkonditionierten war signifikant geringer als in der Kontrollgruppe (10,4 % vs. 48,9 %, p<0,001). Auf Grund einer Korrelation der ASS Einnahme mit dem vorliegen einer IPC konnte für diesen Faktor in der multivariaten Analyse kein signifikantes Ergebnis gezeigt werden. Der Glasgow Coma Scale als Maß für das neurologische Defizit bei Entlassung unterschied sich nicht signifikant (12,9 vs. 12,7). Insgesamt traten bei 35,7 % der Patienten Nachblutungen auf, bei initial unauffälligem CT sogar in 54 %. Die Ergebnisse dieser Studie legen nahe, dass eine IPC vor einem SHT eine Rolle spielen könnte. Da jedoch die vorliegenden Daten zeigen, dass eine Nachblutung nicht zwingend mit einem schlechteren neurologischen Outcome einhergeht, müssen noch andere Faktoren existieren, die den klinischen Verlauf eines SHT-Patienten beeinflussen. Diese Studie belegt erneut die Notwendigkeit von Verlaufskontrollen - z.B. mittels CT - da auch bei initial unauffälligem CT-Befund intraparenchymale Blutungen auftreten

When gut feelings teach the brain to fear pain: Context-dependent activation of the central fear network in a novel interoceptive conditioning paradigm

The relevance of contextual factors in shaping neural mechanisms underlying visceral pain-related fear learning remains elusive. However, benign interoceptive sensations, which shape patients’ clinical reality, may context-dependently become conditioned predictors of impending visceral pain. In a novel context-dependent interoceptive conditioning paradigm, we elucidated the putative role of the central fear network in the acquisition and extinction of pain-related fear induced by interoceptive cues and pain-predictive contexts.In this fMRI study involving rectal distensions as a clinically-relevant model of visceroception, N = 27 healthy men and women underwent differential conditioning. During acquisition training, visceral sensations of low intensity as conditioned stimuli (CS) predicted visceral pain as unconditioned stimulus (US) in one context (Con+), or safety from pain in another context (Con–). During extinction training, interoceptive CS remained unpaired in both contexts, which were operationalized as images of different rooms presented in the MRI scanner.Successful contextual conditioning was supported by increased negative valence of Con+ compared to Con– after acquisition training, which resolved after extinction training. Although interoceptive CS were perceived as comparatively pleasant, they induced significantly greater neural activation of the amygdala, ventromedial PFC, and hippocampus when presented in Con+, while contexts alone did not elicit differential responses. During extinction training, a shift from CS to context differentiation was observed, with enhanced responses in the amygdala, ventromedial, and ventrolateral PFC to Con+ relative to Con–, whereas no CS-induced differential activation emerged.Context-dependent interoceptive conditioning can turn benign interoceptive cues into predictors of visceral pain that recruit key regions of the fear network. This first evidence expands knowledge about learning and memory mechanisms underlying interoceptive hypervigilance and maladaptive avoidance behavior, with implications for disorders of the gut-brain axis

Memory-related hippocampal activity can be measured robustly using FMRI at 7 tesla

High field strength functional magnetic resonance imaging (fMRI) has developed rapidly. However, it suffers from increased artifacts in brain regions such as the medial temporal lobe (MTL), challenging functional imaging of the hippocampus with the objective of high-spatial resolution, which is particularly useful for this region both from a clinical and cognitive neuroscience perspective. We set out to compare a BOLD sequence at 7 T versus 3 T to visualize the MTL activity during an associative memory-encoding task. Twenty-eight healthy volunteers underwent a blocked-design fMRI at either 3 T or 7 T while performing a face-profession associative memory encoding task. Qualitative analyses of overall image quality revealed that functional images at 7 T were of high quality, showing a good white/gray matter contrast, with reasonably acceptable signal dropouts and artifacts at the lower portion of the temporal lobe. Analyses of task-related fMRI data revealed robust activations in the bilateral MTL during associative memory encoding at both field strengths. Notably, we observed significantly stronger memory-related hippocampal activation at 7 T than at 3 T, suggesting higher BOLD sensitivity at 7 T. These results are discussed in the light of the feasibility of 7 T scanning protocols for the MTL

Short Latency Gray Matter Changes in Voxel-Based Morphometry following High Frequent Visual Stimulation

Magnetic resonance imaging studies using voxel-based morphometry (VBM) detected structural changes in the human brain within periods of months or weeks. The underlying molecular mechanisms of VBM findings remain unresolved. We showed that simple visual stimulation by an alternating checkerboard leads to instant, short-lasting alterations of the primary and secondary visual cortex detected by VBM. The rapidness of occurrence (i.e., within 10 minutes) rather excludes most of the proposed physiological mechanism such as neural or glial cell genesis/degeneration or synapse turnover. We therefore favour cerebral fluid shifts to be the underlying correlate of the here observed VBM gray matter changes. Fast onset gray matter changes might be one important explanation for the inconsistency of VBM study results that often raise concern in regard to the validity of presented data. This study shows that changes detectable by VBM may occur within a few minutes after physiological stimulation and must be considered in future VBM experiments to avoid misinterpretation of results

Cortical plasticity in episodic and chronic cluster headache

Cluster headache (CH) is characterized by recurrent episodes of excruciatingly painful, unilateral headache attacks typically accompanied by trigeminal autonomic symptoms. Due to its rhythm with alternating episodes of pain and no-pain, it is an excellent model to investigate whether structural brain changes detected by magnetic resonance based voxel-based-morphometry (VBM) reflect the cause of the disease, may be a consequence of the underlying disease other than pain, or may simply be caused by the sensation of pain itself. We investigated 91 patients with CH in different stages of their disease using VBM and compared them to 78 age- and gender-matched healthy controls. We detected distinct regional gray matter (GM) changes in different brain regions including the temporal lobe, the hippocampus, the insular cortex and the cerebellum. The extent, location and direction of observed GM alterations depended on the state of disease and appeared dynamic in relation to pain state (i.e., pain vs. no-pain). No hypothalamic changes were detected in CH patients compared to healthy controls. The GM changes observed in this study are highly dynamic and thereby reflect the cortical plasticity of the brain in regard to pain. This observed dynamic may provide an explanation of the diverse results of previous VBM studies in pain. Regarding CH the results suggest that the disease is more likely to be caused by a network dysfunction rather than by a single malfunctioning structure

Polarity-specific modulation of pain processing by transcranial direct current stimulation – a blinded longitudinal fMRI study

Abstract Background To enrich the hitherto insufficient understanding regarding the mechanisms of action of transcranial direct current stimulation (tDCS) in pain disorders, we investigated its modulating effects on cerebral pain processing using functional magnetic resonance imaging (fMRI). Methods Thirteen right-handed healthy participants received 20 min of 1.5 mA tDCS applied over the primary motor cortex thrice and under three different stimulation pattern (1.anodal-tDCS, 2.cathodal-tDCS, and 3.sham-tDCS) in a blinded cross-over design. After tDCS neural response to electric trigeminal-nociceptive stimulation was investigated using a block designed fMRI. Results Pain stimulation showed a distinct activation pattern within well-established brain regions associated with pain processing. Following anodal tDCS increased activation was detected in the thalamus, basal ganglia, amygdala, cingulate, precentral, postcentral, and dorsolateral prefrontal cortex, while cathodal t-DCS showed decreased response in these areas (pFWE < 0.05). Interestingly the observed effect was reversed in both control conditions (visual- and motor-stimulation). Behavioral data remained unchanged irrespective of the tDCS stimulation mode. Conclusions This study demonstrates polarity-specific modulation of cerebral pain processing, in reconfirmation of previous electrophysiological data. Anodal tDCS leads to an activation of the central pain-network while cathodal tDCS does not. Results contribute to a network-based understanding of tDCS’s impact on cerebral pain-processing

Fear conditioning in an abdominal pain model: neural responses during associative learning and extinction in healthy subjects.

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS(+)) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS(-)) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS(+). During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS(-) was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain

Positive treatment expectations shape perceived medication efficacy in a translational placebo paradigm for the gut-brain axis

Placebo research has established the pivotal role of treatment expectations in shaping symptom experience and patient-reported treatment outcomes. Perceived treatment efficacy constitutes a relevant yet understudied aspect, especially in the context of the gut-brain axis with visceral pain as key symptom. Using a clinically relevant experimental model of visceral pain, we elucidated effects of pre-treatment expectations on post-treatment perceived treatment efficacy as an indicator of treatment satisfaction in a translational placebo intervention. We implemented positive suggestions regarding intravenous treatment with a spasmolytic drug (in reality saline), herein applied in combination with two series of individually calibrated rectal distensions in healthy volunteers. The first series used distension pressures inducing pain (pain phase). In the second series, pressures were surreptitiously reduced, modeling pain relief (pain relief phase). Using visual analog scales (VAS), expected and perceived treatment efficacy were assessed, along with perceived pain intensity. Manipulation checks supported that the induction of positive pre-treatment expectations and the modeling of pain relief were successful. Generalized Linear Models (GLM) were implemented to assess the role of inter-individual variability in positive pre-treatment expectations in perceived treatment efficacy and pain perception. GLM indicated no association between pre-treatment expectations and perceived treatment efficacy or perceived pain for the pain phase. For the relief phase, pre-treatment expectations ($\it p$ = 0.024) as well as efficacy ratings assessed after the preceding pain phase ($\it p$ < 0.001) were significantly associated with treatment efficacy assessed after the relief phase, together explaining 54% of the variance in perceived treatment efficacy. The association between pre-treatment expectations and perceived pain approached significance ($\it p$ = 0.057) in the relief phase. Our data from an experimental translational placebo intervention in visceral pain support that reported post-treatment medication efficacy is shaped by pre-treatment expectations. The observation that individuals with higher positive expectations reported less pain and higher treatment satisfaction after pain relief may provide first evidence that perceived symptom improvement may facilitate treatment satisfaction. The immediate experience of symptoms within a given psychosocial treatment context may dynamically change perceptions about treatment, with implications for treatment satisfaction, compliance and adherence of patients with conditions of the gut-brain axis