Safety of transcranial focused

ultrasound stimulation: A systematic

review of the state of knowledge from
both human and animal studies Cristina
Pasquinelli & Lars G. Hanson & Hartwig
R. Siebner & Hyunjoo J. Lee & Axel
Thielscher
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Journal Pre-proof

Safety of transcranial focused ultrasound stimulation: A systematic review of the state

of knowledge from both human and animal studies

Cristina Pasquinelli, Lars G. Hanson, Hartwig R. Siebner, Hyunjoo J. Lee, Axel

Thielscher

PII: S1935-861X(19)30338-9
DOI: https://doi.org/10.1016/j.brs.2019.07.024
Reference: BRS 1536

To appear in: Brain Stimulation

Received Date: 20 March 2019

Revised Date: 24 July 2019
Accepted Date: 29 July 2019

Please cite this article as: Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A, Safety of
transcranial focused ultrasound stimulation: A systematic review of the state of knowledge from both
human and animal studies, Brain Stimulation, https://doi.org/10.1016/j.brs.2019.07.024.

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© 2019 Published by Elsevier Inc.

 Safety of transcranial focused ultrasound stimulation:
A systematic review of the state of knowledge from both human and animal
studies

Cristina Pasquinelli1,2, Lars G. Hanson1,2, Hartwig R. Siebner1,3,4, Hyunjoo J. Lee5, Axel Thielscher1,2,*

1 Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging
and Research, Copenhagen University Hospital Hvidovre, Denmark

2 Center for Magnetic Resonance, Department of Health Technology, Technical University of

Denmark, Kgs. Lyngby, Denmark

3 Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark

4 Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen,
Copenhagen, Denmark

5 School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon,
South Korea

* Corresponding Author
Axel Thielscher, Assoc. Prof.
Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging
and Research, Copenhagen University Hospital Hvidovre, Section 714, Kettegaard Allé 30, 2650
Hvidovre, Denmark.
Tel: + 45-38623326
e-mail: axelt@drcmr.dk
Abstract
Background: Low-intensity transcranial focused ultrasound stimulation (TFUS) holds great promise as a

highly focal technique for transcranial stimulation even for deep brain areas. Yet, knowledge about the

safety of this novel technique is still limited.

Objective: To systematically review safety related aspects of TFUS. The review covers the mechanisms-of-

action by which TFUS may cause adverse effects and the available data on the possible occurrence of such

effects in animal and human studies.

Methods: Initial screening used key term searches in PubMed and bioRxiv, and a review of the literature

lists of relevant papers. We included only studies where safety assessment was performed, and this results

in 33 studies, both in humans and animals.

Results: Adverse effects of TFUS were very rare. At high stimulation intensity and/or rate, TFUS may cause

haemorrhage, cell death or damage, and unintentional blood-brain barrier (BBB) opening. TFUS may also

unintentionally affect long-term neural activity and behaviour. A variety of methods was used mainly in

rodents to evaluate these adverse effects, including tissue staining, magnetic resonance imaging,

temperature measurements and monitoring of neural activity and behaviour. In 30 studies, adverse effects

were absent, even though at least one Food and Drug Administration (FDA) safety index was frequently

exceeded. Two studies reported microhaemorrhages after long or relatively intense stimulation above

safety limits. Another study reported BBB opening and neuronal damage in a control condition, which

intentionally and substantially exceeded the safety limits.

Conclusion: Most studies point towards a favourable safety profile of TFUS. Further investigations are

warranted to establish a solid safety framework for the therapeutic window of TFUS to reliably avoid

adverse effects while ensuring neural effectiveness. The comparability across studies should be improved

by a more standardized reporting of TFUS parameters.

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Keywords: transcranial focused ultrasound, TFUS, safety, histology, review

3/42
Introduction
Weak Transcranial Focused Ultrasound Stimulation (TFUS) aims to modulate neural activity by delivering a

focused ultrasonic beam to a small target area in the brain. Currently, interest in TFUS is strongly increasing

as it holds the promise of a far better spatial resolution than established non-invasive stimulation

techniques and of the ability to reach deep brain areas [1]. This might open up intriguing new applications

such as epilepsy treatment or pre-surgical diagnostics prior to electrode implantation for deep-brain

stimulation [2, 3]. TFUS is also attractive because it can be readily combined with neuroimaging modalities

such as functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) without

interfering with the recordings, as it applies acoustic waves rather than electric or magnetic fields.

Firmly establishing its safety profile is a central requirement when aiming to move TFUS from initial pilot

studies towards broader testing in humans in-vivo. Reviews on safety and bio-effects of ultrasound (US) in

diagnostics [4] and therapy [5] as well as guidelines for the clearance of commercial diagnostic and

therapeutic US systems as medical devices [6] are available and constitute a benchmark to avoid harmful

effects also for TFUS. Relating the TFUS parameters to these guidelines, as done in many of the published

studies, might be considered a conservative choice. However, several aspects put TFUS in a special position.

TFUS usually employs lower frequency compared to diagnostic ultrasound (usually upper kHz range vs.

MHz) and longer pulse bursts. TFUS has a static focus so that the total energy delivered at the focal point

can be higher than the maximal local energy deposit for diagnostic US, as the latter uses scanning

approaches. The mechanism-of-action of TFUS is still poorly understood, rendering it more difficult to

principally exclude harmful effects. In addition, current findings about the dose-response curve of TFUS [7]

suggest that future therapeutic applications might aim to use intensities above the safety limits for

diagnostic US in order to increase the robustness of the neural effects. Such a choice requires solid

knowledge about the safety margin of TFUS. Along similar lines, accurate dose control for human TFUS is

complicated by the presence of the skull, which strongly attenuates the beam. The attenuation depends on

the individual skull thickness and composition [8], which are difficult to account for and lead to

4/42
conservative intensity choices with an increased risk of underdosing. If the safety margin of TFUS is not well

established, the use of more lenient dosing strategies to mitigate this problem is not feasible.

There is a pressing need to establish specific safety guidelines for TFUS. Yet, the current knowledge about

the risk-benefit ratio and the therapeutic window of TFUS is still rudimentary because TFUS is at an early

stage of development. Indeed, no dedicated phase I safety human study has been performed so far, but the

safety profile needs to be systematically investigated and monitored to ensure the patients’ safety.

However, relevant information is already available today, because some of the published studies on TFUS in

animals or humans included safety-relevant tests. Here, we systematically summarize these findings to give

an overview of the current state of knowledge about TFUS safety. We start by describing the relevant

physical parameters used to characterize the TFUS stimulus. We then shortly describe the known physical

mechanisms by which ultrasound can cause tissue damage and we introduce the established safety indices,

based on the beam parameters. Finally, we introduce the methods that have so far been applied to test for

adverse effects of TFUS, and list the corresponding results. In the discussion, we summarize the

implications of the available findings for in-vivo human TFUS applications.

Material and Methods

Literature review on the safety of TFUS

For this systematic review, we followed the PRISMA guidelines [9, 10]. Details on the implementation of the

PRISMA requirements in our review are stated in the Supplementary material (Table S1). Our review was

based on searches in PubMed (www.ncbi.nlm.nih.gov/pubmed) and bioRxiv (https://www.biorxiv.org/) for

published and pre-published studies, using the keywords ‘tFUS’, ‘LIFUP’, ‘noninvasive brain stimulation

focused ultrasound’, ‘neuromodulation brain transcranial ultrasound’, ‘focused ultrasound transcranial

brain stimulation’ and ‘pulsed ultrasound brain stimulation’. The eligibility criteria were low intensity, low

5/42
frequency TFUS in the brain of animals or humans with safety assessment, without use of microbubbles.

Additional sources were reviews of the literature lists of relevant papers, and papers pointed out by the

reviewers during the peer-review process. Figure 1 shows details of the literature search. The last

complete search was performed in January 2019 by one of the authors, and the last update was done in

June 2019. From each paper, the sonication parameters and the methods used to assess safety and adverse

effects were extracted as shown in Table 2 and Table 3 and categorized as described further below. Often,

only some of the safety indices were reported. In that case, we give estimated values when possible.

Mechanism of ultrasound neuromodulation

Despite many hypotheses, the exact underlying mechanism of neuromodulation using low-intensity

ultrasound is yet to be understood [11]. The initial hypotheses for the ultrasound neuromodulation were

thermal effects and acoustic cavitation. While an increase in the tissue temperature could perturb neuronal

activity levels, the temperature increase due to low-intensity ultrasound is often less than 0.1°C. Thus, the

thermal effects of low-intensity ultrasound are most likely negligible. The second hypothesis is based on

acoustic cavitation. This hypothesis postulates that the ultrasound generates nanobubbles in the lipophilic

zone of the plasma membrane, which then vibrates according to the pressure variations, alters the local

curvature of the bilayer, and changes overall neuronal excitability [12]. However, since nanobubbles are

formed at an intensity larger than 100 mW/cm2, generation of micro or nanobubbles at the intensity used

in standard neuromodulation protocols must be confirmed. The recent hypotheses now focus more on the

effects of acoustic radiation forces on the permeability of the ion channels, such as mechanosensitive

channels [13] and voltage-gated calcium, sodium, and potassium channels [14]. Another kind of hypotheses

includes plasma deformation, which postulates that vibration of surrounding extra- and intracellular

environment evokes mechanical changes in either the plasma membrane tension or the lipid bilayer and

modulates neuronal activities [14].

6/42
Contrary to these works on the mechanisms involved with direct modulation of ion channels and

membranes, an indirect in vivo ultrasound neuromodulation through auditory or cochlear pathways has

been also recently proposed [15, 16]. These studies demonstrated that ultrasound-induced activities were

eliminated or reduced upon transection of the auditory nerves or removal of cochlear fluids. These results

raised an important question of whether direct activation of neurons in the intact brain is possible. While

more in-depth studies on the experimental protocols such as sharpness of the pulse, pulse repetition

frequency, and bone transduction must be performed, these studies underscore the need for a solid

understanding of the underlying mechanism of ultrasound neuromodulation [16].

Physical parameters and safety indices of US waves

A sketch of an experimental setup for TFUS is shown in Figure 2A, using the stimulation of a rat as

example. The main indices used to assess safety are:

• (spatial peak temporal average intensity) is the temporal average intensity, calculated at the

position of the spatial maximum

• (spatial peak pulse average intensity) is the pulse average intensity, calculated at the position

of the spatial maximum

• (mechanical index) gives an estimation of the likelihood of inertial cavitation

• (thermal index) is the steady-state temperature increase in soft tissue during ultrasound

sonication

• (thermal index for cranial bone) is a modification of TI, when the skull is close to the transducer

face

Ispta, TI and TIC are related to the risk of thermal bio-effects, while Isppa and MI are related to the risk of

cavitation. The upper limits for these five indices allowed for diagnostic ultrasound are shown in Table 1. It

should be noted that another guideline, IEC standard 60601-2-5 for physiotherapy US equipment, sets an

7/42
upper limit for the “effective intensity’’, defined as the ratio of acoustic output power to effective radiating

area, of 3 W/cm2. The standard also states that this value should only be reached for short times to prevent

substantial heating. The “effective intensity’’ of 3 W/cm² is usually interpreted as the upper limit for Ispta

[17, 18, 19]. Lee and colleagues [17] compare the intensities used in their study against this limit rather

than using the FDA guidelines for diagnostic US. Complementary to TI, the temperature increase at the

target can be calculated as ∆ (equation 7 and 8 in Supplementary material) or through the bio-heat

equation [20, 21, 22]. A more detailed explanation of these indices and formulae can be found in the

Supplementary Material.

Mechanisms underlying tissue damage by US

Ultrasound waves may cause harmful effects on tissues via two physical mechanisms, mechanical and

thermal. The main mechanical effect is cavitation, in which vapor cavities (or “bubbles”) form in the soft

tissues during the periods of low pressure (i.e. the minima) of the acoustic wave cycles. Depending on

intensity and center frequency, this can result in a stable oscillation (stable or non-inertial cavitation) or can

result in violent bubble collapses (inertial cavitation) that create large forces in their neighborhood. The air

bubbles can have an endogenous origin (for example in the lungs or intestine), or they can be created by

the mechanical wave itself, if the peak rarefaction pressure (i.e. the pressure during the minima) is small

enough to allow the liquid to reach vaporization. Alternatively, ultrasound contrast agents (UCA), which

contain microbubbles, can be injected for, e.g. clinical purposes [23] or gene and drug delivery [24].

When a mechanical wave propagates linearly in a medium, its amplitude decreases exponentially starting

from the source. The attenuation is caused by both scattering, i.e. the change in the direction of wave

propagation due to the presence of microscopic obstacles along the beam, and absorption. Absorption is

the process by which the wave energy is converted into heat, and therefore the medium is heated. Several

ways to model or monitor the resulting temperature increase in the medium exist, and they will be further

discussed below.

8/42
Types of adverse and side effects caused by TFUS

In this section, we summarize the potential adverse and side effects, which have so far been tested in TFUS

studies, and briefly outline the employed techniques to assess the occurrence of these effects. The majority

of results were obtained in animal studies, which tested for the following effects:

• Blood-brain barrier (BBB) opening: The BBB is a semi-permeable membrane formed by endothelial cells

which separates the vessels and the central nervous system (CNS) [25]. Air bubbles subjected to

cavitation can break the BBB. Exploiting this effect, TFUS combined with US contrast agents is tested as

a method for targeted drug delivery [26] . However, BBB opening is undesired for normal TFUS.

Assessing BBB integrity is usually based on the intravenous injection of a substance, which cannot cross

the barrier under normal conditions, prior to sonication. It is then tested whether TFUS causes the

substance to diffuse into brain tissue. The dyes fluorescein isothiocyanate-dextran (FITC-dextran) [27],

trypan blue [28, 29, 30] or Evans blue [31] have been used for this purpose, and their presence inside

the brain was investigated in post-mortem microscopy analyses of brain slices. Alternatively, an MRI

contrast agent (a gadolinium chelate) was injected before the stimulation and its penetration into brain

tissue was tested by assessing the MRI signal change due to the contrast agent [29].

• Bleeding: The occurrence of bleeding has been investigated using tissue staining, in particular

hematoxylin and eosin (H&E) staining [28, 32, 33, 2, 19, 34, 35, 36, 37, 38, 22], which reliably stain

blood cells. Yet, H&E staining is not specific to blood cells and thus requires experience to correctly

interpret the results.

• Cell death and damage: A general approach to qualitatively analyze the presence of cell death and

damage is through H&E staining [28, 2, 34, 29, 35, 32, 30, 39, 33, 21, 19] [36, 37, 38, 40, 22], as

described above, cresyl violet Nissl staining [22], or luxol fast blue dye (LFB) [21], used to identify

9/42
myelin in nervous tissue. Cell death can be of two types, apoptosis and necrosis. While apoptosis is part

of the normal life cycle of the cells, necrosis is harmful and triggered by external factors or disease. It is

possible to differentiate between both types of cell death based on morphological criteria, but this

requires experience [41]. Additional techniques specifically label apoptotic cells and have therefore

been used to distinguish between apoptosis and necrosis. For example, the presence of fragmented

DNA is a sign of apoptosis, and not necrosis, and it can be labeled by terminal deoxynucleotidyl

transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay [29, 2]. Alternatively, since apoptosis is

mediated by caspase [42], standard immunocytochemistry techniques with antibodies against cleaved

caspase-3 can be used [27, 30].

An alternative approach to detect cell damage is staining for acidophilic cells, for example with VAF

(vanadium acid fuchsin) [30, 43]. Acidophilia refers to the property of cells of staining readily with an

acid dye and occurs after acute neuronal damage and death in brain ischemia.

Finally, also transmission electron microscopy has been used to quantitatively observe the effect of

ultrasound on brain ultrastructure (postsynaptic density, docked vesicles, etc.) [27]. It has been shown

that neural trauma causes an abnormal increase in the number of astrocytes [44] that can be detected

by the expression of GFAP (glial fibrillary acidic protein) [31, 30, 39]. One study assessed possible

permanent tissue damage after sonication in rats using MRI [39].

Irreversible changes of neural activity: Recordings after the sonication can determine whether changes

in neural activity are reversible and characterize the duration of recovery. The effects on local neural

activity in the TFUS target region can be detected directly via invasive recordings or voltage sensitive

dyes [31] or Ca2+ imaging in transgenic mice that express the green fluorescent calcium indicator [31].

TFUS-related changes in extracellular concentrations of excitatory and inhibitory neurotransmitters

such as glutamate and λ-aminobutyric acid (GABA) can be measured via microdialysis techniques [37].

TFUS has also been combined with measurements of the forelimb and hindlimb responses to epidural

cortical stimulation (ECS) to assess the cortical excitability changes after sonication [45]. Alternatively,

10/42
 electroencephalography (EEG) [29], functional MRI [22, 46], PET [32], measurements of peripheral

muscle evoked potentials (MEP) [47], sensory evoked potentials (SEP) [48], somatosensory evoked

potentials (SSEP) [21], visual evoked potentials (VEP) [49] or auditory evoked potentials (AEP) [39] give

non-invasive but less specific measurements of neural activity changes.

• Undesired changes in animal behavior: TFUS may affect normal behavior in unintended ways. In

animals, this is controlled by monitoring of every day behavior, like food uptake, defecation and

movement behavior and checking for signals of pain and distress or change in weight [28, 34, 29, 32,

30, 33, 45, 50]. In addition, tasks such as the rotorod task and wire-hanging task allow for quantitatively

assessing the impact of TFUS on specific aspects of behavior [27]. One study induced ischemic stroke in

mice and compared the behavioral changes of the mice which were treated with TFUS via a balance

test and an adhesive removal test [19].

Adverse effects can be caused by cavitation or tissue heating. As outlined above, cavitation is prevented by

controlling the pressure levels. While the temperature increase in the brain can be roughly estimated using

Equations (7) and (8) in the Supplemetary Material [19, 27, 51, 35, 17, 34, 30, 48], some studies inserted a

thermocouple [27, 28, 48, 33, 45] or an optical fiber based thermal sensor [36] in the brain of the animal

after craniotomy to track the temperature change in real time during sonication. A non-invasive alternative

to this approach is measuring the temperature increase with thermocouples in a phantom [33], or MR

thermometry [29, 52, 39, 21], which exploits temperature sensitive MR parameters such as the water

proton resonance frequency, or T1 and T2 relaxation times [53].

So far, most TFUS studies used animal models. Tests for adverse effects in the few human studies were

based on neurological examinations and/or structural MR imaging before and at one or several time points

after the experiment [51, 17, 54]. In some of the studies, the participants were additionally contacted by

telephone 2 months after the experiment and interviewed about any changes in their mental and physical

health status, including experiences of any discomfort [51, 17]. A pre-print manuscript [55] presents results

11/42
of phone interviews based on a ‘Participant report of symptoms questionnaire’ of 64 participants who had

participated in one or more of seven human TFUS experiments before.

Results

Studies screened in this review

This systematic review follows PRISMA guidelines [10, 9], and the PRISMA checklist can be found in the

Supplementary Methods (Table S1). The reviewing process shown in the PRISMA diagram Flow (Figure 1)

resulted in the selection of 31 peer-reviewed and 2 pre-published studies included in this review. From

each of those papers (a complete list with citations is shown in Table 2), the sonication parameters (Table

2) and the methods used to assess safety and adverse effects (Table 3) were extracted and categorized as

described further below. Often, only some of the safety indices were reported. In that case, we give

estimated values when possible. The risk of bias was assessed and is reported in a separate section in the

Supplementary Material.

BBB opening

BBB opening did not occur in any of the included studies [28, 29, 30], except for two cases where it was

intentionally provoked in control conditions [31, 27], using a high Isppa of 280 W/cm2 [31] or an ultrasound

contrast agent [27].

Bleeding

Several studies [28, 32, 33, 2, 19, 36, 37, 38, 22] tested for bleeding, without finding evidence for it. A

further study [34] tested different sonication parameters on eight sheep in total, and reported four animals

with micro-hemorrhages in the primary visual cortex after undergoing 600 sonications at 6.6 W/cm2 Isppa (6

repetitions of 100 sonications, with 30 s gaps). While the reported value for Isppa is within FDA limits, our

calculated value for Ispta of 3.3 W/cm2 is exceeding the diagnostic limit, and is also slightly higher than the

12/42
limit for physiotherapeutic US of 3 W/cm2. Interestingly, a sheep undergoing a single sonication at an Isppa of

13.4 W/cm2 did not present micro-hemorrhages. In another study [35], 1 of 37 rats was exposed to a high

intensity (11.2 W/cm2 Ispta) for a short period of time (< 9 s using 1 ms TBD, 50% duty cycle and 300 ms SD).

It exhibited several areas containing hemosiderin, which indicate the potential of local bleeding, while none

of the other animals showed any sign of bleeding.

Cell damage or death

Most of the studies testing for cell damage or death [28, 2, 34, 29, 35, 32, 27, 19, 30, 39] [33, 21, 36, 37, 38,

40, 22] did not observe harmful effects of TFUS. One recent study [31] observed no differential GFAP

expression between the control and sonicated hemisphere for Isppa = 0.69 W/cm2, suggesting the absence of

neural trauma. However, an increased number of astrocytes was observed for a control condition with

Isppa=280 W/cm2 (~ 1.5 times above the FDA limit). Interestingly, no damage was observed even when AEP

was not fully recovered after one month [39] in rats.

Long-term change of neural activity

Yoo et al [29] tested parameter ranges for excitatory and inhibitory TFUS effects in craniotomized rats.

While excitatory effects were very short-termed, suppression effects lasted several minutes. A reduction in

the EEG response of up to 80% and a corresponding reduction of the BOLD signal that both lasted up to 10

minutes were reported for a long sonication duration of 9 s. Dallapiazza et al. [21] observed peak

electrophysiological suppression in SSEP 5 minutes post-treatment, and the values returned to near

baseline within 20 minutes. A further study [31] tested the facilitatory effects of ultrasound on

somatosensory evoked potentials by measuring the changes in fractional fluorescence in the brains of mice

dyed with voltage sensitive dyes. The TFUS-related changes disappeared within 20 minutes after ultrasound

stimulation. Yang et al. [37] observed a decreased extracellular GABA level (approximately 20% below

baseline) compared to a control group that lasted up to 100 minutes after the sonication ended. The same

effect was not observed for glutamate. Gulick et al. [45] showed that TFUS significantly suppressed forelimb

13/42
and hindlimb responses to ECS for several minutes after the stimulation blocks, even though effects

immediately after single, short TFUS trials were absent. Kim et al. [32] observed a local increase in glucose

metabolism induced by FUS to rat brain. This effect was demonstrated via PET imaging, which was started

20 minutes after the sonication and performed for 1 hour. After that time, the metabolism had still not

returned to baseline. In a work [22] on primates, the authors observed change in functional connectivity

after a long sonication of 40 s at ISPTA=7 W/cm². The change lasted for more than one hour after sonication.

A similar effect was observed in a related work [46], where they used a sonication of 40 s at a maximum Ispta

of 15.3 W/cm2. Yoo et al. [48] observed that the SEP signals after 10 minutes sonication were distinctively

different compared to the control condition, even 35 min after the sonication. Daniels et al. [39] observed a

full recovery of AEP amplitudes in rats within maximum 1 week post-treatment with Isppa = 2.3 W/cm2, while

the signal from 5 out of 10 rats recovered up to one month post-treatment for an Isppa = 4.6 W/cm2. In the

same study, 1 out of 5 pigs showed a fully recovered signal 1 hour post-treatment while the other did not

show any recovery 3 hours post-treatment (in all 5 cases, Isppa = 4.6 W/cm2). Kim et al. [49] observed an

increase in VEP in rats up to 5 minutes post-treatment with Isppa=5 W/cm2 and a slight increase of VEP 150 s

after treatment when Isppa=3W/cm2. One study [19] induced ischemic stroke in mice and found a better

sensorimotor performance in mice that underwent 20 minutes TFUS session via a balance test and an

adhesive removal test. These improvements lasted for 4 weeks after treatment, suggesting an

enhancement in brain plasticity. In the same study, the TFUS treatment in cerebellar LCN significantly

lowered the percentage change in increased water content and tissue swelling in the ipsilateral hemisphere

to the stroke.

Animal behavior

Several studies tested for changes from normal daily behavior after the sonication studies [28, 34, 29, 32,

30, 33, 45, 50], but did not find any abnormalities. A single study also employed behavioral tasks [29]

(rotorod running task and wire-hanging task), without revealing differences in motor performance.

14/42
Temperature

Theoretical calculations based on Equations (7) and (8) in the Supplementary Methods suggest that

“typical” TFUS parameters used so far in most studies cause negligible temperature increases in brain tissue

[19, 27, 51, 35, 17, 34, 30, 48]. In a recent study [22], this was partly confirmed using the more realistic bio-

heat equation to estimate the temperature increase after 40 s of TFUS through a 3 mm thick skull, with an

Ispta=7 W/cm² in the brain. The maximal increase in the brain was less than 0.2°C. Interestingly, however,

they found rather strong increases in the skull (2.8°C). Also experimental results show mostly only small

temperature increases due to sonication [27, 28, 48, 33, 36]. However, it is important to note that the

overall temperature increase depends on the combination of several TFUS parameters. For example, one

study [36] reported a measured peak temperature increase of 0.2° C for an extended stimulation (~30 min)

at a low Ispta≤230 mW/cm² at 1 MHz (1.6° C at 5 MHz for otherwise same parameters). In contrast, another

study [45] reported a temperature increase up to 3° C after two blocks of 5 minutes stimulation at 200 kHz,

separated by a 2 minutes break, at Ispta = 4.5 W/cm2 and a MI=3.1 (higher than the allowed limit). Both

studies applied longer durations than used in most other TFUS studies so far, but the combination with the

higher Ispta caused noticeable temperature rises in the second study.

A temperature increase of 0.5° C was reported through MR thermometry after 30 s sonication at Isppa = 9.9

W/cm2 [52]. Another study [39] reported temperature variation within the measurement noise level of the

baseline temperatures (±2°C) with MR thermography. The strongest effect was reported by a study using

MR thermometry (sensitivity 0.3±0.06°C [29]), demonstrating an increase of ~0.7°C in the sonicated area

[29], using an Isppa=23W/cm2 for 27 s. Dallapiazza et al. [21] showed a negligible temperature increase

during treatment using both MR thermometry and estimations based on the bio-heat equation.

Findings from human studies

In a recent preprint work [47], the authors tested the effects of ultrasound stimulation on motor cortex

excitability measured by single-pulse transcranial magnetic stimulation (TMS). They report significant

15/42
changes in the recorded muscle responses to TMS only when it was applied during, but not after,

sonication. Follow-up neurological exams and anatomical MRIs after the TFUS experiment did not reveal

any abnormalities or changes in the mental or physical status, nor any discomfort associated with the

procedure [51, 54, 17]. Follow-up interviews at later time points confirmed those observations. A recent

study published as preprint [55] presents results from a follow-up questionnaire after TFUS that could be

obtained from 64 out of in total 120 participants. Seven subjects reported mild or moderate symptoms

(mild neck pain, scalp tingling, headache, difficulty paying attention, muscle twitches and anxiety) that they

felt were possibly or probably related to the experiment. These initial symptoms disappeared upon follow-

up. The authors found a linear correlation (r=0.797, p=0.0319) between Isppa and the occurrence of

observed symptoms among the 7 subjects who reported mild to moderate symptoms that were perceived

as ‘possibly’ or ‘probably’ related to participation in TFUS experiments.

Discussion and Conclusions

Harmful effects of TFUS were absent in the majority of the 33 studies reviewed here. In two cases,

microhemorrhages occurred in a subset of the tested animals when using a high Ispta of 11.2 W/cm2 for a

short duration [35] or an Ispta of ≥3.3 W/cm2 for a high number of sonications (≥500) given at a relatively

short ISI of 1s [34]. Both doses are clearly above the safety limits of the FDA guidelines for diagnostic US

and above the IEC standard 60601-2-5 for physiotherapy US equipment. However, this also holds for

several other included studies, where no adverse effects were reported. While the parameters chosen in

one of the studies [35] did not result in substantial heating, as also pointed out by the authors, the high Ispta

of 11.2 W/cm2 differentiates it from many other TFUS studies. That might indicate that mechanical effects

caused the microhemorrhages, even though the limits for MI and Isppa were not exceeded. However, as this

was observed in only one of the tested animals, this conclusion remains very speculative and a replication

including sham controls would be favorable to ensure that the microhemorrhages were indeed related to

16/42
TFUS. In the second study [34], the chosen parameter combination might have led to a high total energy

deposit, opening the possibility that a thermal mechanism underlay the adverse effects that occurred in

four animals. For example, Gulick et al. [45] observed a temperature increase of 3°C for a less intense

protocol using an Ispta = 4.5 W/cm2 and in total 180 sonications in a time period of 13 minutes. It seems

reasonable to assume that heating might have been even higher in the four animals that showed

microhemorrhages in [34] and indicates that calculating the temperature increase for a single sonication, as

done in [34], can strongly underestimate the real increase.

While Isppa stayed below the safety limit in all studies, MI exceeded the limit in two studies [45, 46] and Ispta

exceeded the FDA limits for diagnostic US in soft tissue in 14 out of the 20 studies in which Ispta was

reported or could be calculated post hoc (values after cranial transmission or for craniotomized animals).

Ispta was also above the physiotherapeutic limit in 11 of the 20 studies. This suggests that Ispta is the most

sensitive safety index in case of TFUS and, unlike current practice, should be reported so that it can be

followed up by a more detailed estimation of the thermal effects when its limits are exceeded. We consider

this relevant as the current studies indicate that TFUS parameters within the FDA limits for diagnostic US

might often lack neural stimulation effectiveness. For example, an Ispta of around 2 W/cm2 for pulsed waves

and 4 W/cm2 for continuous waves was necessary to reach a 50% success rate for stimulation at 500 kHz

[7]. Similarly, while many studies included in this review reported neural effects for parameters within the

safety limits [31, 27, 56, 48, 52, 33, 49, 19, 2], several studies found stable effects only when exceeding at

least one of the safety indices ( [28, 34, 29, 35, 30] and Table 2). In addition, recent studies show that

heating of the skull (potentially causing indirect heating of soft tissue) and/or brain tissue can reach several

degrees for more intense and long protocols [22] [45]. The systematic assessment of heating will thus be

relevant in future studies that might aim at extending the parameter envelope of TFUS and should be part

of any safety test of new sonication regimes in particular for human TFUS.

17/42
It is worth noting that the safety limit of 720 mW/cm² for Ispta, which was generally used in TFUS studies so

far and which we also applied here, was introduced to limit the heating in soft tissue. In case of transcranial

US, the FDA limits for diagnostic US actually apply an even stricter limit of 94 mW/cm² for Ispta to prevent

excessive heating of the skull, which absorbs most of the beam energy. It seems that almost none of the

studies published so far reported neural effects for intensities below this threshold. However, it is

important to stress that both limits are based on worst-case scenarios and exceeding them does not

necessarily mean that strong heating occurs. Rather, the FDA standard for diagnostic US requires a case-by-

case estimation of the maximum temperature rise in soft tissue and skull once they are exceeded, specific

for the used ultrasound parameters and setup. Simulations of the propagations of the TFUS beam through

the skull, combined with evaluations of the bio-heat equation for TFUS [22], might be valuable tools that

allow realistic estimates of the amount of heating for new sonication regimes on a more standard basis.

The neural aftereffects can exceed one hour [22, 32, 46], making TFUS a potent neuromodulation modality.

This is encouraging for therapeutic applications. In contrast to diagnostic US, future TFUS applications

might resort to repeated sessions over extended time periods to achieve and maintain therapeutic efficacy.

As such, a safety framework will also need to cover these more intense settings (see, e.g. [57, 58] for a

related example of adverse effects that only occurred after repeated applications in case of transcranial

direct current stimulation) or combinations of TFUS with other brain stimulation techniques. This will

require safety studies that specifically test this parameter space in order to inform an international

consensus on accepted settings and procedures, similar to established non-invasive brain stimulation

methods [59]. Along similar lines, in the few TFUS studies performed in humans so far, the type and extent

of follow up exams differed strongly [55, 51, 54, 17]. This suggests a need for guidelines that provide a

secure framework for experimental settings and practical procedures, including mandatory safety screening

and appropriate follow-up procedures. For example, the importance of establishing best practices also for

apparently simple procedures was highlighted in a recent review [60] of low-intensity low-frequency US

18/42
(20-100 kHz), showing that US can cause skin damage due to inertial effect cavitation in the coupling gel if

non-degassed gel is employed.

Along similar lines, guidelines are important to prevent intensity hotspots that can occur due to unintended

standing waves and focusing effects of the skull. While these effects more likely emerge in small animals

[50], they have been shown to be also relevant in non-human primates for targets close to the skull base

such as the amygdala [46]. Moreover, a retrospective modeling study [61] suggests that unwanted

secondary hotspots might have been the cause of intracerebral hemorrhages that occurred in a clinical trial

on transcranial low frequency ultrasound for sonothrombolysis [68] and that resulted in the early

termination of the trial. Finally, the reviewed studies differed in regards to the choice of the stated safety-

relevant parameters and the way those were assessed. A more standardized reporting of the relevant pulse

parameters and of all safety indices of the FDA guidelines is a prerequisite for the development of future

TFUS guidelines for human applications. Accurate estimation of the TFUS intensity after cranial

transmission is particularly challenging in humans, as it has to rely on hydrophone measurements based on

“representative” skull samples or computer simulations [62, 51, 17]. The uncertainty range of the intensity

estimates obtained by these procedures seems still unclear [63, 64], and contributes to variations in the

values reported across studies. As such, it seems useful that future studies additionally state intensity

values for a pure water background to ensure good comparability of the baseline TFUS parameters.

Conflicts of interest
None declared.

Acknowledgements
We thank the anonymous reviewers for their helpful comments. CP was supported by a PhD stipend of the

Technical University of Denmark. HRS holds a professorship in Precision Medicine at the Institute of Clinical

19/42
Another random document with
no related content on Scribd:
[Contents]

VII. Jewish Life.

The first paragraph of the Shulchan-aruch runs thus: “ ‘I have set the
Lord always before me’ is one of the most important principles of our
holy Religion;” and, indeed, the more the actions of the Jew conform
to this principle, the nearer does he approach the ideal of a true
servant of God, who is faithful in the service of his Master, and
whose life is the expression of genuine recognition of God’s
sovereignty (‫‏קבלת עול מלכות שמים‬‎) with unconditional obedience to
His Will (‫‏קבלת עול מצות‬‎). Neither attendance at Public Service, nor
the regular recitation of prayers, nor the study of the Law, nor the
performance of certain religious acts, constitute by themselves
Jewish Life, but the supreme influence which the Word of God—the
Torah—is constantly made to exercise over man’s doings. Every
movement of his is regulated by the Law, and wherever he turns he
is met by a Divine precept that elevates his heart towards Him who
gave us the Law. The very garments he wears, though not different
from those of his fellow-men, 144 except by the [468]absence of
shaatnez (combination of wool and linen), include the arba kanfoth,
“the four-cornered garment,” with tsitsith; his house, the same in
every other respect as those of his neighbours, is distinguished by
the mezuzah on the doorposts. These distinctive characteristics,
however, are not intended to attract the attention of others; they only
concern the man himself; they serve him as reminders of God and
His Will. Within the house the furniture and the whole arrangement
are in accordance with the custom and fashion of the place; 145 there
is simplicity or luxury, taste or want of taste, according to the
individual character of the occupier. Only the kitchen and the table
have a distinctly Jewish aspect; these must be adapted to the
requirements of the Dietary Laws. The most striking feature is the
double set of kitchen utensils and of vessels for the table, the one
set for meat, the other for butter and milk.

In the choice of his occupation, trade, or profession, the Jew, like all
his fellow-men, is influenced by his [469]inclination, capabilities, and
opportunities; but, in addition to these, there is another important
factor that must ultimately determine the choice—his religion; and
such occupation as would be likely to compel him to abandon any of
the Divine precepts, cannot be chosen. No manner of labour or trade
is in itself derogatory; on the contrary, all labour is honourable,
unless man degrades it by his conduct, and by the object he aims at
achieving by means of it. Thrift, economy, and temperance are
essential conditions of success. But success, however desirable,
and however sweet when obtained, leads only to the material well-
being of man. As to his spiritual well-being, the Jew, though busy
with urgent work, will try to find some spare moments in which to turn
his attention to “the three things upon which the world is based:
Study of the Torah, Divine Service, and Charity” (Aboth i. 2).

Before the work of the day commences, and when it is finished,

attention is paid to torah and abhodah. The Service, especially the
Morning Service, contains various sections which are not prayers,
but rather lessons for study. In addition to these, the Jew, according
to his capacity or opportunity, should read the Bible, the Mishnah,
and the Talmud. For those who have no opportunity at home, the
Beth ha-midrash is open with its library. Synagogue and Beth ha-
midrash are the places of spiritual recreation where the Jew
refreshes his mind, elevates his heart, and gathers new strength,
courage, and hope for the battle of life.
Charity in its various branches, tsedakah and gemiluth chasadim, is
a virtue practised by the wealthy and the poor alike. Any heart or
house from which this [470]virtue is absent does not deserve to be
called Jewish. Some Jews have charity-boxes in their houses, and
whenever any member of the family has something to spare or is
moved by a special impulse of charity, these boxes receive an
addition to their contents. Others imitate the law of maaser (“tithe”),
and set aside a tenth part of their earnings and profits for charitable
purposes. Hospitality (‫‏הכנסת אורחים‬‎) is another method of charity,
and it forms one of the ornaments of a true Jewish house. Although
societies and public institutions do at present what was formerly
considered to be the duty of the members of the community,
individual hospitality has by no means become superfluous, and
there is ample opportunity for its practice. Hospitality graces
especially the lady of the house; it is her duty to provide for the
comfort of the guests, and to act according to the rule, “Let the poor
be the children of thy house” (Aboth i. 5).

This is one of the privileges possessed by women. According to the

principle of division of labour, woman rules supreme in the house:
“The King’s daughter is all glorious within” (Ps. xlv. 14); whilst man is
more in contact with the outer world, devotes himself to labour, trade,
or profession in order to provide the necessities of life for those who
are dependent upon him. There are, however, many exceptions to
the rule, and there is scarcely any trade or profession in which
women have not been engaged. Women were not excluded even
from the highest honours. The Jews had their prophetesses, and
women were entrusted with judgeship and even with sovereignty.
There are instances of women distinguished by learning, experience,
[471]wit, and especially by piety. Women of piety (‫‏נשים צדקניות‬‎) were
never wanting in Israel; and many a scholar owes the success he
has attained in the field of learning to the piety of his wife, who
willingly undertook her husband’s burdens and cares in trade and
business in order to facilitate his devotion to study. No sacrifice is too
great for a true Jewish mother to have her children instructed in the
Word of God, and nothing adds more to the happiness and pride of
the mother than the progress her son has made in the knowledge of
the Torah. “What is the great merit of women? They have the merit of
making their children attend the school, and of encouraging their
husbands to study the Talmud” (Babyl. Talm., Berachoth 17a).

The moral and the intellectual as well as the physical training of the
children is in its earliest stages almost exclusively in the hands of the
mother. If we add to this the responsibility for having the food
prepared according to the requirements of the Dietary Laws, we
easily understand the reason why Jewish women are exempt from
various religious duties incumbent on the other sex. The rule is this:
“Women are exempt from the fulfilment of all precepts which are
restricted to a certain time” (Mishnah, Kiddushin i. 7), in order to
prevent any collision between these and her principal and most
important duties in the house. Thus it happens that there are Jewish
women who faithfully cling to the inherited religion, and yet are rare
visitors of the Synagogue. On week-days the Synagogue is only in
exceptional cases attended by women. [472]

From this reason women are disqualified for forming the quorum
(minyan) required for public worship (tefillah batsibbur). This and
similar disqualifications are based on the principle of regard for
women and their home-duties, and by no means on a belief in their
inferiority. Passages in the Talmudical and Midrashic Literature which
ascribe to women vanity, levity, and other shortcomings are
outweighed by sayings which evidence a sense of high regard for
the virtues and accomplishments of women. The following sentences
are a few examples; “Woman has been endowed by the Creator with
greater intelligence than man” (Babyl. Talm., Niddah 45b). “Who is
rich? He who possesses a wife fair in her doings” (ibid., Shabbath
25b). “It was through the merit of pious women that the Israelites
were redeemed from Egypt” (ibid., Sotah 11b). 146 Modesty and
reservedness (‫‏צניעות‬‎) are the distinguishing virtues of Jewish
women. The principle, “The daughter of the King is all glorious
within,” was applied literally. In the fulfilment of her home-duties the
daughter of Israel seeks her [473]happiness and her pride. It used to
be opposed to the sense of propriety of Jewish ladies to speak, sing,
or act in public. 147 This ‫‏צניעות‬‎was the main cause of the preservation
of the sanctity of the Jewish home and the purity of Jewish family
life, a treasure and a blessing which ought to be well guarded.

The working days of the week are divided between labour and
devotion. Three Services are attended daily either in the Synagogue
or at home, and every meal is preceded and followed by prayer.
Jewish women have, in addition to the Prayer-book, a small volume
of supplications (‫‏תחנות‬‎) in the vernacular for every day, every
season, and every occasion.

Mondays and Thursdays, on which days a Lesson from the Law is

read during the Morning Service, are considered as special days for
earnest devotion. There have been pious Jews who fasted the whole
or part of these days.—Tuesday is looked upon as a favoured day,
because it is distinguished in the account of the Creation (Gen. i. 10,
12) by a repetition of the phrase, “And God saw that it was good.” It
is therefore called “the day with double ki-tobh (that it was good).”
This circumstance may be the cause of the belief that it is not
advisable to begin a new undertaking on Monday or Wednesday; 148
preference should be [474]given to Tuesday. But this belief, although
seemingly founded on a Biblical phrase, is contrary to Jewish
principles, and is included in the prohibition, “Ye shall not observe
times” (Lev. xix. 26), to declare a particular day as lucky or unlucky.
Friday is an important and busy day in a Jewish house. It is not only
the circumstance that food is being prepared for two days 149 that
causes greater activity, but also the anticipated pleasure at the
approach of a beloved guest. The same is the case when a Festival
is near. Each Festival has its own particular wants and pleasures. In
some houses the activity in preparing for Passover may be noticed a
whole month before, although the actual clearing of the chamets is
done in a very short time. Before Succoth all hands are busy with
preparing and ornamenting the Tabernacle, and selecting esrog and
lulabh. It is genuine religious enthusiasm 150 in the fulfilment of Divine
duties that inspires this kind of activity, and gives to the house a
peculiarly Jewish tone and Jewish atmosphere. We feel in it “the
season of our joy” before and during the Three Festivals, and “the
season of solemnity and earnest reflection” during the penitential
days; grief when the 9th of Ab approaches, [475]and hilarity when
Purim is near. Twice a year we are invited by law and custom to give
ourselves up to gladness and merriment: on Simchath-torah and on
Purim. Although even a certain excess of mirth is considered lawful
on the latter occasion, there are but very few that indulge in this
license.

All the seasons of rejoicing are also occasions for mitsvoth—charity,

and for strengthening the bond of love between husband and wife,
between parents and children, and the bond of friendship between
man and man. Every erebh shabbath and erebh yom-tobh afford the
opportunity of giving challah, 151 kindling Sabbath or Festival lights, 152
and inviting strangers 153 (‫‏הכנסת אורחים‬‎) to our meals. On Sabbaths
and Festivals children, even when grown up, come to their parents
and ask for their blessing. 154 Before Kiddush the husband chants the
section of Prov. xxxi. beginning ‫‏אשת חיל‬‎, in praise of a good wife.
The Shabbath shalom or Good shabbath, Shabhua tobh or Good
woch, Good yom tobh, and similar salutations, remind us that we
ought to have only good wishes for each other. Sabbath and
Festivals afford suitable occasions for home-devotion, in which all
the members of the family, males and females, should take part. The
meals are preceded and followed by the usual berachoth, but it [476]is
customary to add extra psalms and hymns (zemiroth) in honour of
the day, and those who are gifted should add to these, or even
substitute for them, compositions of their own in any language they
like in gloriam Dei. A second kind of home-devotion which ought not
to be neglected, but should rather be revived where it is neglected, is
the reading of the Scriptures. On Friday evening the pious Jew reads
the Sidra twice in the original and once in the Targum; but all should
at least read Sidra and Haphtarah in the vernacular.

The moon by its gradual increase in light from its minimum to full-
moon, and the subsequent decrease from full-moon to its minimum,
has in Agadic and Midrashic Literature frequently served as a
symbol of the history of Israel, of his rise and his fall. The last day of
the decline, the eve of New-moon, is kept by some as a special day
of prayer and fasting, 155 while the first day of the rise, New-moon, is
distinguished by Hallel and Musaph. If people, as a symbol of
happiness (‫‏סימן טוב‬‎), prefer the middle of the month for marriage,
their choice is harmless; but if they hold that season as more lucky
than the rest of the month, they are guilty of superstition. As at the
sight of other natural phenomena, so also has a benediction been
fixed on observing the reappearance of the moon in the beginning of
the month. For the above-mentioned reason, importance is attached
to this berachah, and prayers are added for the redemption of Israel.
The berachah, which is generally recited in the open air, is the chief
element in the ceremony; the additional prayers and reflections are
non-essential. [477]

In the foregoing, Jewish Life has been described as it appears at the

various seasons of the year; in the following, it will be given as it
appears at the various periods of man’s existence.
The first important moment is, of course, the moment of birth. The
father, friends, and relatives are filled with anxiety for the life of both
mother and child. Prayers are daily offered up for the safety and
recovery of the patient and the well-being of the child. The Twentieth
Psalm is sometimes written on a tablet placed in the room where the
confinement takes place, probably as a reminder or an invitation for
visitors to pray to the Almighty; in this sense the custom is to be
commended; but if the tablet is filled with meaningless signs, letters,
and words, and is used merely as a charm, the custom should be
discontinued, being a superstitious practice. In some parts it has
been the custom that during the week preceding the Berith-milah
friends visited the house to pray there for the well-being of the child,
and boys recited there Biblical passages containing blessings, such
as Gen. xlviii. 16. 156 The night before the berith was spent in reading
Bible and Talmud, so that the child might from the beginning breathe,
as it were, the atmosphere of torah. 157 [478]

On the eighth day the male child is initiated into the covenant of
Abraham (Lev. xii. 3). Circumcision is one of “those mitsvoth which
the Israelites in times of religious persecution carried out
notwithstanding imminent danger to life.” The performance of this
Divine precept is therefore made the occasion of much rejoicing. In
some congregations the operation, as a sacred act, takes place in
the Synagogue after the Morning Service; in others the privacy of the
home is preferred. In ancient days mothers circumcised their sons,
but now the operation is only entrusted to a person who has been
duly trained, and has received from competent judges a certificate of
his qualification for the functions of a mohel. 158 Although, according
to the Law, any person, otherwise capable of doing it, may do the
mitsvah, preference is given, and ought to be given, to a person of
genuine piety and of true enthusiasm for our holy Religion, who
performs the act in gloriam Dei. Not only the mohel, but all who
assist in the act do a mitsvah, and the meal which is prepared for the
occasion is a ‫‏סעודת מצוה‬‎(a meal involving a religious act). 159
Immediately after the operation a name is given to the child. 160 [479]

The next important moment in a boy’s life is the “Redemption” (‫‏פדיון‬

‫הבן‬‎) in case of the first-born male child (Exod. xiii. 13, 15), which act
is likewise made the occasion of a ‫‏סעודת מצוה‬‎. A cohen (descendant
of Aaron) receives the redemption-money to the amount of five
shekels (or 15s.), according to Num. xviii. 16. 161

In the case of a female child the naming generally takes place in the
Synagogue on a Sabbath, when the father is called up to the Law. In
many congregations this takes place when the mother has
sufficiently recovered to attend again for the first time the Service in
the Synagogue on Sabbath. Those who live at a great distance from
the Synagogue pay the first visit to the place of worship on a week-
day. A special Service has been arranged for the occasion. 162

Great care is now taken by the parents for the physical well-being of
the child, without entirely ignoring its moral and intellectual
development. “At five years the child is fit to be taught Mikra, i.e.,
reading the Bible” (Aboth v. 21), so the Mishnah teaches. But long
before this the child is taught to pray, and to repeat short Biblical
passages or prayers in Hebrew. It must, of course, be borne in mind
that children are not all alike, and that each child must be taught
according to its own capacities and [480]strength. The knowledge
must be imparted in such a manner that the child should seek it as a
source of pleasure and happiness.

As to the subjects which are to be taught, there is no branch of

general knowledge from which Jewish children are debarred by their
Religion, nor is there any branch of knowledge that is more Jewish
than the rest. Jewish children must learn like other children, as far as
possible, that which is considered necessary and useful, as well as
that which is conducive to the comfort and happiness of life. But
Religion, Scripture, and Hebrew must never be absent from the
curriculum of studies of a Jewish child. The instruction in Religion
need not occupy much time, for the best teaching of Religion is the
good example set by the parents at home and the teacher in the
school. The religious training of a child should begin early; the
surroundings and associations must teach the child to act nobly, to
speak purely, to think charitably, and to love our Religion. “Train up a
child in the way he should go; and when he is old, he will not depart
from it” (Prov. xxii. 6). Early practical training (‫‏חנוך‬‎) is also of great
importance with regard to the observance of religious precepts.
Children should be accustomed to regard with reverence that which
is holy, to honour Sabbath and Festivals, and to rejoice in doing what
the Almighty has commanded. Twice a year we have special
occasion for the fulfilment of this duty, viz., on Simchath-torah and on
the Seder-evening.

In teaching our children Hebrew our aim must be to make them

understand the holy language, to enable them to read the Word of
God in the original, and to [481]pray to the Almighty in the language in
which the Prophets and the Psalmists gave utterance to their
inspirations, and in which our forefathers addressed the Supreme
Being in the Temple.

A special ceremony used to introduce the child into the study of the
Bible in the original. 163 Teacher and pupil went to the Synagogue,
took a sepher from the Hechal, and the pupil was made to read the
first lesson from the sepher. This and similar ceremonies were
intended as a means of impressing on the pupil the great importance
of studying the Word of God in the original language. After having
acquired a sound knowledge of the Bible, the study of other
branches of Hebrew literature, of Talmudical and Rabbinical works,
is approached.
As a rule, boys devote more time to Hebrew studies than girls, only
because girls are considered physically more delicate and not
capable of doing so much work as boys. Girls are by no means
excluded from acquiring a sound Hebrew knowledge; on the
contrary, every encouragement should be given to them, if they are
inclined to study Hebrew beyond the first elements. 164

The boy when thirteen years old is bar-mitsvah (lit., “a son of the
commandment”), bound to obey the Law, and responsible for his
deeds. On the Sabbath following [482]his thirteenth birthday the boy is
called up to the Law; he reads the whole of the Sidra or a section of
it, and declares in the blessings which precede and follow the lesson
his belief in the Divine origin of the Torah, and his gratitude to God
for having given us the Law. 165

The school-years come gradually to a close, and the practical

preparation for life begins. A vocation has to be determined upon.
From a moral and religious point of view all kinds of trade, business,
and profession are equal. They are honourable or base according as
they are carried on in an honourable manner or not. Whatever
course is chosen, the moral and religious training must continue with
unabated energy. When the school-years are over, when the youth is
no longer under the control of the master, and is sometimes left even
without the control of the parents, he is exposed to various kinds of
temptation, especially through the influence of bad society. The vices
against which the youth must guard himself most at this period of life
are sensuality, excessive desire for pleasure, gambling, and
dishonesty, which bring about his moral, social, and physical ruin.
Self-control, acquired through continued religious training, is the best
safeguard against these dangers. It is therefore advisable that those
who have left the school should continue attending some religious
class, or otherwise devote part of their free time to Talmud-torah, to
the study of the Torah, and of works relating to it.
“At the age of eighteen years one is fit for marriage” (Aboth, ibid.) is
an ancient dictum, but which [483]could never have been meant as an
absolute law. For there are other qualifications equally important,
and even more essential than age. Maimonides (Mishneh-torah, Hil.
Deoth v. 11) says: “Man should first secure a living, then prepare a
residence, and after that seek a wife. But fools act otherwise: they
marry first, then look out for a house, and at last think of the means
of obtaining a livelihood.” (Comp. Deut. xx. 5–7 and xxviii. 30.)

Marriage is called in the Bible “a divine covenant” (Prov. ii. 17), or

“the covenant of God.” God is, as it were, made witness of the
covenant; in His presence the assurances of mutual love and the
promises of mutual fidelity are given by husband and wife (Mal. ii.
14). To break this covenant is therefore not only an offence of the
one against the other, but an offence against God.—In addition to
this religious basis of marriage, conditions of a more material nature
were agreed upon. The maiden has been long of use in the house of
her parents, and he who sought the privilege of taking her to his
house and making her his wife had to give to the parents “dowry and
gift” (‫‏מהר ומתן‬‎, Gen. xxxiv. 12). Later on, in the time of the Mishnah,
all that the husband promised to his wife was made the subject of a
written document (‫‏כתובה‬‎), signed by two witnesses. In this document
he guarantees to her 200 zus (or half the sum if she is a widow), the
value of her outfit and dowry (in Hebrew ‫‏נדוניא‬‎), and a certain amount
added to the afore-mentioned obligatory sum (‫‏תוספת כתובה‬‎). He
further promises to honour her, work for her, maintain her, and
honestly provide her with everything necessary for her comfort. [484]

The marriage was preceded by the betrothal (‫‏אירוסין‬‎or ‫‏קידושין‬‎), the

solemn promise on his part to take her after a fixed time to his house
as his wife, and on her part to consider herself as his wife and to
prepare herself for the marriage. Legally she was already his wife,
and infidelity was visited with capital punishment. The interval
between the betrothal and marriage used to be twelve months; at
present the two events are united in the marriage ceremony, and are
only separated from each other by an address or by the reading of
the kethubhah. That which is now called betrothal or engagement is
merely a preliminary settlement of the conditions of the marriage
(‫‏תנאים‬‎“conditions”). The conditions used to be written down,
including a fine (‫‏קנס‬‎) for breach of promise; the agreement used to
be followed by the breaking of a glass 166 and by a feast.

The actual betrothal takes place on the wedding-day, and consists

mainly of the following significant words addressed by the
bridegroom to his bride: ‫‏הרי את מקודשת לי בטבעת זו כדת משה וישראל‬‎
“Behold, thou art consecrated (betrothed) to me by this ring
according to the Law of Moses and of Israel.” While saying this he
places a gold ring 167 on the second finger of the [485]right hand. This
act is preceded by a berachah over wine, read by the celebrant while
holding a cup of wine in his hand, and the birchath erusin (“blessing
of betrothal”), in which God is praised for the institution of Marriage.
Bride and bridegroom, who during the ceremony stand under a
canopy (‫‏חופה‬‎), taste of the wine.

The canopy or chuppah 168 represents symbolically the future home

of the married couple, which they have to guard as a sanctuary, and
to render inaccessible to evil deeds, words, and thoughts that would
pollute it. The top of the canopy, which is formed of a curtain (‫‏פרכת‬‎)
of the Hechal, or of a talith, expresses the idea of sanctity.

After the birchath erusin the bridegroom makes the solemn

declaration 169 mentioned above: “Behold, thou art consecrated
(betrothed) unto me by this ring according to the Law of Moses and
of Israel,” 170 whereupon the kethubhah is read in Aramaic 171 or in
English, [486]and an address is sometimes given. Then follow the
‫‏ברכות נשואין‬‎(“Blessings of Marriage”), called also after their number
‫‏שבע ברכות‬‎“Seven Blessings.” 172 The ceremony concludes with the
breaking of a glass and the mutual congratulations of friends and
relatives, expressed in the words Mazzal-tobh (‫‏מזל טוב‬‎“Good
luck”). 173

A banquet (‫‏סעודת נישואין‬‎) follows, which is a ‫‏סעודת מצוה‬‎. It is

introduced by the usual berachah (‫‏המוציא‬‎), and followed by Grace
and the “Seven Blessings.”

The following are a few of the various customs connected with a

Jewish marriage without being essential elements of the marriage
ceremony:—

(1.) On the Sabbath previous to the wedding-day the bridegroom, his

father, and the father of the bride are called up to the Law, and
offerings are made (mi shebberach) in honour of the bride and the
bridegroom. In some congregations Gen. xxiv. is read after the
Service, on the morning of the wedding-day.

(2.) Bride and bridegroom enter upon a new life; the wedding-day is
to them a day of rejoicing, but also a day of great solemnity. It is kept
as a day of earnest reflections, of prayer and fasting, till after [487]the
ceremony, when the fast is broken and the rejoicing begins. The
bridegroom adds in the Minchah amidah the Confession (‫‏ודוי‬‎) of the
Day of Atonement.

(3.) The good wishes of friends and relatives are variously

expressed. Rice, wheat, or similar things are thrown over the bride
and the bridegroom as a symbol of abundance and fruitfulness.

(4.) The feast is accompanied by speeches in praise of the bride and

bridegroom; it was considered a special merit to speak on such an
occasion (‫‏אגרא דהלולא מילי‬‎, Babyl. Talm., Berachoth 6b). The
bridegroom used to give a discourse (‫‏דרשה‬‎) on some Talmudical
theme, if he was able to do so. He received presents for it
(derashah-presents).

(5.) In the time of the Bible and the Talmud the feasting lasted seven
days.—The first day after the wedding used to be distinguished by a
fish dinner (‫‏סעודת דגים‬‎), in allusion to Gen. xlviii. 16.

In spite of all blessings and good wishes the marriage sometimes

proves a failure, husband and wife being a source of trouble and
misery the one to the other, instead of being the cause of each
other’s happiness. In such a case a divorce may take place, and
man and wife separate from each other. Divorce is permitted (Deut.
xxiv. 1–4), but not encouraged; it is an evil, but the lesser of two
evils. A written document was required (‫‏ספר כריתות‬‎, ‫‏גט‬‎), and later
legislation made the writing and the delivery of the document difficult
and protracted, in order to facilitate attempts at reconciliation; the
fulfilment of the conditions agreed upon in the kethubhah also
tended to [488]render divorce a rare event. The number of cases of
divorce among the Jews is therefore comparatively smaller than
among other denominations, but still unfortunately far too large,
owing to want of foresight and reflection in the choice of a
companion for life.

There is a kind of obligatory marriage (‫‏יבום‬‎) and or obligatory divorce

(‫‏חליצה‬‎), viz., with regard to the widow of a deceased brother who has
died without issue (Deut. xxv. 5–10). Since the abolition of
polygamy 174 by Rabbenu Gershom (eleventh century) the obligatory
marriage has almost disappeared, and the obligatory divorce (‫‏חליצה‬‎)
must take place before the widow can marry again. 175

We acknowledge the principle laid down in the Talmud, “The law of

the country is binding upon us” (‫‏דינא דמלכותא דינא‬‎), but only in so far
as our civil relations are concerned. With regard to religious
questions our own religious code must be obeyed. Marriage laws
include two elements—civil relations and religious duties. As regards
the former, we abide by the decisions of the civil courts of the
country. We must, therefore, not solemnise a marriage which the law
of the country would not recognise; we must not religiously dissolve
a marriage by ‫‏גט‬‎, unless the civil courts of law have already decreed
the divorce. On the other hand, we must not content ourselves
[489]with civil marriage or civil divorce; religiously, neither civil
marriage nor civil divorce can be recognised unless supplemented
by marriage or divorce according to religious forms. Furthermore,
marriages allowed by the civil law, but prohibited by our religious law
—e.g., mixed marriages; that is, marriages between Jews and non-
Jews—cannot be recognised before the tribunal of our Religion;
such alliances are sinful, and the issue of such alliances must be
treated as illegitimate. Those who love their Religion and have the
well-being of Judaism at heart will do their utmost to prevent the
increase of mixed marriages.

“To every thing there is a season, and a time to every purpose under
the heaven: a time to be born, and a time to die” (Eccles. iii. 1, 2).
Life is a precious gift the Creator has given us; while there is breath
in our nostrils we thank Him for it, we pray to Him for its prolongation,
do everything in our power to preserve it, and consider its wilful
destruction a criminal act. But notwithstanding all this “there is a time
to die.” Life and death are equally mysteries to us; we trust in the
mercy of Him who has ordained life and death, that both are for our
good. Death is, therefore, not to be regarded with dread and horror;
it is the transition to another state of life, the real nature of which is
unknown to us. But it is our belief that the future life (‫‏העולם הבא‬‎) is
infinitely superior to the present life (‫‏העולם הזה‬‎); hence the saying in
the Midrash that the words “exceedingly good” (Gen. i. 31) applied to
death. The only fear of death that can reasonably be justified is the
fear of departing from this life before we have completed our task,
before we have sufficiently [490]strengthened “the breaches of the
house” caused by our own dereliction of duty. Our Sages advise,
“Return one day before thy death” (Aboth ii. 15); that is, every day,
the day of death being concealed from our knowledge. In this
manner we constantly prepare ourselves for death without curtailing
our enjoyment of life. “Rejoice, O young man, in thy youth; and let
thy heart cheer thee in the days of thy youth, and walk in the ways of
thine heart, and in the sight of thine eyes: but know thou, that for all
these things God will bring thee into judgment. Therefore remove
sorrow from thy heart, and put away evil from thy flesh: for childhood
and youth are vanity” (Eccles. xi. 9, 10). When passion overcomes
us and evil inclinations invite us to sin, we are told by our Sages to
remember the day of death, which may suddenly surprise us before
we have been able by repentance to purify ourselves from our
transgressions (Babyl. Talm., Berachoth 5a).

When death approaches, and announces itself through man’s

illness, we do everything that human knowledge and skill can
suggest to preserve and prolong the earthly life with which God has
endowed us; in addition, the patient himself and his friends invoke
the mercy of God for his recovery. 176 Even when death appears
invincible, when “the edge of the sword touches already man’s neck,
we do not relinquish our hope in God’s mercy, and continue to pray
to the All-merciful.” The patient is asked to [491]prepare himself for
the solemn moment, although it may in reality be as yet far off. 177
The preparation consists of prayer, meditation, confession of sin,
repentance, and of the profession of our Creed, especially of the
Unity of God, in the words, “Hear, O Israel, the Lord is our God, the
Lord is One.” 178 To visit the sick, to comfort them by kind words and
deeds, to pray with and for the patient, are acts included in the duty
of “visiting the sick” (‫‏בקור הולים‬‎). 179 In the moment of death those
present testify their faith in God by proclaiming the Dominion, the
Omnipotence, and the Unity of God in the same way in which we
make this declaration at the conclusion of the Day of Atonement.
Although Prayer-books contain certain forms of prayer for this
purpose, the patient and those present should rather follow the
impulse of their heart, and commune with the Almighty in any form
their heart suggests.

When life has come to an end friends and relatives give free
expression to their grief; 180 to check it by comforting words at this
moment is useless (Aboth iv. 18). The mourners, 181 father, mother,
son, daughter, brother, and sister, have now to direct all their
attention [492]to the deceased relative, in order that nothing be
neglected in the last honours shown to him; they are therefore free
from all other religious obligations till after the burial. In Palestine and
neighbouring countries, where, in consequence of the higher
temperature, decomposition of the body begins soon after death, the
burial takes place on the same day. 182 In colder climates two or three
days elapse between death and burial. The mourners abstain during
the interval from wine and meat.

Every act of piety in honour of the deceased is a meritorious

religious act, a mitsvah, an act of kindness and truth (‫‏חסד ואמת‬‎), and
in every congregation there exists a society, called ‫‏חברא קרישא‬‎“holy
society,” whose members devote themselves to the fulfilment of
these pious duties.

According to the principle that death equalises all, that “the small and
great are there” (Job iii. 19), the greatest simplicity and equality is
observed in all matters connected with the obsequies 183 of the dead.
Friends and relatives follow to the burial-ground; the ‫‏הלוית המת‬‎, or
attending the dead to their last resting-place, 184 [493]is one of those
mitsvoth “the fruits of which a man enjoys in this world, while the
stock remains for him for the world to come.”

Burying the dead is a very old custom, to which the Jews adhered
firmly at all ages. The custom of the Greeks, who burnt their dead,
found no advocates among the Jews. In the Written and the Oral
Law only the burying of the dead is mentioned. To leave a human
body unburied and unattended was considered by Jews, as by other
nations, an insult to the deceased person, and whoever found such a
body was bound to take charge of it and to effect its burial. 185

In the Burial Service we acknowledge the justice of God, and resign

ourselves to the Will of the Almighty (‫‏צדוק הדין‬‎). When the burial is
over our attention is directed to the living; words of comfort are
addressed to the mourners 186 who return home and keep ‫‏שבעה‬‎
“seven days of mourning.” A certain degree of mourning is then
continued till the end of [494]the year by the children of the deceased,
and till the end of the month (‫‏שלשים‬‎“thirty days”) by other
relatives. 187

Our regard for the deceased (‫‏יקרא דשכבי‬‎) and our sympathies with
the mourners (‫‏יקרא דחיי‬‎) are expressed in different ways.

The funeral oration (‫‏הספד‬‎) occasionally spoken at the grave, or in the

house of mourning, or in the Synagogue, generally combines both
elements; it contains a eulogy upon the deceased and words of
sympathy and exhortation for the living.

The special prayers offered up on such occasions likewise include

these two elements: petitions for the well-being of the soul of the
deceased, that it may find Divine mercy when appearing before the
Supreme Judge, and petitions for the comfort and relief of the
mourners. The Kaddish of the Mourners, however, does not contain
such prayers, but merely expresses their resignation to the Will of
the Almighty, their conviction that He is the only Being that is to be
worshipped, and that He alone will be worshipped by all mankind in
the days of Messiah, and their wish that the arrival of those days
may be hastened.
There are, besides, the following customs, the object [495]of which is
to express our regard for the memory of the deceased: (1.) A
tombstone (‫‏מצבה‬‎) is set up in front of or over the grave with the
name of the deceased, the date of his death, and such words of
praise as are dictated by the love and the esteem in which the
deceased was held by the mourners. (2.) A lamp is kept burning 188
during the week, or the month, or the year of mourning, and on the
anniversary of the day of death (Jahrzeit). (3.) By observing the
anniversary of the death as a day devoted to earnest reflection, and
to meditation on the merits and virtues of the deceased; we keep
away from amusements, and say Kaddish in the course of the
Services of the day. Some observe the anniversary as a fast-day. (4.)
By doing some mitsvah 189 in commemoration of the deceased. (5.)
By regarding with respect and piety the wishes of the departed
relative or friend, especially those uttered when death was
approaching. Our Sages teach: “It is our duty to fulfil the wishes of
the departed.” 190 The absence of this inner respect and piety makes
all the outward signs of mourning, however conscientiously
observed, valueless and illusory. [496]