Acute social isolation evokes midbrain craving responses similar to hunger

May combine two claims.

In the midbrain functional ROI, social cues were numerically but not significantly higher after isolation than baseline and showed a trend to be lower after fasting.

“whereas social cues were numerically but not significantly higher after isolation than baseline and showed a trend to be lower after fasting (b = 0.01, t = −1.8, 95% CI = (−0.11,−0.004), P = 0.07”

• AssumptionRests on an assumption: The baseline day represents a nondeprived state for both food and social needs.

May combine two claims.

Self-reported food craving on fasting days and social contact craving on isolation days were both higher than on the baseline day.

“Self-reported food craving on fasting days and social contact craving on isolation days were both higher than on the baseline day (Food_Craving_CIC: t(39) = 7.94, P < 0.001, two tailed; Social_Craving_CIC: t(39) = 4.15, P < 0.001, two tailed).”

• AssumptionRests on an assumption: The baseline day represents a nondeprived state for both food and social needs.

May combine two claims.

Midbrain regions showed selective responses to food cues after fasting and to social cues after isolation.

“Midbrain regions showed selective responses to food cues after fasting and to social cues after isolation.”

May combine two claims.

Self-reported cravings for food and social interaction were moderately correlated at baseline, but less correlated after either need was deprived.

“self-reported cravings for food and social interaction were moderately correlated at baseline (r = 0.48), but less correlated after either need was deprived (mean r = 0.14, z = 1.64, P = 0.05).”

May combine two claims.

An exploratory whole-brain random-effects analysis yielded selective responses to food craving in the NAcc, ACC, periaqueductal gray and amygdala, and selective responses to social craving in the caudate, OFC and dorsomedial prefrontal cortex.

“An exploratory whole-brain, random-effects analysis yielded converging results: selective responses to food craving in the NAcc, ACC, periaqueductal gray and amygdala, and selective responses to social craving in the Ca, OFC and dorsomedial prefrontal cortex”

• AssumptionRests on an assumption: The CIC task cues, including pictures of favorite social activities, favorite foods and flowers, selectively evoke craving for the deprived target.

May combine two claims.

Despite the restricted sample, substantial variability between individuals was observed at baseline in both self-reported social craving and SN/VTA response to social cues.

“Yet despite our restricted sample, we observed substantial variability between individuals at baseline, in both self-reported social craving and in SN/VTA response to social cues.”

May combine two claims.

The study found a more selective SN/VTA response to social cues after isolation, as well as to food cues after fasting.

“In all, our finding of a more selective SN/VTA response to social cues after isolation, as well as to food cues after fasting, fits the intuitive idea that positive social interactions are a basic human need, and acute loneliness is an aversive state that motivates people to repair what is lacking, similar to hunger.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The two social network size measures were highly correlated (r(39) = 0.58, P < 0.001).

“However, because the measures were highly correlated (r(39) = 0.58, P < 0.001), we z-transformed and averaged the two measures for each participant.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Data for food craving were truncated at the upper limit of 10.

“As the data for food craving were truncated at the upper limit of 10 (Fig. 3c)”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the unsmoothed data, there was no above-chance decoding (α = 0.001) of social cues from flowers after isolation (mean accuracy = 0.521, bootstrapped CI = (0.503,0.542), P = 0.041) or after baseline (mean accuracy = 0.526, bootstrapped CI = (0.501,0.546), P = 0.021).

“In the unsmoothed data, we found no above-chance decoding (α = 0.001) of social cues from flowers after isolation (mean accuracy = 0.521, bootstrapped CI = (0.503,0.542), P = 0.041) or after baseline (mean accuracy = 0.526, bootstrapped CI = (0.501,0.546), P = 0.021).”

Probably not a substantial claim: may not pass S3 (load-bearing).

In unsmoothed data, the classifier was unable to decode food cues from flowers after isolation and baseline (isolation: mean accuracy = 0.522, bootstrapped CI = (0.500,0.544), P = 0.021; baseline: mean accuracy = 0.525, bootstrapped CI = (0.501,0.557), P = 0.022).

“In addition, in unsmoothed data, the classifier was also unable to decode food cues from flowers after isolation and baseline (isolation: mean accuracy = 0.522, bootstrapped CI = (0.500,0.544), P = 0.021; baseline: mean accuracy = 0.525, bootstrapped CI = (0.501,0.557), P = 0.022).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Omission of smoothing showed slightly lower mean accuracy across subjects (mean accuracy = 0.542), but still resulted in successful above chance (50%) decoding of food cues from flower images after fasting (P = 0.002, 95% CI = 0.513-0.570).

“In the present study, we found that omission of smoothing showed slightly lower mean accuracy across subjects (mean accuracy = 0.542), but still resulted in successful above chance (50%) decoding of food cues from flower images after fasting (P = 0.002, 95% CI = 0.513–0.570).”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the unsmoothed data, the authors were not able to decode stimulus or motivational state across sessions.

“we also ran the classification analyses on unsmoothed data and found that we were not able to decode stimulus or motivational state across sessions in the unsmoothed data”

May combine two claims.

The study sample was small (n = 40) and consisted of healthy, well-connected young adults, mostly students, in one cultural context.

“A second limitation is that we studied a small sample (n = 40) of healthy, well-connected young adults, mostly students, in one cultural context.”

Classified as probably not a substantial claim.

In domains such as drug addiction and hunger, researchers have struggled to establish a gold-standard behavioral metric of subjective craving with better external validity than self-report.

“Note, however, that, also in domains such as drug addiction and hunger, researchers have struggled to establish a gold-standard behavioral metric of subjective craving with better external validity than self-report45.”

• cites [45] Sayette, M. A. et al. The measurement of drug craving. Addiction 95, S189–S210 (2000). sourceNot checked yet

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May combine two claims.

These results suggest a reliable individual difference in craving responses after deprivation, shared across both fasting and isolation, consistent with a common neural response to both modes of deprivation.

“These results suggest that there is a reliable individual difference in craving responses after deprivation, shared across both fasting and isolation, consistent with our observation of a common neural response to both modes of deprivation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Chronic loneliness could be a consequence, rather than a cause, of general low responsiveness in the SN/VTA.

“Chronic loneliness could thus be a consequence, rather than a cause, of general low responsiveness in the SN/VTA.”

May combine two claims.

Responses in the SN/VTA were similar and overlapping for food craving and social craving, whereas responses in the striatum were dissociable.

“Thus, although the responses in SN/VTA were similar and overlapping for food craving and social craving, responses in the striatum were dissociable.”

May combine two claims.

At baseline participants' motivation may be spread across multiple sources of reward, and specific acute deprivation may serve to narrow and focus the brain's motivational responses to the deprived target, rather than to enhance it.

“Thus, at baseline participants’ motivation may be spread across multiple sources of reward, and specific acute deprivation may serve to narrow and focus the brain’s motivational responses to the deprived target, rather than to enhance it.”

• AssumptionRests on an assumption: The baseline day represents a nondeprived state for both food and social needs.

Classified as probably not a substantial claim.

The study measured craving using passive viewing of craving-related cues and self-report measures of craving, rather than a direct test of motivation such as willingness to expend effort or money.

“First, we measured craving using passive viewing of craving-related cues and self-report measures of craving, rather than a direct test of motivation, such as participants’ willingness to expend effort or money to fulfill a need.”

May combine two claims.

Despite differences in duration and setting of social isolation and in anatomy of DA midbrain structures, both humans and mice seem to show midbrain craving responses for social interaction, as well as for food.

“Despite differences in the duration and setting of social isolation, and in the anatomy of DA midbrain structures, both humans and mice seem to show midbrain craving responses for social interaction, as well as for food.”

Classified as probably not a substantial claim.

Fasting was confirmed through self-report on arrival.

“Fasting was confirmed through self-report on arrival.”

• AssumptionRests on an assumption: Participants adhered to the 10 h food fasting.

Probably not a substantial claim: may not pass S3 (load-bearing).

The study did not measure people's social behaviors at baseline or other traits broadly relevant to social interaction.

“We did not measure people’s social behaviors at baseline (for example, number and quality of social interactions) or other traits broadly relevant to social interaction (for example, trait extroversion, depression, anxiety).”

May combine two claims.

The finding fits the idea that positive social interactions are a basic human need and acute loneliness is an aversive state that motivates people to repair what is lacking, similar to hunger.

“In all, our finding of a more selective SN/VTA response to social cues after isolation, as well as to food cues after fasting, fits the intuitive idea that positive social interactions are a basic human need, and acute loneliness is an aversive state that motivates people to repair what is lacking, similar to hunger.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The order of the three experimental sessions was counterbalanced between participants, with pseudo-random assignment such that all six possible sequences were approximately equally likely in the full sample.

“Between participants, the order of sessions was counterbalanced; each participant was pseudo-randomly assigned to one of the possible orders of the three different sessions, with the restriction that all six possible sequences were approximately equally likely in the full sample.”

Probably not a substantial claim: may not pass S3 (load-bearing).

An initial power analysis targeted detection of medium effects (d = 0.5, α = 0.05, 1 − β = 0.80) and suggested a sample size of n = 34.

“An initial power analysis in G*Power 3.0 (ref.51) targeted on the detection of medium effects (d = 0.5, α = 0.05 and 1 − β = 0.80) suggested a sample size of n = 34.”

• cites [51] Faul, F., Erdfelder, E., Lang, A. G. & Buchner, A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods 39, 175–191 (2007). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Forty-two participants were recruited to account for potential attrition or exclusion for MRI data quality; 2 were dropped, leaving 40 complete datasets.

“We therefore recruited 42 participants to account for potential attrition or exclusion for MRI data quality; 2 participants were unable to complete all experimental sessions and so were dropped from analysis, leaving 40 complete datasets.”

Classified as probably not a substantial claim.

The targeted effect size was chosen based on findings from studies employing CIC paradigms for drug craving, food cravings, and internet gaming craving, which report medium-to-large effect sizes in cue reactivity.

“The targeted-effect size was chosen based on findings from studies employing CIC paradigms for drug craving52, food cravings25,37,53,54 and internet gaming craving27, which report medium-to-large effect sizes in cue reactivity52.”

• cites [52] Carter, B. L. & Tiffany, S. T. Meta-analysis of cue-reactivity in addiction research. Addiction 94, 327–340 (1999). sourceNot checked yet

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• cites [25] Malik, S., McGlone, F., Bedrossian, D. & Dagher, A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab. 7, 400–409 (2008). sourceNot checked yet

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• cites [37] Goldstone, A. P. et al. Fasting biases brain reward systems towards high-calorie foods. Eur. J. Neurosci. 30, 1625–1635 (2009). sourceNot checked yet

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• cites [53] Stice, E., Burger, K. & Yokum, S. Caloric deprivation increases responsivity of attention and reward brain regions to intake, anticipated intake, and images of palatable foods. Neuroimage 67, 322–330 (2013). sourceNot checked yet

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• cites [54] Stevenson, R. J., Francis, H. M., Attuquayefio, T. & Ockert, C. Explicit wanting and liking for palatable snacks are differentially affected by change in physiological state, and differentially related to salivation and hunger. Physiol. Behav. 182, 101–106 (2017). sourceNot checked yet

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• cites [27] Zhang, J. T. et al. Effects of craving behavioral intervention on neural substrates of cue-induced craving in Internet gaming disorder. Neuroimage Clin. 12, 591–599 (2016). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The scanning parameters were extensively piloted (n = 11) using the functional localizer task, and the parameters showing the best signal-to-noise ratio were selected for the study.

“The scanning parameters were extensively piloted (n = 11) using the functional localizer task (see “Functional localizer task”) and the parameters showing the best signal-to-noise ratio were selected for the study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Data collection was not performed blind to the conditions of the experiments.

“Data collection was not performed blind to the conditions of the experiments.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Any run containing a framewise displacement >0.4 mm on >25% of the total frames was excluded from additional analyses.

“Any run containing a framewise displacement >0.4 mm on >25% of the total frames was excluded from additional analyses.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A potential limitation of the functional localizer approach is that it targeted voxels responding to secondary reinforcers (money) rather than primary reinforcers (food and social contact).

“A potential limitation of this approach is that it was targeting voxels responding to secondary reinforcers (that is, money) rather than primary reinforcers (such as food and social contact).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Conditioned stimuli are somewhat less effective than primary rewards in terms of response magnitude and fractions of neurons activated.

“Conditioned stimuli are somewhat less effective than primary rewards in terms of response magnitude and fractions of neurons activated67.”

• cites [67] Schultz, W. Getting formal with dopamine and reward. Neuron 36, 241–263 (2002). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The functional localization method was complementary to an anatomical ROI, which would not be affected by the secondary-reinforcer issue.

“In addition, our functional localization method was complementary to an anatomical ROI, which would not be affected by this issue.”

Classified as probably not a substantial claim.

In animal models, dopamine neurons in the midbrain exhibit burst firing in response to both primary reinforcers and conditioned stimuli once conditioning has been established.

“In animal models, dopamine neurons in the midbrain exhibit burst firing in response to both primary reinforcers and conditioned stimuli once the conditioning has been established (for example, see refs.65,66).”

• cites [65] Day, J. J., Roitman, M. F., Wightman, R. M. & Carelli, R. M. Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens. Nat. Neurosci. 10, 1020–1028 (2007). sourceNot checked yet

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• cites [66] Overton, P. & Clark, D. Burst firing in midbrain dopaminergic neurons. Brain Res. Rev. 25, 312–334 (1997). sourceNot checked yet

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Classified as probably not a substantial claim.

Midbrain DA neurons in the SN/VTA respond to both novelty and reward.

“As midbrain DA neurons in the SN/VTA respond to both novelty and reward62–64, we contrasted new and rewarding stimuli against familiar and nonrewarding stimuli.”

• cites [62] Krebs, R. M., Heipertz, D., Schuetze, H. & Duzel, E. Novelty increases the mesolimbic functional connectivity of the substantia nigra/ventral tegmental area (SN/VTA) during reward anticipation: evidence from high-resolution fMRI. Neuroimage 58, 647–655 (2011). sourceNot checked yet

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• cites [63] Bunzeck, N. & Duzel, E. Absolute coding of stimulus novelty in the human substantia nigra/VTA. Neuron 51, 369–379 (2006). sourceNot checked yet

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• cites [64] Schultz, W. Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology. Curr. Opin. Neurobiol. 14, 139–147 (2004). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The slice angle was approximately 20° away from the plane of the standard anterior commissure-posterior commissure to avoid placing the SN/VTA and the sphenoid sinus in the same slice plane, reducing geometric distortion to the point that standard distortion correction methods could be applied.

“The angle of the slices was approximately 20° away from the plane of the standard anterior commissure–posterior commissure to avoid placing the SN/VTA and the sphenoid sinus in the same slice plane. This reduced geometric distortion to the point that standard distortion correction methods could be applied28.”

• cites [28] Duzel, E. et al. Midbrain fMRI: applications, limitations and challenges. in fMRI: From Nuclear Spins to Brain Functions (eds Uludağ, K., Uğurbil, K. & Berliner, L.) 581–609 (Springer, 2015). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Three participants missed filling out the first or last round of the online questionnaire during fasting, so analyses involving this questionnaire used n = 37.

“Three participants missed filling out the first or last round of the online questionnaire during fasting, so statistical analyses involving this questionnaire were conducted with a sample size of n = 37.”

Probably not a substantial claim: may not pass S4 (based).

Both food and social cues would be similarly affected by the functional localizer limitation, so the key claim of similarity between these responses would not be undermined.

“Importantly, both food and social cues would be similarly affected, so our key claim of similarity between these responses would not be undermined.”

Probably not a substantial claim: may not pass S3 (load-bearing).

By localizing the SN/VTA based on activity in response to anticipated financial rewards, the study may have identified only a subset of voxels that respond to primary rewards.

“Thus, by localizing the SN/VTA based on activity in response to anticipated financial rewards, we may have identified only a subset of voxels that respond to primary rewards.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The preregistered hypotheses focus on the anatomical localization strategy, so analyses of the functionally localized regions are treated as exploratory.

“However, our preregistered hypotheses focus on the anatomical localization strategy, so we treat analyses of the functionally localized regions as exploratory.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Exclusion criteria were pre-established in the preregistration, and three runs of fMRI data from two participants were excluded based on the framewise displacement criterion.

“Exclusion criteria were pre-established in our preregistration (https://osf.io/cwg9e). We excluded three runs of fMRI data from the overall sample (from two participants from the CIC task) based on the following criterion: any run containing a framewise displacement >0.4 mm on >25% of the total frames will be excluded from additional analyses.”

Classified as probably not a substantial claim.

SN/VTA activity is sensitive to novelty.

“The stimuli were images of strangers, rather than images of the participant’s own friends and family, to (1) match the food and control images for novelty, because SN/VTA activity is sensitive to novelty62, (2) match image quality across conditions and participants, and (3) avoid unmeasured variability in the quality or current status of participants’ relationships with specific individuals.”

• cites [62] Krebs, R. M., Heipertz, D., Schuetze, H. & Duzel, E. Novelty increases the mesolimbic functional connectivity of the substantia nigra/ventral tegmental area (SN/VTA) during reward anticipation: evidence from high-resolution fMRI. Neuroimage 58, 647–655 (2011). sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The method of correction for multiple comparisons used in the exploratory whole-brain analyses is probably biased toward false positives.

“We note that this method of correction for multiple comparisons is probably biased toward false positives97,98.”

• cites [97] Eklund, A., Knutsson, H. & Nichols, T. E. Cluster failure revisited: impact of first level design and physiological noise on cluster false positive rates. Hum. Brain Mapp. 40, 2017–2032 (2019). sourceNot checked yet

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• cites [98] Eklund, A., Nichols, T. E. & Knutsson, H. Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proc. Natl Acad. Sci. USA 113, 7900–7905 (2016). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The nonparametric permutation approach used for group-level hypothesis testing does not depend on assumptions about the distribution of classification accuracies.

“This nonparametric approach does not depend on assumptions about the distribution of classification accuracies94,95.”

• cites Stelzer et al.94 Stelzer, J., Chen, Y. & Turner, R. Statistical inference and multiple testing correction in classification-based multi-voxel pattern analysis (MVPA): random permutations and cluster size control. Neuroimage 65, 69–82 (2013). sourceNot checked yet

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• cites [94] Stelzer, J., Chen, Y. & Turner, R. Statistical inference and multiple testing correction in classification-based multi-voxel pattern analysis (MVPA): random permutations and cluster size control. Neuroimage 65, 69–82 (2013). sourceNot checked yet

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• cites [95] Allefeld, C., Görgen, K. & Haynes, J.-D. Valid population inference for information-based imaging: from the second-level t-test to prevalence inference. Neuroimage 141, 378–392 (2016). sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

The Craving_CIC measure was exactly comparable across sessions and simultaneous with the fMRI data acquisition.

“This measure was exactly comparable across sessions and simultaneous with the fMRI data acquisition.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The authors corrected for multiple comparisons using whole-brain family-wise error correction.

“We corrected for multiple comparisons using whole-brain family-wise error correction.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Smoothing has been shown not to substantially affect information in multivariate data.

“Although smoothing has been shown not to substantially affect information in multivariate data91–93”

• cites [91] Hendriks, M. H. A., Daniels, N., Pegado, F. & Op de Beeck, H. P. The effect of spatial smoothing on representational similarity in a simple motor paradigm. Front. Neurol. 8, 222 (2017). sourceNot checked yet

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• cites [92] Kamitani, Y. & Sawahata, Y. Spatial smoothing hurts localization but not information: pitfalls for brain mappers. Neuroimage 49, 1949–1952 (2010). sourceNot checked yet

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• cites [93] Op de Beeck, H. P. Against hyperacuity in brain reading: spatial smoothing does not hurt multivariate fMRI analyses? Neuroimage 49, 1943–1948 (2010). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The Craving_Q measure provides the most direct measure of the effect of deprivation because it can be compared with the self-report at the start of each session.

“but this measure provides the most direct measure of the effect of deprivation because it can be compared with the self-report at the start of each session.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Statistical inference for the exploratory whole-brain analyses was performed using a threshold of P < 0.05 corrected for multiple comparisons over the whole brain, using the Gaussian random fields approach at cluster level with a voxel-level intensity threshold of P < 0.001.

“These analyses were exploratory and statistical inference was performed using a threshold of P < 0.05 corrected for multiple comparisons over the whole brain, using the Gaussian random fields approach at cluster level with a voxel-level intensity threshold of P < 0.001 (ref.96).”

• cites ref.96Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Following the recommendation of Barr et al., maximal models were used, including participants as a random effect with both random intercepts and random slopes.

“Following the recommendation of Barr et al.87, we used maximal models, including participants as a random effect with both random intercepts and random slopes.”

• cites [87] Barr, D. J., Levy, R., Scheepers, C. & Tily, H J. Random effects structure for confirmatory hypothesis testing: keep it maximal. J. Memory Lang. 68, 255–278 (2013). sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The planned analyses modeled effects in the anatomically defined SN/VTA (preregistered analysis) and in the functionally defined ROI (exploratory analysis).

“We modeled these effects in the anatomically defined SN/VTA (preregistered analysis) and in the functionally defined ROI of voxels maximally sensitive to reward and novelty (exploratory analysis).”