Khalsa et al. [ 18] further emphasized that next to insula and anterior cingulate cortices, primary and secondary somatosensory cortices inner- vating the skin of the chest area are also essential for the self-report of cardiac sensations.

Pollatos et al. [ 19] showed that IAc as assessed by the heartbeat perception task according to Schandry [9] was positively correlated with blood-oxygen- level dependent (BOLD) activity at right insula, inferior parietal lobule and the medial frontal gyrus extending into the cingulate gyrus.

Critchley et al. [ 5] used a heartbeat dis- crimination task and could demonstrate that interoceptive attention was associated with activation in anterior insula, lat- eral somatomotor and adjacent parietal cortices, anterior cingulate and supplementary motor cortices.

IAc was strongest related to activity in right anterior insula/operculum.

Impor- tantly, the authors also examined interoceptive sensibility using questionnaire data and found positive correlations of subscales of the body perception questionnaire with anterior insula activity.


Till now, existing research has been mainly based on correlational findings, and the effects of causal manipulation of brain activity in interoceptive areas by means of brain stimulation remain unknown.


Therefore, transcranial magnetic stimulation (TMS) is a way to experimentally manipulate brain activity in regions associated with certain aspects of interoceptive signal proces- sing that might also be used as an innovative technique in several clinical groups characterized by alternations of inter- oceptive processing such as depression, eating disorders or anxiety disorders [6,12,20 -23].


The so-called heartbeat-evoked potential (HEP) is another methodology for examining the cortical processing of cardiac afferent signals and assessing individual differences in interoceptive processing.

HEPs are related to the automatic processing of cardiac information, and were initially thought to be independent of attentional processes involved in perceiv- ing or detecting internal signals.

The measurement of HEPs uses methods analogous to other evoked potentials.

Typically, electrocortical (encephalographic, EEG) activity is averaged to individual heartbeats, using the electrocardiogram (ECG) R-wave [24].

Individual differences in HEP amplitude are related to IAc, as shown using heartbeat counting tasks [8,25-27].

The sources of the HEP have been localized to insu- lar, somatosensory, rostral cingulate and prefrontal cortices [7].

Because afferent signals from the cardiovascular system con- tinuously reach cortical structures, HEP amplitudes assessed during rest can be interpreted as indicators of central represen- tation of cardiac interoceptive signals independent of overt attention or conscious awareness of cardiac sensations [28].

Therefore, the HEPs are one way to objectively measure one basic aspect of automatic afferent interoceptive processing.


In this context, two recent models of neural structures ser- ving interoceptive processes and their connections to emotions are of great interest.

A recent multihierarchical model of emotion processing proposed by Smith & Lane [29] suggests distinctions between discrete body features rep- resented in somatosensory cortices, posterior insula, nucleus of the tractus solitarii, hypothalamic nuclei and the para- brachial nucleus, while so-called whole-body patterns are represented in the mid and anterior insula.

Emotional con- cepts then occur by appraisal mechanisms involving other brain regions such as the anterior cingulate and the medial prefrontal cortices that refer to this mapping of the body- state.

It is a multistage interoceptive/somatosensory process by which these body state patterns are detected and assigned conceptual emotional meaning [29].

These assumptions are in accordance with other studies showing that the insular cortex and the anterior cingulate cortex (ACC) play crucial roles in connecting interoceptive processes and emotions [24].

Their activation was found to be modulated by cognitive [30] and emotional factors in several studies [31,32].

This view is also in accordance with recent findings from interoception research [33,34] suggesting that subjective appraisal of interoceptive sig- nals reflect processes independent of interoceptive perception accuracy and are related to mechanisms of self-regulation and top-down control.


A second branch of models refers to assumptions of pre- dictive coding with respect to interoceptive processing.

Friston et al. [ 35- 37] suggested that proprioceptive and kinaesthetic perceptions of the body arise from predictions through the same computational principles of active inference as do visual and auditory perceptions of the external world.


Comparable ideas on predictive coding have been summar- ized and used by Seth et al. [ 38] in order to outline how interoception is associated with conscious presence and its disturbances.

The core concept of this model is that a sense of presence arises when informative interoceptive prediction signals are successfully matched to inputs, so that prediction errors are suppressed.


Brain areas contributing to interocep- tive predictive coding include specific brainstem, subcortical and cortical (insular, orbitofrontal, anterior cingulate) regions.

Seth et al. [ 38] suggest that these regions potentially form at least a loose hierarchy: posterior and mid insula sup- port the primary cortical representation of interoceptive signals, with the anterior insula operating as a comparator error module (see [5,39,40]).


Up to now, only a few studies exist testing whether damage or disturbance of critical neural structures involved in intero- ceptive processing leads to assumed deficits.

Ronchi et al. [ 41] demonstrated in one patient that IAc as measured by the heart- beat detection task by Schandry was decreased after right insula resection.

Terasawa and co-workers [42] also found reduced IAc in patients suffering from insula damage.

Up to today, there is no study that has investigated whether an experimental approach using TMS might affect interoception comprising different aspects and levels of interoceptive processing.


Here, we investigated whether interoceptive processes were disturbed by TMS.

Depending on the parameters of stimulation, it has been suggested that repetitive TMS may either increase or decrease the excitability of the targeted corti- cal structure (see [43-45]).

As Huang and co-workers [44] rstb.royalsocietypublishing.org Phil.

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B 371: 20160016 summarized, several studies have shown that when delivered over the primary motor cortex (M1), continuous theta-burst stimulation (cTBS) decreases M1 excitability when delivered in a continuous fashion.


Eighteen healthy young male partici- pants received either cTBS over right insular and right somatosensory cortices or sham stimulation over occipital areas before performing heartbeat detection and a respiratory load estimation task.

Furthermore, the HEP during heartbeat perception (as the most objective marker of automatic proces- sing of cardiac information), assessed after stimulation, was also examined.


We hypothesized that cTBS over somatosen- sory and insular cortices would yield a decrease in accuracy of interoceptive signal processing.

We also hypothesized a deflation of the HEP amplitude after somatosensory and insula stimulation.

An alternation of the emotional aspects of interoceptive signals was hypothesized after insula inhibition only.

A modulation of interoceptive sensibility was assumed after insula stimulation, as this facet refers especially to 'whole-body' patterns.

Whether confidence of interoceptive signal processing is affected by cTBS over insula and somato- sensory cortices should be assessed in an exploratory fashion.


Eighteen healthy male participants were recruited by advertise- ment at the University of Ulm.

Mean age was 23.9 years (s.d. 2.9).

In order to reduce variance owing to menstrual cycle [46,47], we recruited males only.

The sample was not selected with respect to any other criteria.

They gave written informed consent prior to the study and received compensation of E60.

Exclusion criteria were history of brain injury, past or current psychiatric or neurological disorders, severe somatic illness or intake of medication as assessed by anamnestic questionnaire.

Experiments were conducted in accordance with the Declaration of Helsinki with the approval of the local ethics committee.


Participants were informed about the study by staff and they received written information about the experiment.

At each data collection time, participants were examined at the labora- tories of the Clinical and Health Psychology department in Ulm.


First, there was a screening session in which the tasks used in the stimulation sessions were introduced and they were made familiar with the TMS procedure.

At this screening, exclusion criteria and important side effects of cTBS were explained.


From 20 participants screened, 18 took part in the main experiment.


At the first session of the main experiment, the participants were seated in a sound-attenuated chamber, which was connected to the neighbouring equipment room by intercom.


Passive electrodes for EEG (32 channels using a cap, see below), ECG, respiration (belt), electromyography (EMG) (first dorsal interosseous, FDI; muscle of the left hand) and elec- trooculograms (EOG) were attached and individual resting motor threshold was assessed over left primary motor cortex using a PowerMAG 100 stimulator (Mag & More, Munich, Germany) with biphasic pulses and a figure-of-eight coil (PMD70).


First, optimal cortical representation of FDI muscle (motor hot spot) was assessed by determining a coil position over the EEG cap yielding the highest amplitude of the motor evoked potential (MEP).

Resting motor threshold (MEPs . 100 mV in at least 5/10 trials, cf.

[ 48]) was determined, and cTBS intensity was calibrated to 80% of resting motor threshold in accordance with former studies [49].


This value was then used for all stimulation protocols of the participant including the second and third experimental session.


All three experimen- tal sessions were identical to the first one except for the fact that the motor threshold was assessed only at the first session.


The stimulation site (right insular, right somatosensory cortices or central occipital cortex as sham location) was selected using a randomized protocol for all three experimental sessions, i.e. each participant was stimulated three times in a repea- ted measurements design with identical test protocols.


The experimental procedure is depicted in figure 1.


Coil position for each stimulation site was located on the basis of the 10/20 system supplied by the EEG cap (see below).

Optimal coil positions with respect to the 10/20 system were derived in the following way: TMS neuronavigation (PowerMag View) was used with standard head model, and the positions derived were vali- dated in two subjects prior to the experimental sessions using their structural magnetic resonance imaging (MRI) images while wearing an EEG cap to define coil positions targeting the three stimulation sites (see also [50,51]).

Target areas of stimulation were obtained using MRI structural information and an MRI atlas as depicted in figure 1.


(a) The right anterior insula was reached with a coil position over frontotemporal locations building a triangle corresponding to EEG positions FT10, F8, FC6, pointing to FT8 (F6/AF8).

( b) The primary and secondary somatosensory cortices, chest/trunk location, were reached with the centre of the coil within a triangle corresponding to EEG positions CPZ, C2 and CP4, directed to CZ.

Primary and secondary somatosensory cortices of the trunk are not distinguishable by means of TMS navigation.

( c) Central occi- pital cortex (V2/V3) was reached with the coil placed over OZ, directed straight to the horizontal plane.

In all experimental ses- sions, the coil was placed according to these EEG coordinates.

Coil positioning and TMS target areas are depicted in figure 1.


The experimental design is summarized in figure 1 and was the following: first, participants had to rest for 5 min, while baseline measures (heart rate, breathing) were recorded with a sampling rate of 1000 Hz.

They then filled in an interoceptive sensibility state questionnaire designed to assess the momentary subjec- tive perception of bodily sensations focusing on the perception of five bodily systems (heart beat, respiratory functions, trembling, temperature/sweating, gastrointestinal sensations; see examples in the electronic supplementary material, Methods section).


Next, the cTBS took place with 600 pulses applied in 40 s (bursts of three pulses at 50 Hz every 200 ms (5 Hz)) over one of three locations according to the random scheme.

After stimulation, par- ticipants were asked to fill in the interoceptive sensibility state questionnaire once again.

Then, the heartbeat detection task took place.

During the first heartbeat perception task, EEG was also assessed and later used for HEP analyses (see below).

Four heartbeat counting phases of the mental tracking method were used (see [8,9] and also the electronic supplementary material).

After each trial, they were asked to report their confidence of their estimation using a nine-point Likert scale, where one endpoint was labelled 'no confidence at all', and the other endpoint was 'complete confi- dence' (see [4]).

At the end of the task, the participants were asked to evaluate their feelings during heartbeat perception (cardiac inter- oceptive evaluation; see the electronic supplementary material).


IAc was calculated as the mean heartbeat perception score according to the following transformation 1 4 X 1 À ðjrecorded heartbeats À counted heartbeatsjÞ recorded heartbeats : IAc scores typically range from 0 to 1.

Higher scores indicate small differences between the counted and recorded heartbeat and consequently a better IAc.


The respiratory load estimation task took place next.

As no standard test for IAc in the respiratory system exists, we designed a task similar to the one used by Petersen et al. [ 11,12].

The task rstb.royalsocietypublishing.org Phil.

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B 371: 20160016 manipulated breathing effort via respiratory load by switching the diameter of a breathing device (Pari PEP w S-system) resulting in varying expiratory resistance (diameters 1-5 mm, eight levels, in 0.5 mm steps diameter change).

Participants were instructed to maximally expire with constant flow as naturally as possible and not to apply high levels of effort or force in doing so; as the resist- ance levels applied were rather low, the impact of breathing flow or effort on performance is expected to be negligible.

Participants were asked to judge respiratory effort on an eight-point Likert scale, using the highest and lowest loads as anchors.

Several train- ing intervals were used to make the participants familiar with the range of the scale used.


The test then used six trials with varying diameters.

A respiratory accuracy score was calculated analogous to the heartbeat perception task, using the weighted difference scores of the six trials according to the following formula 1 À P 6 k¼1 jestimated resistance À objective resistancej 2625 ðmean difference with random distribution of errors) : Identical to the heartbeat detection, participants rated confidence after each trial.

At the end of the task, participants reported valence, arousal and anxiety when attending to their respiratory functions.


Afterwards, another paradigm was used that will be not reported here.

The first session lasted about 2 h, the second and third sessions lasted about 90 min.


During the heartbeat perception task, EEG activity was recorded continuously from 32 leads (FP1, FPZ, FP2, AF3, AFZ, AF4, F7, F5, Fz, F6, F8, FC5, FCZ, FC6, C5, C1, CZ, C2, C6, CP5, CP1, CPZ, CP2, CP6, P5, PZ, P6, PO3, PO4, O1, OZ, O2), using the Easy-Cap electrode system (Falk Minow Services, Germany) with non-polarizable passive Ag/AgCl electrodes at equidistant positions.

Cz served as a reference and the ground electrode was attached at electrode position F4.

Horizontal and vertical EOGs were recorded.

Impedances were maintained below 5 kV. The signals were amplified using an active amplifier system (Brain Products, Germany) and digitized at a sampling rate of 1000 Hz.

ECG was measured with non-polarizable Ag/AgCl electrodes placed at the right clavicula and left chest.

ECG, EMG and respiration were recorded equivalent to the EEG using an amplifier system (Brain Products, Germany) and were digitized at a sampling rate of 1000 Hz.


All steps of EEG analysis were conducted with the BRAIN VISION ANALYZER v. 2.1 (Brain Products, Germany).

ECG R- waves were detected either automatically online or offline semiautomatically in ECG raw data for later EEG averaging.

EEG was visually inspected and filtered (0.05- 20 Hz).

EEG data were examined for ocular, muscular and other sources of artefacts.

Trials were rejected from the analysis if the voltage exceeded + 50 mV ms 21 in any channel.

EEG data were segmen- ted relative to the detected R-wave triggers, whereby segments were built in epochs ranging from 200 ms before the R-wave trig- ger to 800 ms after the R-wave trigger.

After baseline correction (200 ms pre R-wave trigger as baseline), average HEP waves were computed of R-triggered EEG segments.

HEP amplitude analyses were conducted in accordance with former studies, using a time window of 400 - 600 ms after R-wave during which the electric field artefact is assumed to be negligible (see [52,53]).


Data analyses were performed with the program SPSS (v. 22).

Referring to the cardiac and respiratory system, separate repeated- measures ANOVAs were calculated with the factors location (I, S, O) examining IAc, confidence and interoceptive evaluation (valence, arousal, anxiety).


Furthermore, interoceptive sensibility was examined with the factors location (I, S, O) and time (pre- stimulation, post-stimulation).

For HEP analyses, we selected frontocentral electrodes with highest HEP amplitudes for statistical evaluation and conducted repeated-measures ANOVAs with the factors location (I, S, O) and electrode.


Statistical significance levels reported correspond to p-values less than 0.05, 0.01 and 0.001, rstb.royalsocietypublishing.org Phil.

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B 371: 20160016 respectively.

In the Results section, uncorrected F-values are reported together with the Greenhouse-Geiser epsilon values and corrected degrees of freedom.

In case of multiple comparisons, we used the Bonferroni correction to adjust the alpha errors.


The mean obtained heartbeat perception scores for the three locations are summarized in figure 2 depicting the locations I, S and O. We observed a significant main effect of location (F 2,34 ¼ 6.67; p , 0.01; h 2 ¼ 0.28; 1 ¼ 0.80): post hoc Bonferroni corrected comparisons revealed that IAc was significantly lower after stimulation over right insula as well as over right somatosensory cortices when compared with occipital stimulation ( ps , 0.05).


Figure 3 summarizes the mean obtained confidence scores for the three locations.

We observed a significant main effect of location (F 2,34 ¼ 6.36; p , 0.01; h 2 ¼ 0.27; 1 ¼ 0.87): confidence was significantly lower after insula stimulation when com- pared with somatosensory stimulation ( p , 0.05).

No other significant differences were observed.


Valence, arousal and anxiety during heartbeat perception are summarized in table 1.

Referring to anxiety, a significant main effect of location (F 2,34 ¼ 6.36; p , 0.01; h 2 ¼ 0.27; 1 ¼ 0.87) showed that after insula cTBS anxiety was significantly higher when compared with both other locations.


Respiratory IAc scores are depicted in figure 2.

We observed a significant main effect of location (F 2,34 ¼ 3.44; p , 0.05; h 2 ¼ 0.17; 1 ¼ 0.58).

Post hoc Bonferroni corrected comparisons revealed that IAc was significantly lower after stimulation over right insula when compared with occipital stimulation ( p , 0.05), whereas the observed smaller IAc after somatosensory cTBS did not reach significance.


Cardiac and respiratory IAc were positively correlated after cTBS over somatosensory cortex (r ¼ 0.39, p , 0.05), whereas correlation coefficients for the other locations were not significant (occipital: r ¼ 0.18, p ¼ 0.24; insula: r ¼ 0.25, p ¼ 0.16).


We observed a significant main effect of location (F 2,34 ¼ 6.14; p , 0.05; h 2 ¼ 0.27; 1 ¼ 0.77): confidence was significantly lower after cTBS over right anterior insula when compared with occipital stimulation ( p , 0.05).


Valence, arousal and anxiety during respiratory load estimation are summarized in table 1.

No significant effects were observed.


Mean obtained IS scores are summarized in figure 4.

We observed a significant main effect of time (F 1,17 ¼ 9.84; p , 0.01; h 2 ¼ 0.37; 1 ¼ 0.84) and a significant interaction for location Â time (F 2,34 ¼ 4.99; p , 0.05; h 2 ¼ 0.23; 1 ¼ 0.61).

Post hoc tests showed that mean IS increased only after insula and somatosensory stimulation when compared with before cTBS stimulation (I: F 1,17 ¼ 19.95; p , 0.001; h 2 ¼ 0.54; 1 ¼ 0.99; S: F 1,17 ¼ 8.46; p , 0.01; h 2 ¼ 0.33; 1 ¼ 0.78).


Mean HEPs distribution and HEP amplitudes (at right fronto- central and central locations) are depicted in figure 5 contrasting the three cTBS locations.


Owing to technical problems, only 15 complete datasets could be included.

After visual inspection of the data, we selected FC6 and C6 (in accordance with former research also reporting the most pronounced HEP amplitudes at frontocentral rstb.royalsocietypublishing.org Phil.

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B 371: 20160016 and central locations [8,54]) as the electrodes for statistical analyses.


The repeated-measures ANOVA yielded significant main effects for location (F 2,28 ¼ 3.95; p , 0.05; h 2 ¼ 0.22; 1 ¼ 0.57).

Post hoc Bonferroni corrected comparisons revealed that the HEP amplitude was significantly lower after stimulation over right insula when compared with occipital stimulation ( p , 0.05), whereas the observed smaller HEP amplitude after somatosensory cTBS when compared with occipital stimu- lation did not reach significance (trend level at C6: p ¼ 0.08).


This study showed differential effects for IAc, interoceptive sensibility, subjective feelings and confidence judgements evoked by cTBS of right anterior insular and right somato- sensory cortices (S1 -S2, chest region).

As hypothesized, compared with inhibition of occipital cortices as a reference condition, cTBS of right anterior insula and right somatosen- sory cortices resulted in a significant decline in cardiac IAc, while only cTBS of right anterior insula significantly reduced respiratory IAc.

Cardiac and respiratory accuracy were posi- tively correlated after cTBS over the somatosensory location, whereas for the two remaining locations, correlation coeffi- cients were not significant.

Larger sample sizes are needed to support our interpretation that similar to observed corre- lations between perception accuracy in the cardiovascular and gastrointestinal system [10,15], there is a comparable, but weaker association between these two inner systems.


Whether confidence of interoceptive signal processing is affected by cTBS over insula and somatosensory cortices was assessed in an exploratory fashion.

Interestingly, analyses of confidence judgements of participants' perception accuracy demonstrated that individuals' confidence judgements were reduced after anterior insula stimulation for both cardiac and respiratory signals, whereas somatosensory inhibition affected only cardiac confidence in the opposite direction, i.e. here par- ticipants were more convinced of having accurately perceived their heartbeats although objective perception accuracy declined.

These results suggest that while inhibition of anterior insula reduces both IAc and confidence judgements in a consist- ent way, inhibition of somatosensory cortices is associated with a dissociation of these processes.

This interpretation is in rstb.royalsocietypublishing.org Phil.

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B 371: 20160016 accordance with assumptions proposed by Garfinkel and co- workers [4] highlighting that the relative balance of accuracy, sensibility and awareness dimensions could account for cogni- tive, emotional and clinical associations of interoceptive ability.


Going beyond IAc, cTBS of right anterior insula and right somatosensory cortices led to an immediate increase in interoceptive sensibility as assessed by self-report.

As former studies found a correlation between insula activation and sensibility [5], and this facet of interoceptive processing refers especially to the idea of 'whole-body' patterns as intro- duced by Smith & Lane [29], a modulation of interoceptive sensibility was assumed to occur after insula stimulation.

The fact that cTBS inhibiting somatosensory cortices also modulated interoceptive sensibility in the same direction as cTBS over right anterior insula highlights that, within the assumed hierarchical structure of interoception, hampering a region processing a discrete body feature leads to greater 'noise' in the whole system.

Referring to predictive coding [38], the anterior insula is the key error module that might detect such 'noise' in the system.

This might then lead to an increase of attentional processes examining ongoing dis- crete body sensations and therefore explain why our participants were more aware of a variety of bodily sen- sations including cardiac and respiratory functions, but also trembling, temperature/sweating and gastrointestinal sen- sations.

The latter underscores that effects of cTBS definitely occurred and affected bodily sensations.


As hypothesized, an alternation of the emotional aspects of interoceptive signals as captured by the interoceptive evaluation was modulated only in relation to anxiety after inhibition of anterior insula.

This underpins its pivotal role for processes related to anticipation of aversive stimuli or anxiety disorders [55].

According to the model of Smith & Lane [29], it might be argued that inhibiting anterior insula functions could have primarily disturbed 'whole-body pat- terns' and therefore, the reduction of IAc becomes evident or conscious to the participants, leading to a corresponding decline in metacognitive beliefs of perception security.

In a similar way, together with models of 'interoceptive predic- tion error', this could explain the increases of self-reported subjective feelings of anxiety and arousal and more aver- sive feelings after inhibition of anterior insula.


Considering the role of the insula in integrating bodily representations, affective and cognitive representations and expectations, dis- turbance of its function should evoke an incoherence or mismatch of the patterns of ongoing real-time basic body feedbacks, subjective feelings and beliefs about it, as well as predictions of bodily reactions based on experience.

This disturbance of the interoceptive network in its basic function, as subserved by the insula, may thus induce feelings of gen- eral discomfort, arousal and anxiety, i.e. feelings of a vague conscious notion that an otherwise intact interplay bet- ween these processes and its neuroanatomical basis has been disturbed.


Our results support the notion that the anterior insula is also a key structure for metacognitive awareness of interocep- tive processes.

This interpretation is in accordance with Farb et al. [ 56], who suggested that anterior insula activity during interoception may reflect endogenous attention demands associated with manipulation of interoception at the level of conscious awareness.

Additionally, there is evidence that the insular cortex supports different levels of representation of cur- rent and predictive states and that anterior insula activity may also reflect feelings of general uncertainty during interoception [57].

In the EPIC model of Barrett & Simmons [58], intero- ceptive perception is largely a construction of beliefs that are kept in check by the actual state of the body.

This is achieved by an 'interoceptive system' in the frontal cortex including the cingulate and the anterior insula [58] and could explain why anterior insula inhibition could also affect the whole interoceptive system including the beliefs about one's accuracy.


This also fits with assumptions of the interoceptive pre- dictive coding model of conscious presence in which the anterior insula is the likely locus of a key neural comparator mechanism [38].

This view might also explain why an inhi- bition of somatosensory cortices does not systematically reduce confidence as demonstrated for cardiac and respirat- ory signals in this study.

Leaving the anterior insula function intact does not compromise the basic integration of 'whole-body' representations, including feelings of general discomfort as described above; however, it disturbs another process that is possibly related to the evaluation/appraisal and expectations of and the matching to on-going discrete bodily reactions that have been suggested to be associated with somatosensory cortices [29].

Furthermore, tactile input from the chest might play a role in the detection of heartbeat.

While it is clear that the mechanical contraction of the myocardium generates the stimuli for heartbeat detection, the convergence of cardiac with somatosensory afferences during the transmission of information results in subjects localizing cardiac sensations in those parts of the body that share afferent trajectories with the heart.


Because cutaneous sensations are more distinctly rep- resented than visceral sensations and therefore more discriminable, sensations originating in the viscera are often referred to the skin [59].

Therefore, hampering somatosensory input from the chest region might affect cardiac perception to a greater extent than is the case for respiratory perception.

Favouring this assumption, Khalsa et al. [ 18] demonstrated that somatosensory afferents from the skin can also contrib- ute to cardiac judgements.

Another reason why effects on the respiratory load estimation task and related measures of confidence and evaluation were less pronounced might refer to the fact that we applied a fixed order (figure 1), with assessment of the respiratory system always after the car- diovascular system.

Although the prior parts of the experiment were rather short (about 8 -10 min), and though there are several studies showing that cTBS effects last at least 20 min or significantly longer [44,60], it cannot be ruled out that the effects of cTBS were already diminish- ing when compared with the assessment of interoceptive processes in the cardiovascular system.


Following Smith & Lane [29], discrete body features are represented in somatosensory cortices and disturbing these discrete features might affect the relative balance of accuracy, sensibility and confidence dimensions.

Favouring this assump- tion, both insula and somatosensory stimulation led to an increase of interoceptive sensibility as assessed by question- naire.

The HEP as a marker quantifying basic processes of automatic cardiac signal processing was found to be reduced after inhibition of anterior insula.

We suppose that the HEP pri- marily mirrored bottom-up guided automatic cardiac signal processing [7].

As sources of the HEP are located in insular, somatosensory, cingulate and prefrontal cortices (see [7]), both cTBS locations might affect these HEP generators.

The observed HEP modulation goes along with a reduction of IAc on a behavioural level for cardiac signals.


An additional hint that the interplay between different levels of interoceptive processes was affected might be the fact that cardiac IAc was not correlated to the HEP amplitude at central and frontocentral locations as observed in some former studies [8].

Mirroring behavioural results, effects on the HEP amplitude were more pronounced after insula cTBS suggesting that at least during overt attention to one's heart- beats-there was no baseline or rest condition after cTBS to compare with-this region might be more crucial for the inte- gration of cardiac signals as inhibition of right somatosensory cortices affected the HEP amplitude to a lower extent.

This assumption confirms ideas that the ability to be 'aware' of interoceptive signals is thought to depend upon further propa- gation of interoceptive signals to the anterior insula, which has been argued to reflect the integration of afferent physiological signals with higher-order contextual information [17,61], thereby becoming consciously accessible, enabling a subjective affective experience or feeling state [2].


There are several issues to be critically discussed in this study.

One essential point is that there is no guarantee of reaching the anterior insula with a TMS coil positioned over the skull.

We would argue that the effects obtained seem to be specific enough and in accordance with proposed theoretical models to say that anterior parts of the right insula were indeed targeted.


Second, further support stems from research on the auditory cortex where the topographic situ- ation is directly comparable to the attempts to stimulate primary auditory cortex in the case of tinnitus.

It has been shown that chronic tinnitus with a functional correlate in pri- mary auditory cortex can be modulated by rTMS [62,63], despite the larger distance of the coil to the primary auditory cortex ( planum temporale [64]).

Because we compared effects from the frontal stimulation site with two other sites, we are sure that the frontal effects are not unspecific but related to the particular stimulation site, at least close to the anterior insula.


An important limitation refers to the fact that there were no baseline assessments of the HEP and the IAc tasks before the respective stimulation of brain areas.

As we already used a repeated measurements design with three ses- sions per participant, we wanted to reduce effects of repetition on all tasks used.

Other experimental set-ups asses- sing only one or two locations in each participant and using a between-group design might be used in future to address this issue.


An important limitation refers to the fact that IAc in this opportunistic sample was higher than in other studies [65-67]; after occipital stimulation, the observed mean score was 0.77 when compared with, for example, 0.69 observed in a large sample of more than 400 healthy participants [66].

A cause for this might be that we assessed only male participants who have higher IAc in some studies [1,68].

It might also be the case that the TMS procedure itself increased stress and sym- pathetic activation which then, in turn, could facilitate heartbeat rstb.royalsocietypublishing.org Phil.

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B 371: 20160016 detection.

Other studies could show that a sympathetic increase as induced by short-term food deprivation [33] or physical stress [69] increased IAc.

Future studies should therefore use more participants with a greater distribution of IAc to examine whether TMS effects interact with the absolute level of IAc as found for the interplay of different interoceptive levels in a former study [4].

We nevertheless argue that changes in intero- ceptive processes on various levels, as well as modulation of the HEP amplitude, are favouring the interpretation that also in a sample with substantially lower IAc similar effects are to be expected.


Another limitation is that this study concentrated on right lateral effects of cTBS on structures of the interoceptive network.

This can be explained by the fact that right anterior insula has been identified as the most significant site that is strongly related to IAc [5,19].

The right-hemisphere anterior insular cortex provides one cortical focus for the integration of exteroceptive and interoceptive signals [17,70] and this region has been proposed as a neural substrate for self-awareness in the form of the 'material me' [71].

This may be most relevant for effects of interoceptive metacognition and interoceptive sen- sibility, and their relation to effects of IAc, as there is ample evidence for hemispheric laterality of emotion processing and cognitive functions as well as interhemispheric interplay [72].


In conclusion, this is the first study that has demonstrated that cTBS inhibiting right anterior insula and right somatosen- sory cortices efficiently disturbs different facets of interoceptive processing.

Inhibiting anterior insula resulted in a signifi- cant decline in cardiac and respiratory IAc and in a coherent decrease in perception security.

cTBS over somatosensory cortices reduced cardiac IAc and affected metacognitive aware- ness.

Inhibiting right anterior insula and right somatosensory cortices increased interoceptive sensibility.

The HEP, as marker of automatic cardiac signal processing, was decreased after cTBS over right anterior insula.

Our findings strongly suggest that cTBS is indeed an effective tool to investigate the neural network supporting interoceptive processes.

However, it remains to be further elucidated why cardiac and respira- tory perception did not perfectly match and how long TMS effects on interoceptive signal processing remain detectable.


Obviously, future studies should include a broader range of interoceptive tasks as well as a longer observation interval and should also consider potential differential effects of hemispheric laterality when investigating the function of inter- oceptive target regions of the brain via stimulation techniques.

As interoceptive processes are altered in several psychopatho- logic syndromes [6,12,21-23], brain stimulation techniques are a promising tool for interventions.

While cTBS is used to inhibit certain brain regions, other TMS protocols could be applied to improve the access to bodily sensations and empower concomi- tant therapeutic approaches as demonstrated for various disorders, e.g. in the decrease of relapse rates in depression [73].

More clinical research is needed to further elucidate future therapeutic avenues.


Ethical approval by the local ethics board was obtained.

Written informed consent was obtained.


In the field of interoception research, one outstanding question is the precise nature of the neural networks underlying interoceptive processing [1].

The anterior insula (AI) is a key component of contemporary interoception models [2].

However, most evidence implicating the AI in interoceptive processing is correlational and it remains unclear what its precise role in interoception is.

This issue was tackled by Pollatos and co-workers [3].

Using an inhibitory form of transcranial magnetic stimulation (TMS), continuous theta burst stimulation (cTBS), they aimed to provide causal evidence for the involvement of the AI in interoception.

The main results suggest that stimulation aiming to inhibit the AI or the somatosensory cortex disrupted performance, and confidence in this performance, for interoceptive tasks relative to stimulation applied to an occipital control site.

The same stimulation also altered the heartbeat evoked potential (HEP), an EEG measure thought to index cortical processing of one’s heartbeats [4].

The authors interpreted these findings as the impairment of certain aspects of interoceptive processing following cTBS to the right AI, concluding that “cTBS is an effective tool to investigate the neural network supporting interoceptive processes” [3, p. 1].

This study should be commended for its originality, the use of a within-subject design, and multiple concurrent multimodal measures of interoceptive processing.

However, two critical issues cast doubt on the conclusions that can be drawn from these data.


The AI is a deep cortical region, positioned behind frontal cortical regions (including the inferior frontal gyrus and operculum).

Because of the AI’s neuroanatomical position and depth, it is doubtful that TMS could directly reach this region with the parameters used by Pollatos and co-workers.

While anatomically near regions to the AI such as the auditory cortex have been targeted in other areas of research (e.g. using TMS to modulate tinnitus symptoms [5]), it is unclear whether the observed effects are due to stimulation of deeper regions or more lateral association areas that are more likely to be modulated by TMS (e.g. [6,7]).

TMS administered using a figure-of-eight coil is thought to only stimulate brain regions 1.5–3 cm below the scalp [8], while insula depth is estimated at 4–5 cm [9].

Direct stimulation to the cortical depth of the AI may be achieved using double-cone or helmet-shaped coils, although focality of the electrical field is compromised in comparison with superficial cortical stimulation [9].

To establish if TMS could reach the AI with the stimulation parameters employed by Pollatos and co-workers, we used the SimNIBS software [10] to run calculations of the electric field induced using these parameters.

All parameters and results of this simulation are accessible online (https://osf.io/5qbcs/).

As shown in figure 1, the results of this simulation suggest that with these stimulation parameters, only a negligible portion of the electric field reaches the AI.

In their discussion, the authors concede that “there is no guarantee of reaching the AI with a TMS coil positioned over the skull” (p. 8), but then argue that their pattern of results seems specific enough to say that the anterior part of the insula was indeed targeted.

In the light of our simulation results, we contend that it is unlikely that AI activity was directly influenced by the stimulation.


We therefore suggest two possible reinterpretations of Pollatos and co-workers’ results.

Firstly, it is possible that the AI may have been indirectly disrupted via inhibition of cortical regions it is connected to.

Indeed, there is evidence that TMS can affect activity of deeper regions through stimulation of connected cortical areas.

For example, cTBS to other frontal regions (dorsolateral prefrontal cortex) has been shown to indirectly suppress insula activation through modulation of fronto-insular connectivity ([11], see also [12]).

As direct stimulation of the AI in Pollatos et al. ’s experiment was unlikely, one reinterpretation of this data is that worsening of interoceptive performance was the result of indirect modulation of AI activity, via inhibition of more superficial cortical regions.

Alternatively, affected regions in the ventrolateral prefrontal cortex may make a unique contribution to interoceptive processes (indeed, the frontal opercular regions are also activated during interoception tasks; see [13,14]), or during non-interoceptive aspects of interoception tasks.

These cortical regions are considered to play an important role in language and decision-making [15,16], disruption to which could feasibly have impacted on the tasks used by Pollatos and co-workers.

Without control tasks however, the nature of this disruption is unclear, leading us onto our second point: it is unclear whether affected performance on the interoception tasks was specific to interoception, or reflective of a more general transient cognitive impairment.


Future researchers wishing to use similar methods to examine the role of brain regions in interoceptive processing will of course need to consider which control tasks best suit their experimental question, but it is crucial to use a control task that is similar in nature and difficulty to the interoceptive tasks in order to ensure that decrease in performance is not related to alteration of general processes such as attention, memory or sensation.

Such tasks include, but are not limited to, time estimation [17], tone perception [18] and tactile perception [19].

The absence of a control condition is also problematic for the EEG measures used.

Indeed, the authors measured the HEP over right fronto-central sites close to the AI and somatosensory stimulation sites, but further from the occipital control site.

It is therefore possible that cTBS over the right fronto-central areas altered the electrical brain response of these areas in a non-specific manner.

To claim that the disruption of electrocortical potentials caused by the stimulation is specific to the HEP, it is necessary to show that stimulation effects are not generalized to other non-interoceptive evoked potentials (e.g. visual or somatosensory evoked potentials).


In conclusion, non-invasive neurostimulation is arguably one of the most informative tools available in cognitive neuroscience and has certainly been underused in the study of interoception.

The recent report of Pollatos and co-workers is in this regard an innovative exploratory study.

However, we wish to emphasize that stimulating the AI using this technique is a challenging endeavour, and should be carried out with appropriate cautions and control conditions.


We want to respond to the two main points raised by Coll, Penton and Hobson as comment on our article ‘Changes in interoceptive processes following brain stimulation’ [1,2].

First, we want to discuss in more detail the question raised by Coll and co-workers in their comment, namely which regions were stimulated by our set-up.

We are grateful to the authors providing results of a simulation of field distribution using SimNIBS.

Indeed, as we already addressed in the discussion of our article, we cannot be sure that transcranial magnetic stimulation (TMS) directly reaches the anterior insula (AI).

We also refer to the arguments already discussed in our article, but especially important for this issue: The topographic situation when stimulating the AI is directly comparable with the attempts to stimulate primary auditory cortex in the case of tinnitus referring to the auditory cortex. And it has been shown that chronic tinnitus can be modulated by rTMS [3,4], despite the larger distance of the coil to the primary auditory cortex (planum temporale, e.g. [5]).

However, field simulation only demonstrates field distribution relative to a given range.


As it is not yet possible to determine a threshold for a cortical stimulation site (with the exception of primary motor cortex and visual cortex) we do not know down to which relative field strength neurons respond to the TMS pulses.

Using the field model provided by Coll, Penton and Hobson in their comment, we compared the field distribution windowed from 0 to 2.2 (maximum of norm E-field) with a window from 0 to 1 norm E-field (figure 1).

Here, at least the upper part of the AI is directly reached by a field strength of about 0.5, about a quarter of the maximum norm E-field.

Of course, large parts of prefrontal and temporal cortex covering the insula are exposed to a higher field strength.

We can neither exclude a trans-synaptic activation of the AI from prefrontal cortex closer to the skull, nor a direct contribution of areas exposed under the coil to the observed effects.


The second main point refers to the question whether these effects are specific to interoceptive processes.

The authors argue that the study lacks a control condition not related to interoceptive processes targeting attention processes or working memory performance in general that might be affected by frontal stimulation.

We want to argue against the claim that attention processes or working memory performance in general might underlie the observed results after frontal stimulation.

Effects of inhibiting somatosensory cortices were comparable in many aspects to effects of inhibiting AI, both on performance level as well as on EEG level as assessed by the HEP.

These results contradict the idea that a change in interoceptive processes might be due to side effects of the TMS frontal stimulation site and therefore a general effect of affecting attention or working memory circuits.

We in contrast argue that the fact that major results were comparable between stimulation sites aiming to inhibit AI and somatosensory cortices is a strong empirical evidence that indeed nodes of the interoceptive network were affected by TMS and that these effects were specific for interoceptive processes and are not related to other main functions in attention or working memory.

We agree with the authors that a control task e.g. assessing performance and acoustic evoked potentials measured by EEG might have been a useful condition to prove whether TMS stimulation sites have an impact on other functions not related to interoceptive processes, but as TMS effects are time critical we decided to use a control site instead of a control condition as suggested by the authors.


We conclude that further empirical evidence is needed to further elucidate whether observed results can be replicated and are specific for interoceptive target areas, e.g. using new methodological approaches such as protocols with combined TMS stimulation and neuroimaging.


- Using the Heisenberg uncertainty principle, we may infer that for detecting an arbitrarily small scale, tools of sufficiently high energy (high momen- tum) are required.

Thus, essential quantum phenomena must be probed at high energies.

Interestingly, gravity also becomes important at high energies.

Therefore, we must resort to quantum gravity theories when trying to address fundamental areas of physics.

One of the major aims of physics has always been to reconcile gravity and quantum mechanics in the same framework and possibly arrive at a consistent and complete theory of quantum gravity.

In this regard, many theories such as string the- ory, canonical quantum gravity etc. have been formulated that have emerged as strong candidates for the same.


Interestingly, all theories of quantum gravity and black hole physics predict the existence of minimum length scale called the Planck length (l pl ≈ 10 −35 m) [1-7].

This leads to the modification of usual Heisenberg uncertainty prin- ciple.

The new uncertainty relation that we get from these theories is called the generalized uncertainty prin- ciple (GUP) [4, 8-12].

The GUP as derived from string theory and black hole physics is given as : ∆p∆x ≥ 2 1 + β 0 l 2 pl 2 ∆p 2 (1) where, l pl = G c 3 = 10 −35 m is the Planck length and β 0 is a constant, assumed to be of the order of unity.

Evidently, the new second term on the RHS of the above equation is important only when ∆x ≈ l pl or ∆p ≈ p pl ≈ 10 16 TeV/c (Planck momentum) i.e. at very high energies / small length scales.


The commutator algebra between x i , p j from string theory and double special relativity can be reconciled into [11,13]: [x i , p j ] = i δ ij − α pδ ij + p i p j p + α 2 (p 2 δ ij + 3p i p j ) (2) where α = α0 M pl c = α0l pl .

Here α 0 is normally assumed to be of the order of unity.

Both ∆x min and ∆p min arise as an implication of the above algebra.

In one dimension, it leads to the following form of GUP [7]:


The above mentioned modified Heisenberg algebra can be derived if we represent the position and momentum oper- ators in the following way [7]: x i = x 0i , p i = p 0i (1 − αp 0 + 2α 2 p 2 0 ) (4) where x 0i and p 0j satisfy the usual canonical commuta- tion relations [x 0i , p 0j ] = i δ ij and are interpreted as low energy position and momenta respectively.

On the other hand x i and p i are the position and momentum at high energy respectively.

Since α 0 is of the order of unity, α dependent terms become important only at energy (mo- mentum) scales comparable to Planck energy (momen- tum) scale.

The GUP and its effects have been studied p-1 H. Verma et al. extensively over the past decade [14]- [35].

Apart from its important implications in cosmology [15-17] and black hole physics [18, 19], Klein-Gordan [30] and Dirac equa- tions [21, 31] have also been modified to include quantum gravity effects.

Various non-relativistic quantum systems such as particle in a box, SHO, Landau levels [7, 32], co- herent and squeezed states [26-29,33], PT symmetric non- Hermitian systems [23-25] have been investigated in the framework of GUP to note the effects of quantum gravity in those.

A particularly interesting case with a proba- ble observable effect has been developed in [7] by study- ing variations in current of scanning tunnel microscope (STM) when tunnelling phenomenon is subject to GUP corrections.


Recently, GUP modified angular momentum algebra has been constructed and the corrections in CG coefficients due to GUP are obtained [34].

However, their results are inconsistent (as mentioned by the authors themselves) as the CG coefficients obtained by applying J − to the highest J m value state and is different from that of obtained by applying J + to the lowest J m value state.

This motivate us to revisit the coupling angular momentum in the frame- work of GUP.

In this work, we construct GUP modified angular momentum algebra by using Schwinger's model of angular momentum (SMAM) [36].


In the first step we develop the operator formulation for the GUP modified SHO.

By modifying the creation/annihilation operators appropriately, we write the GUP modified SHO hamilto- nian as ω 2 [A † A + AA † ] with the commutation relation between A and A † as [A, A † ] = 1 + O(α).

Angular mo- mentum algebra is then constructed by considering two such independent oscillators.

This GUP modified alge- bra is then used to study two-particle angular momentum system.

We explicitly calculate the CG coefficients.

We found CG coefficients obtained by applying J − and J + are same unlike the case in Ref.

[ 34].

We further found that CG coefficients remain unaffected in upto quadratic GUP, even though the angular momentum algebra gets modi- fied.

This is very interesting result in the GUP framework.

However, it is not surprising as the GUP modified angular momentum algebra can be mapped to usual angular mo- mentum algebra by redefining the Planck constant.


We now present the plan of the paper.

In the next section, we develop the complete GUP modified formalism of SHO in the operator formulation and then use SMAM to derive GUP modified angular momentum algebra in Sec. 3.

We discuss angular momentum coupling in a composite two- particle system in the GUP framework in Sec.4.

In Sec. 5, CG coefficients are calculated explicitly for two particles system.

Finally, Sec. 6 is for the concluding remarks.


GUP modified Harmonic Oscillator. - In this section, we discuss the operator formulation of SHO in the framework of GUP using both high energy and low energy momentum variables.


The corrections to the harmonic oscillator model due to GUP have been ad- dressed mostly using perturbation theory [7] and also treated in phase space [35].

In the present work, we formulate the operator formalism for the GUP corrected SHO.

The GUP modified harmonic oscillator hamiltonian is given as: H = ω x 2 x ′2 + p 2 p ′2 (5) where x and p are the high energy position and momen- tum operators.

This GUP corrected Hamiltonian can be written in terms of low energy operators upto O(α 2 ) as :


Here, H 1 is the correction due to GUP, x ′ = 2 mω and p ′ = √ 2m ω and x 0 and p 0 are usual low energy position and momentum operators respectively.

Now we modify the usual creation (a † ) and annihilation (a) operators of 1-d harmonic oscillator in the following manner:


in which, the usual creation/annihilation operators a † = x0 x ′ − i p0 p ′ and a = x0 x ′ + i p0 p ′ are modified by replacing p = p 0 (1 − αp 0 + 2α 2 p 2 0 ) and x = x 0 and including corrections to the order α (β 1 (x 0 , p 0 )) and α 2 (β 2 (x 0 , p 0 )).

We demand the Hamiltonian in Eq.6 to be in the following form: H = ω 2 (AA † + A † A) (10) by constructing appropriate β 1 and β 2 as given by:


We now calculate the commutator [A, A † ], which comes out upto O(α 3 ) as: [A, A † ] = 1 − 2αp 0 + 6α 2 p 2 0 ≡ 1 − C. (13) where C is the correction due to GUP.

In absence of GUP corrections, i.e. when α = 0, this formulation reduces to p-2


Schwinger's Model of Angular Momentum with GUP the usual operator formulation of 1-d SHO.

We now wish to redefine the creation/annihilation operators in GUP corrected formalism.

For this purpose, we henceforth con- sider the GUP corrections as C rather than C. This has been considered under the assumption that, in experimen- tal conditions, GUP correction to any operator manifests as expectation value.

In the next section, we will use the GUP modified creation/annihilation operators to gener- ate the angular momentum algebra.

Therefore, C is the averaged value of GUP corrections and our assumption stands correct (Ref.

[ Eq.36] in [34]).

Hence, Eq. 13 is rewritten as:


We may now assume two new operatorsÃ andÃ † such that,


Here,Ã = A/ 1 − C andÃ † = A † / 1 − C .

If |1 , |2 , ..., |N are eigenvectors of Hamiltonian in Eq.10, then, in a general momentum regime, we can write,


where, C = 2α p 0 − 6α 2 p 2 0 such that commutation relation in Eq. 14 is satisfied.

In the above equations and in the later sections, we have expressed GUP effects solely in terms of expectation value of C based on aforementioned arguments.


Now, we would like to show that conclusion of the previous section can also be achieved while remaining in the high momentum regime (i.e. GUP modified momentum).

The GUP modified cre- ation/annihilation operators A and A † are defined in terms of high energy variables (x,p) as: A † = x x ′ − i p p ′ (20) A = x x ′ + i p p ′ (21) where x and p are in high momentum regime and x ′ = 2 mω and p ′ = √ 2m ω.

Then the GUP modified Hamil- tonian is written as H = ω 2 [AA † + A † A] and the commu- tator [A, A † ] in the regime is obtained as: [A, A † ] = 1 − 2αp + 4α 2 p 2 (22) which is exactly same as in Eq.13 when p is expressed in terms of low energy variables as p = p 0 (1 − αp 0 + 2α 2 p 2 0 ).


In general momentum regime, similar to the discussion for low energy momentum, we have,


Schwinger's Model of Angular Momentum. - In this section, we would like to calculate the GUP modified angular momentum algebra by considering two such GUP modified harmonic oscillators.

Two uncoupled SHOs (we call them type 1 and 2) are considered with number states denoted as n 1 and n 2 with their usual independent alge- bra.

Then the general eigenket is constructed in SMAM as:


and similar relations are obtained when a † 2 and a 2 act on these states.

Next, in SMAM the following angular mo- mentum operators are constructed [36]:


which satisfy the angular momentum algebra [L z , L ± ] = ± L ± , [L + , L − ] = 2 L z .

We now make a canonical trans- formation to n 1 and n 2 in the above.


Then, the Eq.28, 29, 30 reduce to the usual form of angular momentum algebra as shown in Eq.32, 33, 34


where λ ± = [(l ∓ m)(l ± m + 1)] 1/2 and the eigenvalues of the quadratic operator L 2 become


Thus, we see that angular momentum algebra is con- structed using two SHO algebra when eigenstates are re- labelled by replacing |l + m, l − m by |l, m .

We follow the same technique now for GUP modified harmonic oscilla- tor in the high energy momentum regime.

Repeating the p-3 H. Verma et al. same steps of SMAM (Eq.32,33,34,35) with GUP modified SHO algebra (Eq. 22, 23,24), we obtain,


The form L x , L y are then constructed using:


We now find the various commutation relations between


Thus, we have,


Similarly, on calculation using Eq.36,37,38,39, we get the following :


Commutation relation given by Eq.44 implies that the lad- der operator doesn't change the magnitude of total angu- lar momentum (l).

Also, due to occurrence of the correc- tion factor term, the spacing between consecutive eigen- values of L z changes.


Also, Eq. 47 implies that L ± |l, m is an eigenstate of L z .

Now, using,


we can calculate the norm of raised lowered states L ± |l, m as,


Therefore, as in the usual quantum mechanics [36] we have limit on the values of m, which we denote m max (maxi- mum m value or upper bound) and m min (minimum m value or lower bound).

Application of raising operator L + on state characterised by m max and lowering operator L − on state characterised by m min would both give zero i.e.


Clearly, we observe that if we consider → (1 − C ) in the usual QM, we get the GUP modified formalism, where C = 2α p − 4α 2 p 2 .


Effect on two-particle system.

- Till now all the algebra derived above involves single particle.

In this sec- tion, the effect of GUP on multi-particle algebra will be examined.

We will start with two-particle angular momen- tum algebra and the results can be extended for N-particle systems accordingly.


Consider the addition of angular momentum includ- ing GUP for a system of two particles with l i and m i (i = 1, 2) ,the azimuthal and magnetic quantum numbers of the particles.

The total angular momentum and the z−component for the composite system is


We have two alternative choices of the basis for represent- ing the combined system as


1. With simultaneous eigenkets of


We chose the later one and the combined state in Hilbert space is represented as,


Gordan coefficients.

The CG coefficients may be calcu- lated by applying J − .

To discuss the addition of angular momentum for this composite system further, we need the following equations.

Operating J z on the combined state we obtain Eq.53, 54.

The following point may be noted in analogy to ordinary quantum mechanics and as done in [34],


Now, let us consider the ladder operator for two - particle system.


From the commutation relations Eq.42,43 we find that,


where, C 1 , C 2 are the correction factors due GUP for |j 1 , j 2 ; m 1 , m 2 state for first and second particle respec- tively.

Also, for any state expressed as in Eq.52, we have found the operation of J z J ± on the RHS states.

As for the LHS of Eq.52, the solution is easy to calculate.

Eq.60 shows that the RHS is no longer an eigenstate of J z , un- like the α = 0 case.

The above discussions on two- particle system can be also generalised for a system of N-particles on similar lines as done above.


In this section we calculate the Clebsch-Gordan coeffi- cients explicitly for two particles.

We start with the high- est m value state in the highest multiplet and apply J − . which lowers the m value.

We now resort to the notation


The coefficient is j 1 ; j 2 | J m , J m = 1 by normaliza- tion.


2. For J = J m , M = J m − 1 :


By applying J − we calculate,


Normalization of |J m , J m − 1 in Eq.62 provides,


3. For J = J m , M = J m − 2 :


Applying J − again we obtain Eq. 64 Normalization of |J m , J m − 2 in Eq.64 provides Eq. 65 In the same manner we can find the coefficients for all other states in this (highest) multiplet.

The normalization conditions in the above states implies C 1 = C 2 = C .

This condition is further consistent with normalization of all other states.

This in turn implies that the CG coefficients are independent of C 1 , C 2 and C .

CG coefficients for states in other multiplets then are obtained by using standard method and naturally are found to be independent of C 1 , C 2 and C .


Now we proceed to find the coefficients using J + . Let us start with the initial lowest m value state in the highest multiplet.

We obtain the following results


1. For J = J m , M = −J m , where J m stands for J max = (j 1 + j 2 ):


The coefficient is −j 1 ; −j 2 | J m , J m = 1 by normal- ization.


2. For J = J m , M = −J m + 1 :


We get ,


On normalization of |J m , −J m + 1 in Eq.67 , we get the following condition:


J = J m , M = −J m + 2 which on calculation gives Eq.69 Again, on normalization, of |J m , −J m + 2 in Eq.69 , we get the condition given in Eq. 70.


The solution of normalization conditions in Eqs 68 and 70 implies that C 1 = C 2 = C .

This condition is fur- ther consistent with normalization of all other states.

This further implies that the C 1 , C 2 and C dependence is dropped out from the Eqs 67 and 69 and hence all the CG coefficients are independent of C 1 , C 2 and C .


The above results can be verified explicitly with specific examples.

We have verified it for J 1 = 1 2 = J 2 , J 1 = 1 = J 2 and J 1 = 1 2 , J 2 = 3 2 .

However, the results for two spin p-5 H. Verma et al.


1/2 particles only are presented below.


The normalization to the states |1, 0 and |1, −1 provide condition similar to Eq.63,65 and are now written as


Solving both the equations simultaneously, we get, C = C 1 = C 2 This condition is consistent with the normal- ization of the state |0, 0 .

Also, if the starting state is considered as the normalized state |J = 1, M = −1 = | − 1/2; −1/2 , we obtain from Eq.68, 70, the same condi- tions as Eq.63, 65 and hence conclude the same condition on C, C 1 , C 2 .

With this information, we find the CG co- efficients for the specific case where j 1 = j 2 = 1/2 and m 1 (or m 2 ) = ±1/2 from Eq.62, 64, 67, 69 and list them in the table 1 .


In case of standard QM, the CG-coefficients for a par- ticular state are always same irrespective of the method of calculation, i.e, using J + or J − .

The same thing is true for GUP modified quantum mechanics also.

This resolves the anomaly reported in [34] where CG coefficients obtained by applying J − to the highest J m value state are differ- ent than that of when calculated by applying J + to the lowest J m value state in the same multiplet.

We further showed that CG coefficients do not receive any correction due to quadratic order GUP and any angular momentum coupling remains unaffected even though the angular mo- mentum algebra gets modified.

Explicit examples were also considered to support our claim.

Further this result can be generalized for all composite systems in a straight- forward manner.


of which we have tried to address in the paper.


Using this formalism and SMAM, we have derived GUP mod- ified angular momentum algebra.


While the GUP SHO may be useful in its own right, the angular momentum al- gebra developed may be used to investigate GUP induced effects in Hydrogen atom, Quantum Rotor and other mod- els involving the angular momenta operators.


As such, a wide number of problems in atomic and molecular physics can be approached using the algebra developed.


Further, using this GUP modified angular momentum algebra, we have studied the effect of GUP in the coupling of angular momentum for an arbitrary two particle composite sys- tem.


We have also found the associated CG coefficients in the GUP modified systems.


Some anomalies in calculating CG coefficient reported in the literature are removed in our formulation.


Interestingly, we observe that CG coefficients receive no corrections up to quadratic GUP.


This has been verified explicitly for two particle systems.


The coupling of angular momentum remains unaffected to quantum grav- ity effects is indeed an important result and may have very important consequences in the study of Black holes and many other astro-physical problems where gravity plays an important role.


In this note, we show that the methodology and conclusions of “Schwinger’s Model of Angular Momentum with GUP” [2] are flawed and that the conclusions of “Generalized Uncertainty Principle and angular momentum” (P. Bosso and S. Das) [1] remain valid.


In [1], we studied the modification of the angular momentum algebra dictated by a modification of the commutation relations between position and momentum.

This led to interesting results concerning the angular momentum spectrum, energy spectrum of the hydrogen atom, interactions between magnetic fields and angular momenta, and a description of multi-particle systems, including corrections to Clebsch-Gordan coefficients.

Among the noteworthy results of that paper, we have that the commutation relations for angular momentum operators now involve also functions of the linear momentum operator.

However, following usual steps, we showed that the spectrum involves only expectation values of this function.

Notice that the appearance of expectation values at this level is not the result of any approximation or assumption.


On the other hand, when the radial Schrödinger equation for the hydrogen atom is studied, the assumption that the modification appears only via its expectation value is considered. This is clearly an approximation, useful in that the equation resembles that of standard quantum mechanics with corrections that have implications in the emission/absorption wavelengths.

It is important to notice that this approximation is considered only in the study of the hydrogen atom and of the interaction between magnetic fields and angular momenta.

The rest of [1] does not rely on this assumption.


That paper concludes with an analysis of the theory of angular momentum for systems of many particles.

Specifically, we computed some of the Clebsch-Gordan coefficients.

We showed that the Clebsch-Gordan coefficients are modified due to GUP.

However, we also showed that the modification is associated with an ambiguity: coefficients for the same system but computed starting from higher or lower angular momentum states are in general different.

This is something to expect, because the spectrum of the angular momentum operators, as well as the action of the ladder operators J+ and J-, is influenced by the linear momentum of the states to which they are applied.

This ambiguity is a direct consequence of the modified position-momentum uncertainty relation considered in [1] and needs further study.


Verma et al., in [2], have tried a possible resolution of the above ambiguity.

Below, we comment on the main aspects of their paper.


Ladder operators for a simple harmonic oscillator (SHO): The authors define a couple of operators, A and A†, in terms of the position and momentum operators.

As the authors themselves show, these operators are not ladder operators for a SHO since [A, A†] ≠ 1.

To avoid this problem, they divide each operator by the square root of the expectation value of [A, A†].

This strategy can only be considered as an approximation, not as a rigorous method to obtain ladder operators.

Furthermore, this approximation leads to trivial results, effectively accounting for a scaling of the Planck constant.

Finally, it is not necessary.

In fact, it is always possible to construct a new set of operators that act as ladder operators for the GUP-modified system under study, as shown in [3] (see [4] for an application).


Substituting the modification C by its expectation value: The authors motivate its use by saying that it was previously used in our work [1].

However, as we explained above, this is not entirely true.

This substitution was in fact used to obtain GUP-modifications for some specific examples, namely the hydrogen atom and the magnetic field-angular momentum interaction, and which can potentially be verified experimentally.

However, the rest of the results in [1] are not based on such substitution.

In particular, the commutation relations between angular momentum operators are computed implementing directly the modified commutation relation between position and momentum operators.

Furthermore, the appearance of the expectation value ⟨C⟩ in the angular momentum spectrum was derived from rigorous standard procedures.

Nonetheless, this does not motivate in general an indiscriminate substitution C → ⟨C⟩.


The Jordan map and Schwinger’s model for the angular momentum: The Jordan map connects a set of matrices to a set of harmonic oscillator operators [5].

In the specific case of the angular momentum, to each matrix representing an angular momentum operator, with elements J_ij, the Jordan map associates an operator J = Σ_ij J_ij a†_i a_j.

Therefore, in the standard theory of quantum mechanics, we find the following expressions [6].

Notice that the expressions, used by Verma et al. in [2], are constructed from the representation of the angular momentum operators as Pauli matrices.

A property of the Jordan map is that it preserves commutation relations.

In other words, whatever the commutation relations for the angular momentum matrices are, the operators in terms of ladder operators will have the same relations, since they are inherited from the matrices.

Notice therefore that (i) the procedure used in [2] is flawed, because their A, A† operators are not ladder operators, as explained above, (ii) tautological, as starting from a representation of the standard (non GUP) angular momentum algebra, the authors use the Jordan map to find the commutation relations for the angular momentum operators, which necessarily are the standard one.


As a final comment, it is worth noticing that their results concerning the commutation relations of the angular momentum operators do not match the results in [1], obtained via direct computations.


Clebsch-Gordan coefficients for a system of two particles with GUP: Finally, we comment on the computation of the Clebsch-Gordan coefficients.

The authors compute the coefficients starting from a maximal angular momentum state and applying the operator J- = j1,- + j2,-.

They proceed by imposing normalization conditions.


It is important at this point to focus on a particular aspect.

Consider the tower of states derived by repeated applications of J- on the top state |L, L⟩. Each of these states has to be normalized independently from the others.

On the other hand, each of these states can be in general represented in multiple ways in terms of the constituent states.

More precisely, given a total angular momentum state |L, M⟩, this describes any composition of two systems, with angular momentum states |l1, m1⟩ and |l2, m2⟩, such that |l1 - l2| ≤ L ≤ l1 + l2 and M = m1 + m2.

In particular, for every value M, in general several configurations will be possible such to obtain different values of L. Every choice of these compositions is described by a different Clebsch-Gordan coefficient.


Having this picture in mind, it is clear that the normalization of Clebsch-Gordan coefficients has to be performed considering the independent normalization of states |L, M⟩ with different values M and the orthogonality among the states of equal M but different L. However, in [2] the authors seem to normalize states belonging to different values of M simultaneously, resulting in constraints such as ⟨C1⟩ = ⟨C2⟩ = ⟨C⟩, where C1 and C2 represent the modifications associated with the two constituent systems, while C is the modification associated with the entire system.

Such a relation is clearly unacceptable, since it implies conditions on the linear momenta of a composite system and its constituents.

Since the constituents’ momenta are independent physical quantities, no such conditions can exist.

Furthermore, the only condition on the composite momenta is that it is the vector sum of the constituent momenta.


The results of [1], therefore, still stand, and the objections raised in [2] are invalid.

Nevertheless, it is possible that a correct application of the Jordan map to the GUP-modified angular momentum operators may be a useful tool in gaining insight into the problem in question and its possible resolution.


Introduction.

– Through this document, we wish to respond to the comments [1] made on our manuscript entitled “Schwinger’s model of angular momentum with GUP”.

First of all, the authors have wrongly presumed that we have invalidated/questioned their results in [2].

In the abstract section, they claim that their work is valid, on which, we made no claims suggesting the contrary in the paper [3].

In fact we have used some of their results in our work.


The only issue which we found was that the Clebsch-Gordan (CG) coefficients for the same state, obtained in their work by applying J− and J+ operators were different.

This is clearly unacceptable.

This situation can be better described with the word “inconsistency” rather than with the word, “ambiguous”.

We feel that there was, in fact, no ambiguity in the mathematical calculations of CG coefficients using the operators J− and J+ in their works.

In our work we have removed this inconsistency.


Now, we shall try to address the specific points raised by the authors.


Comments.


Ladder operators for simple harmonic oscillator.

We tried to construct the ladder operators using the proposition that the Hamiltonian be expressed as H = ¯hω 2 (AA† + A†A).

We then found the commutation relation between the operators.


The authors have suggested that the method adopted is not rigorous and leads to a seemingly trivial result.

We would like to emphasize that the results are mathematically correct and may have led to rescaling of Planck’s constant but that is not wrong or violates any first principles in physics or more specifically, anything in operator formalism/algebra.


The later discovery of ladder operators for GUP-modified systems by the authors themselves [4] was absent during the formulation of the manuscript and we concur that it proposes a more rigorous method.

That does not deem any of the previous works unnecessary or wrong.


In fact any scientific progress does not necessarily negate or out-date the previous works.

Therefore, we strongly disagree with the comments made by the authors in this particular context.


Substituting the modification of C by its expectation value.

The authors seem to have not noticed the peculiarity in their own paper [2] or may have ignored an important aspect of the aforementioned substitution.

We certainly borrowed this result from their work which has been used in that paper extensively.

This has been done for many angular-momentum operators specifically ladder operators for angular momenta.

This is clear from eq. ( 104) which has been taken from eq. ( 30) [2].

If C is not replaced by ⟨C⟩ in the angular-momentum algebra, the algebra is not closed, which will lead to difficulties in describing angular-momentum coupling and calculating the CG coefficients.

We made the substitution motivated by their work only and, therefore, if the substitution of C by ⟨C⟩ is questionable in our work, it is questionable in their work, too.


In this reference, apart from the equations mentioned before, we would like to point out that eq. ( 30) falls under sect.

3 with heading “Modified angular momentum spectrum” in their paper and is specifically L±|plm⟩ = ¯h(1−C) L(L + 1) − M (M ± 1)|plm±1⟩ whereas eq. ( 104) falls under the sect.

6 with heading “Multi particles system” and reads L±|plm⟩ = ¯h(1 − ⟨C⟩) L(L + 1) − M (M ± 1)|plm ± 1⟩. The authors have wrongfully claimed that the above substitution of C with ⟨C⟩ was only made in the context of hydrogen atom.

On examination, one discovers that hydrogen atom is described in a totally different section, sect.

4, and in no way relates sect.

3 to sect.

In fact one can independently calculate “Multi particles systems” angular-momentum algebra from “Modified angular momentum spectrum” which we hope that the authors would inarguably agree with.


The introduction of hydrogen atom section in this discussion is totally unwarranted and serves no purpose at all.

This fact is clearly indicated just above eq. ( 104) in their paper where it is mentioned that eq. ( 104) is obtained from eq. ( 30).

Their final results on CG coefficients rely heavily on eq. ( 104) and hence, indirectly on the argued substitution.

That being said, we have also clearly mentioned our motivation in this context in the paper which is that we wish to use the harmonic-oscillator formalism to derive angular-momentum algebra which, in turn, is used to derive the coupling of angular momentum —essentially a physical phenomenon.


The Jordan map and Schwingers model for the angular momentum.

Nowhere have the authors questioned the mathematical formulation and calculation of the result using Schwinger’s model of angular momentum.

Rather they have pointed it out as trivial or “tautological”.

Again, we subscribed to the basic formalism suggested and used it to obtain angular-momentum algebra which, of course, is not incorrect.

Just because it leads to the same commutation result it should not be interpreted as “tautological”.

We do concur that the correction factor obtained for GUP correction in angular-momentum operators is different from [2].

This only invites more research and insight into the field.


Clebsch-Gordan coefficients for a system of two particles with GUP.

The coupled angular-momentum states in [2] are not normalized and hence, the CG coefficients associated in those states have no physical meaning.

This further leads to the inconsistency in the CG coefficients in their work (see, for example, eqs. ( 106), (107)).

We do concur that the different |L, M⟩ states should be normalized separately and should be orthogonal to states with different L value [5].


By the single solution suggested in our paper, one can carry out the normalizations and orthogonalization for all the angular-momentum states in a given system, simultaneously.

This formulation has been shown to work for 2-particles system of arbitrary individual spins.

We do not rule out the possibility of other solutions to this problem for systems with more than two particles.

Conforming to the proposed solution, one obtains a strong condition on C, C1 and C2.


Conclusions.

– In the light of the arguments being raised, we would reiterate the correctness in physics and mathematics in our paper.

In conclusion, we cannot agree with the comments made.

We do concur that our results affirm the angular-momentum algebra derived in their paper though using a different approach.

That being said, they have correctly pointed out that the correction factor due to GUP up to quadratic order is slightly different.

This is a point of worry and we feel that the understanding of angular momentum under GUP is not at all complete.


A 28-year-old man sought care for a diffuse vesicu- lar rash that had developed over the preceding 24-48 hours.

He had traveled on a flight from Lagos, Nige- ria, and arrived in the United States the day he sought care.

While in Nigeria, he visited relatives, stayed in hotel lodging without travel to rural regions, and had no interactions with animals or animal carcasses.

Dur- ing his flight from Lagos, he noticed a burning sensa- tion on his skin, followed by development of discrete vesicles on his forehead and nose, which spread to his arms, trunk, and inner thighs over several hours.

He denied having associated symptoms, including fever, chills, or headache.


At examination, we observed right cervical lymphadenopathy and numerous 2-4-mm pustules on an erythematous base.

Some of these pustules had central umbilication and were present dif- fusely with acrofacial propensity, favoring the face, neck, and hands.

A few 2-3-mm round erosions were noted on the oral mucosa, and an intact pus- tule was observed on the lower mucosal lip (Figure 1).

The patient was given intravenous acyclovir for empiric treatment of disseminated varicella zoster virus infection, admitted, and subjected to contact and airborne isolation precautions pending further evaluation.

Within 24 hours of admission, no new


A case of monkeypox was diagnosed in a returning trav- eler from Nigeria to Maryland, USA.

Prompt infection con- trol measures led to no secondary cases in 40 exposed healthcare workers.

Given the global health implications, public health systems should be aware of effective strat- egies to mitigate the potential spread of monkeypox.


We obtained a 4-mm punch biopsy specimen from an intact pustule on the abdomen of the pa- tient.

This specimen showed epidermal necrosis, reticular degeneration, and vesiculation by staining with hematoxylin and eosin.

We found dyskeratotic keratinocytes, neutrophil exocytosis, and intracyto- plasmic inclusion bodies consistent with Guarnieri bodies in the epidermis.

We also detected a diffuse, mixed, superficial dermal infiltrate of lymphocytes, histiocytes, neutrophils, and occasional eosinophils (Figure 2).


Based on the travel history of the patient and his- topathologic findings, we suspected monkeypox, likely acquired by human contact in the absence of any ani- mal exposures.

Additional specimens of the skin lesions were identified by the Maryland Department of Health as non-variola orthopox by real-time reverse transcrip- tion PCR (RT-PCR) and the CDC Laboratory Response Network protocol.

CDC used viral culture and RT-PCR to confirm the diagnosis of monkeypox, further iden- tifying the specimen as part of the West African clade, which has driven the outbreak in Nigeria since 2017.


Upon confirmation of the monkeypox diagno- sis, we identified all healthcare workers (HCWs) involved in the case and classified 40 as contacts by CDC guidelines (8).

No HCW met the criteria for high-risk exposure, and no doses of preventive small- pox vaccine were administered.

Hospital-based pub- lic health officials contacted each HCW daily for 21 days (the duration of incubation period for monkey- pox) and instructed them to measure their tempera- ture twice a day and monitor any symptoms.

At the conclusion of the surveillance period, we did not de- tect disease transmission.


Previously considered a rare zoonotic infection, hu- man monkeypox has reemerged as a clinically seri- ous disease after decades of quiescence.

Monkeypox has an overall case-fatality rate of up to 11% (1), and increasing human populations have no immunity to poxvirus; therefore, future progress in understanding monkeypox is critical.

The World Health Organization Research and Development Blueprint in 2018 classi- fied monkeypox as an emergent disease requiring ac- celerated research, development, and public health action (8).

The epidemic potential of monkeypox was demonstrated during the outbreak in the United States in 2003, and had the predominant virus strain been the more virulent and aggressive Congo Basin strain instead of a virus in the West African clade, a higher mortality rate would have been possible (9).


Although the public health experience addressing monkeypox in the United States has been limited, this case illustrates the effectiveness of the basic principles of infection control: rapid identification and isolation of the index patient; use of personal protective equip- ment by HCWs; and thorough contact tracing, includ- ing monitoring for secondary cases throughout the totality of the incubation period.

Using these interven- tions alone, our hospital system and community were able to avoid additional disease transmission.

Hospital systems should ensure that their healthcare teams, par- ticularly frontline workers, are aware of infection con- trol policies, especially pertaining to patients with pos- sible infectious diseases.

In particular, any patient who has a fever and disseminated vesicular or pustular rash should immediately be placed on airborne and contact precautions because these are the typical symptoms as- sociated with orthopoxvirus infection (10).


Although vaccination was not required in this case, public health recommendations to prevent secondary disease transmission of monkeypox include the small- pox vaccine (11).

The vaccine has been estimated to con- fer 85% protection against monkeypox (12), and waning population immunity since routine smallpox vaccine administration ended is postulated to have contributed to its resurgence (2).

The 2 Food and Drug Admin- istration-approved vaccines are ACAM2000 and JYNNEOS.

Either vaccine can be administered pre- emptively for monkeypox exposures, which is recom- mended for persons involved in monkeypox outbreak investigations.

JYNNEOS is a nonreplicating, live vi- rus, licensed specifically for monkeypox prevention; ACAM2000 is the only recommended vaccine for mon- keypox postexposure prophylaxis.

On the basis of the ef- fectiveness of postexposure smallpox vaccine, the CDC advises postexposure prophylaxis to high-risk contacts within 4 days and up to 14 days of initial contact with monkeypox (11).

This intervention has been safely and effectively used by public health officials in the United States, the United Kingdom, and Singapore (5,6,13).


In addition to smallpox vaccine, vaccinia im- mune globulin is available and can be used as pro- phylaxis for severely immunocompromised pa- tients (when smallpox vaccine should be avoided), although the benefit is unclear (10).

The Food and Drug Administration-approved antiviral drugs to treat smallpox are tecovirimat and brincidofovir, which can also be used to treat monkeypox, but there are no monkeypox-specific antiviral drugs for treatment or postexposure prophylaxis.

Because there are multiple orthopoxvirus vaccine guidance documents, formulation of consolidated recommen- dations is ongoing (14).


In summary, we report a case of monkeypox in a traveler returning to the United States from Nigeria and review infection control measures to prevent sec- ondary cases.

Multiple appearances beyond disease- endemic countries indicate that monkeypox has be- come a relevant travel-related disease, and physicians should remain vigilant in combatting transmission of this virus.


To the Editor: Costello et al. described a patient in Maryland, USA, with a diffuse vesicular rash initially diagnosed as disseminated varicella zoster virus (VZV) infection.

Only after a biopsy revealed unexpected findings was monkeypox suspected [1].

Monkeypox is commonly confused with VZV in countries where both infections are endemic.

High fever, lymphadenopathy, and a deep-seated, well-circumscribed, umbilicated rash in the same stage of development (i.e., macule, papule, vesicle, or scab) in distinct anatomic locations are characteristic of monkeypox [2].

Although the patient in Maryland experienced lymphadenopathy and rash with umbilicated lesions suggestive of monkeypox, he was afebrile, denied other prodromal signs and symptoms (e.g., headache and chills) that typically precede monkeypox rash, and improved while receiving intravenous acyclovir, features more consistent with VZV.


However, the unusual clinical signs and symptoms experienced by this patient were similar to those observed in other patients in the evolving 2022 multinational monkeypox response.

Because differential diagnosis can be challenging, public health authorities should be consulted promptly when monkeypox is possible.

US Laboratory Response Network laboratories (https://emergency.cdc.gov/lrn) can enable rapid testing of specimens (e.g., lesions swab), and pathogen-specific antiviral medications can be acquired through consultation with the Centers for Disease Control and Prevention.

Public health investigation for a single case of monkeypox can be intensive and complicated; case-patient contacts outside of the hospital must be identified, monitored, and potentially given 1 of the 2 orthopoxvirus vaccines offered for postexposure prophylaxis in the United States [3-5].


Factors that should raise suspicion for monkeypox in a patient with related signs and symptoms include history of travel outside of the United States to a country with confirmed cases or where monkeypox virus is endemic, contact with a person with a similar-appearing rash or who has received a diagnosis of confirmed or probable monkeypox, contact with Africa-endemic wild animal or pet species (living or dead), or use of a product derived from those animals (e.g., game meat, creams, lotions, powders).

Monkeypox should also be considered in patients with close or intimate contact with persons in social networks experiencing high monkeypox activity, including men who have sex with men who meet partners through a website, digital application, or social event.

Prompt consultation with public health authorities is essential for providing clinical guidance, expediting testing and treatment, and preventing secondary cases [3].


We appreciate Minhaj et al. for their correspondence regarding our experience treating an imported case of monkeypox from an international traveler [1].

Their letter reaffirms the instructive points of our case: monkeypox poses a diagnostic challenge because its clinical presentation shares features with a variety of additional infectious diseases, including varicella zoster virus (the infection we initially suspected), and prompt coordination with public health officials is critical for diagnosing, treating, and mitigating secondary spread.


Since our report of monkeypox in November 2021, there have been outbreaks of monkeypox throughout multiple countries [2], including one case identified in the United States [3].

Monkeypox had never previously been diagnosed in several of these countries and, remarkably, in only 1 of these cases [4] was there a history of travel to a monkeypox-endemic country, in direct contrast to nearly all prior cases that have been reported outside of Africa [5-7], which were epidemiologically linked to a monkeypox-endemic region.


In our case report [8], we had concluded that monkeypox had become clinically relevant within the confines of a travel-related illness.

However, the additional cases diagnosed since November 2021 strongly suggest that community transmission is now occurring, and a history of travel to a monkeypox-endemic country is no longer prerequisite to contracting this disease.

Community prevalence rates remain unknown, so healthcare providers should consider monkeypox in any patient who manifests with fever and lymphadenopathy accompanied by a disseminated vesicular, pustular, or umbilicated rash.

Under those conditions, the provider should immediately initiate infection control and contact public health authorities.

Monkeypox is an emerging zoonotic disease with incompletely appreciated clinical features, and healthcare providers should be made aware of its increasingly widespread incidence.


The objective of the present study was to evaluate the use of a single lumen 16 G central venous catheter for the drainage of uncomplicated pleural effusions in intensive care unit patients.


A prospective observational study was performed in two intensive care units of university- affiliated hospitals.

The study involved 10 intensive care unit patients with non-loculated large effusions.

A 16 G central venous catheter was inserted at the bedside without ultrasound guidance using the Seldinger technique.

The catheter was left in situ until radiological resolution of the effusion.


Fifteen sets of data were obtained from 10 patients.

Three patients had catheters inserted for bilateral pleural effusions.

One of these patients, who suffered from chronic pancreati- tis, subsequently had a unilateral left pleural effusion drained twice during further re-admissions to hospital.

Twelve sets of data were obtained when the patients were mechanically ven- tilated.


Four patients had pancreatitis, with the remaining six patients having a variety of underlying medical conditions including perforated intra-abdominal viscus, liver transplantation and recent cardiac surgery.

Three of these patients had pneumo- nia complicating their primary medical condition.

Table 1 summarises the biochemical profile of the pleural fluid and the cumulative volume of effusion drained at 1, 6 and 24 hours post catheter insertion.

The mean volumes drained at 1, 6 and 24 hours were 454 ± 241 ml, 756 ± 403 ml and 1010 ± 469 ml, respectively.

As we did not simultaneously determine serum lactate dehydrogenase levels and serum total protein levels, we classified exudates as having pleural fluid lactate dehydrogenase levels ≥ 200 IU [6] or pleural fluid total protein levels ≥ 30 g/l [7].

Twelve samples were classi- fied as exudates and two samples as transudates.

The results for one sample were not available.


No patients had a pneumothorax on the first radiograph per- formed within 8-12 hours after catheter insertion and on review of subsequent radiographs.

There were no instances of hemothorax or re-expansion pulmonary edema.

None of the catheters slipped out and there were no accidental discon- nections of the drainage system.


All ventilated patients were successfully weaned.

Mechanical ventilation was avoided in the three instances where the large effusions had caused respiratory distress in these non- intubated patients.

The longest duration that a single catheter remained in situ was 14 days, and it drained a total of 5050 ml over this period.

This same patient had a contralateral catheter inserted, which drained 6030 ml over 11 days.

In total, five patients had the catheter in situ for between 7 and 9 days.

The daily drainage ranged from 70 to 1700 ml/day.

There were no instances of catheter blockage despite fibrinous material being seen in the collection bag of two patients.


The use of an indwelling 16 G central venous catheter is efficacious in draining uncomplicated large pleural effusions.

It is well tolerated by patients and is associated with minimal complications.

It has the potential to avoid repeated thoracentesis or the use of large-bore chest tubes.


This study was conducted in the ICUs of a Singaporean hos- pital and an Australian hospital.

Informed consent was obtained from the patient or a relative.

Ten patients were studied prospectively.

Patients were included if they had large pleural effusions clinically and on a chest radiograph, which were judged to be contributing significantly to their res- piratory impairment.

Patients were excluded if there was a suspicion that the effusions were loculated, if they had signifi- cant pre-existing coagulation abnormalities or if they had structural chest abnormalities.

Ultrasound confirmation of the non-loculated nature of the effusion was obtained in three patients.


The procedure was performed with the patient lying in a semi- recumbent manner at an angle of 45° because most of the patients were ventilated and sedated.

The ipsilateral arm was raised over the head and held in place by the nurse assistant.

The site of insertion was determined by physical examination or had been marked by the ultrasound technician in the three cases where the ultrasound investigation had been per- formed.

The skin was prepared with 0.05% chlorhexidine (Baxter, Old Tongabbie, Australia) and 10% povidine-iodine solution and was then draped in a sterile manner.

Local anes- thetic (3-5 ml of 1% lidocaine) was infiltrated from the subcu- taneous plane down to the parietal pleura with a 21 G needle.

Pleural fluid was aspirated via this needle to confirm its free flowing consistency.