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"Obyektif: Bunyi frekuensi rendah intensitas tinggi (FRIT) merupakan inovasi stimulasi auditorik yang menggunakan gelombang sinusoidal dengan frekuensi di bawah 100 Hz dan intensitas 110–140 dB SPL untuk memperoleh respons tubuh khususnya otak. Pajanan diberikan dalam kondisi tidur sedasi untuk memperoleh efek yang optimal. Respons dihasilkan akibat resonansi gelombang pajanan dengan irama otak. Kepastian keamanan pajanan ditentukan oleh emisi otoakustik (OAE). Desain studi: Penelitan ini adalah tahap pendahuluan dengan uji coba pada hewan. Metode: Penelitian dilakukan dengan dua tahap, yakni pembuatan instrumen dan eksperimen pada hewan coba. Instrumen stimulasi bunyi terdiri dari generator sinyal yang dibuat khusus, penguat sinyal analog, dan headphones. Eksperimen menggunakan dua monyet (M1 dan M2) jantan dewasa di Pusat Studi Satwa Primata Institut Pertanian Bogor pada waktu yang tidak bersamaan. Masing-masing terdiri dari 3 kali pertemuan untuk adaptasi intrumentasi dan anestesi, kemudian 1 kali pertemuan untuk pajanan bunyi. M1 diberikan sedasi ketamin dan pajanan bunyi 80 atau 40 Hz dengan intensitas 110–140 dB, sedangkan M2 diberikan sedasi propofol dan pajanan bunyi 10 Hz dengan intensitas 110–120 dB. Pengukuran OAE dilakukan setelah peningkatan pajanan per 10 dB SPL. Analisis sinyal dikerjakan secara offline dengan segmen elektroensefalografi (EEG) selama 2 menit. Hasil: Sedasi ketamin menghasilkan daya pita beta rendah EEG yang dominan, sedangkan propofol menghasilkan daya pita delta yang tertinggi. Pajanan bunyi FRIT 80 dan 40 Hz memberikan respons yang bermakna pada nilai spektral EEG dibandingkan tanpa pajanan. Pajanan 10 Hz meskipun tidak bermakna secara statistik, namun memberikan gambaran asimetri alfa frontal pada intensitas 120 dB. Intensitas optimal dicapai pada frekuensi 80 Hz adalah 125 dB SPL, pada frekuensi 40 Hz adalah 130 dB SPL, dan pada frekuensi 10 Hz adalah 120 dB SPL. Perbedaan intensitas berpengaruh pada perubahan nilai spektral EEG. Pajanan bunyi HILF berpengaruh pada nilai OAE, namun tidak mengganggu fungsi pendengaran. Simpulan: Peningkatan daya pita beta EEG diharapkan memperbaiki performa sensorimotorik, sedangkan asimetri alfa frontal EEG meningkatkan motivasi. Pajanan bunyi frekuensi rendah meskipun diberikan dalam intensitas tinggi tidak merusak koklea, justru terjadi hal sebaliknya yang sangat menarik untuk dielaborasi lebih lanjut.

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Objective: High-intensity low-frequency sound (HILF) is a novel auditory stimulation that utilizes sinusoidal waves with frequencies below 100 Hz and intensities of 110–140 dB SPL to elicit a response from the body, particularly the brain. To achieve the best effect, exposure is given while sedated. Resonance between the exposure wave and the rhythm of the brain generates the response. Otoacoustic emission (OAE) is used to ensure exposure safety. Study Design: This is a preliminary study using animal testing. Methods: The study was divided into two stages: instrument development and animal testing. The sound stimulation device includes a custom-made signal generator, an analog signal amplifier, and headphones. Experiments with two adult male cynomolgus monkeys (M1 and M2) conducted at different times at the Center for Primate Animal Studies, Bogor Agricultural Institute. Each comprised of three meetings for instrumentation and anesthetic adaption, followed by one meeting for sound exposure. M1 was sedated with ketamine and exposed to 80 or 40 Hz sounds with an intensity of 110–140 dB, whereas M2 was sedated with propofol and exposed to 10 Hz sounds with an intensity of 110–120 dB. The intensity increase step is 5 dB. OAE measurements were taken following a 10 dB SPL increase in exposure. Two-minute segments of electroencephalography (EEG) signals were analyzed offline. Results: Ketamine sedation provided the most dominant low beta band EEG, whilst propofol produced the most delta band power. Exposure to 80 and 40 Hz FRIT sound resulted in a significant change in EEG spectral values in comparison to no exposure. Despite the fact that the 10 Hz exposure was not statistically significant, it produced a 120 dB appearance of alpha frontal asymmetry. At a frequency of 80 Hz, the optimal intensity is 125 dB SPL, at a frequency of 40 Hz it is 130 dB SPL, and at a frequency of 10 Hz it is 120 dB SPL. Changes in EEG spectral value are influenced by differences in intensity. Exposure to HILF sound has an effect on OAE values but does not impair hearing function. Conclusion: Increasing the power of the EEG beta band is expected to improve sensorimotor performance, whereas increasing the power of the EEG alpha band promotes motivation. Exposure to low-frequency sound, even at high intensity, does not harm the cochlea; on the contrary, the opposite occurs, which deserves further investigation."

"Latar belakang: Halusinasi auditorik verbal (HAV) dialami 70% dari 23 juta penderita gangguan skizofrenia di seluruh dunia. Data pasien skizofrenia di rawat jalan Departemen Psikiatri RSCM/FKUI periode tahun 2016-2017 kasus HAV resisten pengobatan berkisar 25-30%. Tujuan penelitian ini mengetahui abnormalitas spasiotemporal aktivitas neural otak kondisi istirahat yang berhubungan dengan HAV pada orang dengan skizofrenia (ODS) dan peran rTMS dalam memodulasi abnormalitas tersebut. Metode: Penelitian ini dilakukan di Departemen Psikiatri dan Departemen Neurologi FKUI/RSCM selama Maret 2017 sampai Maret 2019 dengan desain uji klinis acak plasebo tersamar ganda. Studi  mengikutsertakan 120 orang yaitu 40 ODS dengan halusinasi, 40 ODS tanpa halusinasi, 20 subjek saudara kandung dan 20 subjek sehat. Kriteria kelompok intervensi rTMS pasien skizofrenia HAV resisten pengobatan usia dewasa 18-59 tahun. Pemeriksaan dimensi temporal dan spasial aktivitas otak keadaan istirahat menggunakan perekaman elektroensefelografi (EEG). Pemeriksaan simtom halusinasi menggunakan instrumen PSYRATS dan uji kemampuan pemantauan-sumber. Dilakukan rTMS 1 Hz 90% AM 1000 pulse di titik T3P3 selama 10 hari berturut-turut. Data klinis pasien diperoleh dari wawancara atau catatan medis. Informed consentdiperoleh dari pasien dan orang tua atau pasangan pasien. Hasil: Ditemukan perbedaan kekuatan amplitudo gelombang theta di prefrontal kiri dan kanan (skizofrenia = 15.19±4.54 mV, sehat= 7.37±2.49 mV, p 0.004), frontal kiri dan kanan (skizofrenia=18.62±17.55 mV, sehat = 9.90±3.77 mV p 0.007), temporal kiri dan kanan (skizofrenia= 6.97±7.26 mV, sehat= 3.59±1.34 mV , p 0.010). Kelompok skizofrenia ditemukan penurunan gandeng-fase amplitudo theta/gamma di frontal-parietal kiri F3-P3 (sehat=28.06, skizofrenia=24.06), frontal-temporal kiri F3-T3 (sehat=30.89, skizofrenia=22.47) dan frontal sentral kanan FP2-C4 (sehat=25.78, skizofrenia=25.00). Didapatkan peningkatan konektivitas fungsional di jejaring mode-standar yang berkaitan dengan kemampuan ODS memantau sumber stimulus. Antara jejaring mode-standar dengan sentral-eksekutif didapatkan korelasi positif di BA 8L-39L (r = 0.792, p = 0.000), BA 29L-40L (r = 0.522, p = 0.032) dan BA8R-39R (r = 0.480, p = 0.004). Korelasi positif abnormal antara jejaring mode-standar dan eksekutif-pusat berhubungan dengan kesulitan ODS membedakan sumber stimulus. Pemberian rTMS 1 Hz menurunkan konektivitas jejaring mode-standar dan menurunkan gandeng theta-gamma yang menghasilkan perbaikan gejala HAV dan kemampuan pemantauan sumber. Simpulan: Pada ODS keseimbangan aktivitas otak istirahat bergeser ke kekuatan frekuensi rendah, demikian juga peningkatan koherensi kortikal. Didapatkan hiperkonektivitas jejaring mode standar, korelasi abnormal antara DMN dan CEN, serta gandeng theta-beta DMN yang berhubungan dengan halusinasi auditorik verbal. Pemberian rTMS bisa memodulasi abnormalitas spasiotemporal tersebut mendekati kondisi normal dan berakibat perbaikan gejala halusinasi. EEG concordance alfa prefrontal frontal otak berpotensi menjadi kandidat penanda biologi respon terhadap terapi rTMS. 

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Background: Auditory Verbal Hallucinations (AVH) occur in 70% of 23 million people with schizophrenia worldwide. According to the 2016-2017 data on schizophrenia patients in the Outpatient Clinic of the Department of Psychiatry RSCM / FKUI, AVH treatment-resistant cases reach about 25-30%. The aim of this study was to determine the spatiotemporal properties of resting brain neural activities that cause changes in perceptions and abnormal space-time experience in people with schizophrenia, which then manifest as auditory verbal hallucinations, and also to determine the role of transcranial magnetic repetitive stimulation (rTMS) on modulating spatiotemporal abnormalities. 

Method: This study was a double-blind placebo-controlled clinical trial conducted in the Department of Psychiatry and the Department of Neurology of FMUI/RSCM  from March 2017 to March 2019. The study included 120 subjects consisting of 40 schizophrenia patients with hallucinations, 40 schizophrenia patients without hallucinations, 20 siblings of the patients, and 20 healthy subjects. The criteria for the rTMS intervention group were treatment-resistant schizophrenia with AVH of 18-59 years of age. Electroencephalography (EEG) was used to examine temporal and spatial dimensions of resting brain activities. The PSYRATS instrument and source-monitoring ability test were used to assess symptoms of hallucinations. Patients clinical data were collected from interviews or medical records. Informed consents were obtained from patients and their parents or spouses.

Results: Differences in amplitude strength of theta fequency were found at the left and right prefrontal cortices (schizophrenia = 15.19±4.54 mV, healthy = 7.37±2.49 mV, p 0.004), left and right frontal cortices (schizophrenia=18.62±17.55 mV, healthy = 9.90±3.77 mV p 0.007), left and right temporal cortices (schizophrenia= 6.97±7.26 mV, healthy = 3.59±1.34 mV , p 0.010). Temporal cortical activities were shifted to low frequency fluctuations, and there were also decreasing relationships between various brain frequencies. The increase of functional connectivity in default-mode networks was found, which relates to schizophrenics ability to monitor sources of stimuli. This abnormal positive correlation between the default mode and the central executives network might disturb schizophrenics ability to distinguish internal stimuli from external stimuli. The administration of 1Hz of rTMS decreases connectivity in default-mode networks and theta-gamma coupling resulting in improved symptoms of HAV and source monitoring capabilities.

Conclusion: In people with schizophrenia, the balance of resting activity shift to low frequency power, as well as increase in its cortical coherence. It also found functional hyperconnectivity in default mode network among schizophrenia patients with HAV and abnormal positive correlation between DMN-CEN. The resting state theta-gamma coupling was increased in patient with schizophrenia that might underlie HAV. The administration of rTMS modulate spatiotemporal abnormalities to near-normal conditions, resulting in the improvement in hallucinatory symptoms. The alpha EEG cordances of prefrontal and frontal cortices has the potential to become a biological marker of response to rTMS therapy."