Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies.

BackgroundBurden of headache has been assessed in adults in countries worldwide, and is high, but data for children and adolescents are sparse. The objectives of this study were o develop a questionnaire and methodology for the global estimation of burden of headache in children and adolescents, to test these in use and to present preliminary data.MethodsWe designed structured questionnaires for mediated-group self-administration in schools by children aged 6-11 years and adolescents aged 12-17 years. In two pilot studies, we offered the questionnaires to pupils in Vienna and Istanbul. We performed face-to-face interviews in a randomly selected subsample of 199 pupils to validate the headache diagnostic questions.ResultsData were collected from 1,202 pupils (mean 13.9 ± 2.4 years; 621 female, 581 male). The participation rate was 81.1% in Istanbul, 67.2% in Vienna. The questionnaire proved acceptable: ≤5% of participants disagreed partially or totally with its length, comprehensibility or simplicity. The sensitivity, specificity, positive and negative predictive values ranged between 0.71 and 0.76 for migraine and between 0.61 and 0.85 for tension-type headache (TTH). Cronbach’s alpha was 0.83. The 1-year prevalence of headache was 89.3%, of migraine 39.3% and of TTH 37.9%. The prevalence of headache on ≥15 days/month was 4.5%. One fifth (20.7%) of pupils with headache lost ≥1 day of school during the preceding 4 weeks and nearly half (48.8%) reported ≥1 day when they could not do activities they had wanted to. The vast majority of pupils with headache experienced difficulties in coping with headache and in concentrating during headache. Quality of life was poorer in pupils with headache than in those without.ConclusionThese pilot studies demonstrate the usefulness of the questionnaires and feasibility of the methodology for assessing the global burden of headache in children and adolescents, and predict substantial impact of headache in these age groups.

BackgroundHeadache is a leading disabler in adults worldwide. In children and adolescents, the same may be true but the evidence is much poorer. It is notable that published epidemiological studies of these age groups have largely ignored headaches not fulfilling any specific set of ICHD criteria, although such headaches appear to be common. A new approach to these is needed: here we introduce, and investigate, a diagnostic category termed “undifferentiated headache” (UdH), defined in young people as recurrent mild-intensity headache of < 1 h’s duration.MethodsWe conducted a nationwide cross-sectional survey in 31 schools in six regions of Turkey selected by mixed convenience-based and purposive modified cluster-sampling. A validated, standardised self-completed structured questionnaire was administered by a physician-investigator to entire classes of pupils aged 6–17 years.ResultsOf the identified sample of 7889 pupils, 7088 (89.8%) participated. The 1-year prevalence of UdH was 29.2%, of migraine (definite and probable) 26.7%, and of tension-type headache (TTH) (definite and probable) 12.9%. UdH differed with respect to almost all headache features and associated symptoms from both migraine and TTH. Burden of headache and use of acute medication were lower in UdH than in migraine and TTH. Headache yesterday was less common in UdH than migraine (OR 0.32; 95% CI 0.28–0.37) and TTH (OR 0.64; 95% CI 0.56–0.77). Quality of life (QoL) was better in UdH (33.6 ± 5.2) than in migraine (30.3 ± 5.6; p < 0.001) and TTH (32.4 ± 5.3; p < 0.001), but worse than in pupils without headache (35.7 ± 4.7; p < 0.001).ConclusionsThis large nationwide study in Turkey of pupils aged 6–17 years has shown that many children and adolescents have a headache type that does not conform to existing accepted diagnostic criteria. This new diagnostic category of presumably still-evolving headache (undifferentiated headache) is common. UdH differs in almost all measurable respects from both migraine and TTH. Although characterised by mild headaches lasting < 1 h, UdH is associated with significant adverse impact on QoL. Longitudinal cohort studies are needed to evaluate the prognosis of UdH but, meanwhile, recognition of UdH and its distinction from migraine and TTH has implications for epidemiological studies, public-health policy and routine clinical practice.

In article number 1902583, Roland Beisteiner and co‐workers describe a brain activation technique for treatment of Alzheimer's disease. Transcranial pulse stimulation (TPS) applies ultrashort ultrasound pulses to activate neuronal resources. A therapeutic breakthrough is secure clinical targeting and access to deep brain areas. After 2 weeks of treatment, memory performance improves for up to 3 months.

BackgroundBased on recent findings and our own impressions we took a closer look at the relationship between (inter)ictal photophobia and psychometric variables in migraine patients with photophobia.FindingsFor this study we included 29 (27 female) migraine patients and 31 (18 female) controls with a mean age of 31.6 ± 12.5 years and 24.0 ± 4.1 years, respectively. All participants filled out the Depression Anxiety Stress Scale (DASS).Interictal photophobia in patients was significantly higher than photophobia in controls (p = .001). Patients showed statistically significantly higher levels of depressive symptoms (p < .001), anxiety symptoms (p < .001) and stress (p < .001) than controls. Among all participants, (interictal) photophobia correlated positively with age (rho = .318, p = .013) as well as with the levels of depressive symptoms (rho = .459, p < .001), anxiety symptoms (rho = .346, p = .008) and stress (rho = .368, p = .005), but not with gender. In the patients, ictal photophobia correlated positively with age (rho = .473, p = .01) and interictal photophobia (rho = .423, p = .022). Linear regression analysis revealed only a trend towards statistical significance for (interictal) photophobia as a predictor for the level of depressive symptoms (rho = .457, p = 0.056) in the whole sample.ConclusionsConsidering higher levels of photophobia in depression and the comorbidity of migraine and depression, it might be possible that depression contributes to interictal photophobia in patients with migraine. The same may be true for anxiety and stress. Both are also related to migraine and their possible impact on photophobia in migraine may be explained by pupillary dysfunction.

Background Photophobia, the aberrantly increased sensitivity to light, is a common symptom in migraine patients and light discomfort is frequently found as a trigger for migraine attacks. In behavioral studies, planned exposure to light was found to reduce headache in migraine patients with photophobia, potentially by increasing habituation to this migraine trigger. Here, we aimed to elucidate neurophysiological mechanisms of light exposure versus light deprivation in migraine patients using functional magnetic resonance imaging (fMRI). Methods Ten migraine patients (9 female, age = 28.70 ± 8.18 years) and 11 healthy controls (9 female, age = 23.73 ± 2.24 years) spent one hour on 7 consecutive days exposed to flashing light (Flash) or darkness (Dark) using a crossover design with a wash-out period of 3 months. Study participants kept a diary including items on interictal and ictal photophobia, presence and severity of headache 7 days before, during and 7 days after the interventions. One week before and one day after both interventions, fMRI using flickering light in a block design was applied. Functional activation was analyzed at whole-brain level and habituation of the visual cortex (V1) was modeled with the initial amplitude estimate and the corrected habituation slope. Results Mean interictal photophobia decreased after both interventions, but differences relative to the baseline did not survive correction for multiple comparisons. At baseline, flickering light induced activation in V1 was higher in the patients compared to the controls, but activation normalized after the Flash and the Dark interventions. V1 habituation indices correlated with headache frequency, headache severity and ictal photophobia. In the Flash condition, the individual change of headache frequency relative to the baseline corresponded almost perfectly to the change of the habituation slope compared to the baseline. Conclusions On average, light exposure did not lead to symptom relief, potentially due to the short duration of the intervention and the high variability of the patients’ responses to the intervention. However, the strong relationship between visual cortex habituation and headache symptoms and its modulation by light exposure might shed light on the neurophysiological basis of exposure treatment effects. Trial registration NCT05369910 (05/06/2022, retrospectively registered).

In article number 1902583, Roland Beisteiner and co‐workers describe a brain activation technique for treatment of Alzheimer's disease. Transcranial pulse stimulation (TPS) applies ultrashort ultrasound pulses to activate neuronal resources. A therapeutic breakthrough is secure clinical targeting and access to deep brain areas. After 2 weeks of treatment, memory performance improves for up to 3 months.

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