A new angle on transcranial magnetic stimulation coil orientation: A targeted narrative review.

Transcranial magnetic stimulation (TMS) is used to treat several neuropsychiatric disorders including depression, where it is effective in approximately half of patients for whom pharmacological approaches have failed. Treatment response is related to stimulation parameters such as the stimulation frequency, pattern, intensity, location, total number of pulses and sessions applied, as well as target brain network engagement. One critical but underexplored component of the stimulation procedure is the orientation or yaw angle of the commonly used figure-of-eight TMS coil, which is known to impact neuronal response to TMS. However, coil orientation has remained largely unchanged since TMS was first used to treat depression and continues to be based on motor cortex anatomy which may not be optimal for the dorsolateral prefrontal cortex treatment site. This targeted narrative review evaluates experimental, clinical, and computational evidence indicating that optimizing coil orientation may potentially improve TMS treatment outcomes. The properties of the electric field induced by TMS, the changes to this field caused by the differing conductivities of head tissues, and the interaction between coil orientation and the underlying cortical anatomy are summarized. We describe evidence that the magnitude and site of cortical activation, surrogate markers of TMS dosing and brain network targeting considered central in clinical response to TMS, are influenced by coil orientation. We suggest that coil orientation should be considered when applying therapeutic TMS and propose several approaches to optimizing this potentially important treatment parameter.

The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Exploring Brain and Heart Interactions during Electroconvulsive Therapy with Point-of-Care Ultrasound.

BACKGROUND: Electroconvulsive therapy (ECT) is a procedure commonly used to treat a number of severe psychiatric disorders, including pharmacologic refractory depression, mania, and catatonia by purposefully inducing a generalized seizure that results in significant hemodynamic changes as a result of an initial transient parasympathetic response that is followed by a marked sympathetic response from a surge in catecholamine release. While the physiologic response of ECT on classic hemodynamic parameters such as heart rate and blood pressure has been described in the literature, real-time visualization of cardiac function using point-of-care ultrasound (POCUS) during ECT has never been reported. This study utilizes POCUS to examine cardiac function in two patients with different ages and cardiovascular risk profiles undergoing ECT. METHODS: Two patients, a 74-year-old male with significant cardiovascular risks and a 23-year-old female with no significant cardiovascular risks presenting for ECT treatment, were included in this study. A portable ultrasound device was used to obtain apical four-chamber images of the heart before ECT stimulation, after seizure induction, and 2 min after seizure resolution to assess qualitative cardiac function. Two physicians with expertise in echocardiography reviewed the studies. Hemodynamic parameters, ECT settings, and seizure duration were recorded. RESULTS: Cardiac standstill was observed in both patients during ECT stimulation. The 74-year-old patient with a significant cardiovascular risk profile exhibited a transient decline in cardiac function during ECT, while the 23-year-old patient showed no substantial worsening of cardiac function. These findings suggest that age and pre-existing cardiovascular conditions may influence the cardiac response to ECT. Other potential contributing factors to the cardiac effects of ECT include the parasympathetic and sympathetic responses, medication regimen, and seizure duration with ECT. This study also demonstrates the feasibility of using portable POCUS for real-time cardiac monitoring during ECT. CONCLUSION: This study reports for the first time cardiac standstill during ECT stimulation visualized using POCUS imaging. In addition, it reports on the potential differential impact of ECT on cardiac function based on patient-specific factors such as age and cardiovascular risks that may have implications for ECT and perioperative anesthetic management and optimization.

Transcranial Magnetic Stimulation in Primary Care: Indications, Risks, and Outcomes.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2024;26(2):23f03614. Author affiliations are listed at the end of this article.

Development and validation of a multimodal neuroimaging biomarker for electroconvulsive therapy outcome in depression: a multicenter machine learning analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, monocenter studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers. The objective of this study was to develop and validate neuroimaging biomarkers for ECT outcome in a multicenter setting. METHODS: Multimodal data (i.e. clinical, sMRI and resting-state fMRI) were collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluate which data modalities or combinations thereof could provide the best predictions for treatment remission (HAM-D score ⩽7) using a support vector machine classifier. RESULTS: Remission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82-0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers (N = 109), and remained acceptable when validated using leave-one-site-out cross-validation (0.70-0.73 AUC). CONCLUSIONS: These results show that multimodal neuroimaging data can be used to predict remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. Future development of a clinical decision support tool applying these biomarkers may be feasible.

Predicting Dimensional Antidepressant Response to Repetitive Transcranial Magnetic Stimulation using Pretreatment Resting-state Functional Connectivity.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression and has been shown to modulate resting-state functional connectivity (RSFC) of depression-relevant neural circuits. To date, however, few studies have investigated whether individual treatment-related symptom changes are predictable from pretreatment RSFC. We use machine learning to predict dimensional changes in depressive symptoms using pretreatment patterns of RSFC. We hypothesized that changes in dimensional depressive symptoms would be predicted more accurately than scale total scores. Patients with depression (n=26) underwent pretreatment RSFC MRI. Depressive symptoms were assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17). Random forest regression (RFR) models were trained and tested to predict treatment-related symptom changes captured by the HDRS-17, HDRS-6 and three previously identified HDRS subscales: core mood/anhedonia (CMA), somatic disturbances, and insomnia. Changes along the CMA, HDRS-17, and HDRS-6 were predicted significantly above chance, with 9%, 2%, and 2% of out-of-sample outcome variance explained, respectively (all p<0.01). CMA changes were predicted more accurately than the HDRS-17 (p<0.05). Higher baseline global connectivity (GC) of default mode network (DMN) subregions and the somatomotor network (SMN) predicted poorer symptom reduction, while higher GC of the right dorsal attention (DAN) frontoparietal control (FPCN), and visual networks (VN) predicted reduced CMA symptoms. HDRS-17 and HDRS-6 changes were predicted with similar GC patterns. These results suggest that RSFC spanning the DMN, SMN, DAN, FPCN, and VN subregions predict dimensional changes with greater accuracy than syndromal changes following rTMS. These findings highlight the need to assess more granular clinical dimensions in therapeutic studies, particularly device neuromodulation studies, and echo earlier studies supporting that dimensional outcomes improve model accuracy.

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Measures of Cortical Excitability: A Systematic Review and Considerations for Clinical Practice.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative for the treatment of major depressive disorder (MDD), although its clinical effectiveness varies substantially. The effects of sex hormone fluctuations on cortical excitability have been identified as potential factors that can explain this variability. However, data on how sex hormone changes affect clinical response to rTMS is limited. To address this gap, we reviewed the literature examining the effects of sex hormones and hormonal treatments on transcranial magnetic stimulation (TMS) measures of cortical excitability. Results show that variations of endogenous estrogen, testosterone, and progesterone have modulatory effects on TMS-derived measures of cortical excitability. Specifically, higher levels of estrogen and testosterone were associated with greater cortical excitability, while higher progesterone was associated with lower cortical excitability. This highlights the importance of additional investigation into the effects of hormonal changes on rTMS outcomes and circuit-specific physiological variables. These results call for TMS clinicians to consider performing more frequent motor threshold (MT) assessments in patients receiving high doses of estrogen, testosterone, and progesterone in cases such as in vitro fertilization, hormone replacement therapy, and gender-affirming hormonal treatments. It may also be important to consider physiological hormonal fluctuations and their impact on depressive symptoms and the MT when treating female patients with rTMS.

Brain volumetric correlates of electroconvulsive therapy versus transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) are effective neuromodulation therapies for treatment-resistant depression (TRD). While ECT is generally considered the most effective antidepressant, rTMS is less invasive, better tolerated and leads to more durable therapeutic benefits. Both interventions are established device antidepressants, but it remains unknown if they share a common mechanism of action. Here we aimed to compare the brain volumetric changes in patients with TRD after right unilateral (RUL) ECT versus left dorsolateral prefrontal cortex (lDLPFC) rTMS. METHODS: We assessed 32 patients with TRD before the first treatment session and after treatment completion using structural magnetic resonance imaging. Fifteen patients were treated with RUL ECT and seventeen patients received lDLPFC rTMS. RESULTS: Patients receiving RUL ECT, in comparison with patients treated with lDLPFC rTMS, showed a greater volumetric increase in the right striatum, pallidum, medial temporal lobe, anterior insular cortex, anterior midbrain, and subgenual anterior cingulate cortex. However, ECT- or rTMS-induced brain volumetric changes were not associated with the clinical improvement. LIMITATIONS: We evaluated a modest sample size with concurrent pharmacological treatment and without neuromodulation therapies randomization. CONCLUSIONS: Our findings suggest that despite comparable clinical outcomes, only RUL ECT is associated with structural change, while rTMS is not. We hypothesize that structural neuroplasticity and/or neuroinflammation may explain the larger structural changes observed after ECT, whereas neurophysiological plasticity may underlie the rTMS effects. More broadly, our results support the notion that there are multiple therapeutic strategies to move patients from depression to euthymia.

Extension of transcranial magnetic stimulation treatment for depression in non-responders: Results of a naturalistic study.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) shows efficacy in the treatment of major depressive disorder using a standard course of 20-36 treatment sessions. However, research efforts are being made to improve overall response and remission rates. Evidence from open-label extension studies of randomized control trials suggests that extending the rTMS treatment course beyond 36 treatments may improve outcomes, however, little has been published on the benefit of extended TMS treatment courses in clinical practice. OBJECTIVE: In this retrospective naturalistic observational study, we studied response rates on continuation of rTMS following failure of the first round of 36 treatments. METHODS: From 142 patients who received conventional rTMS and 29 who underwent theta-burst stimulation (TBS) at Massachusetts General Hospital TMS clinical service, 28 non-responders (23 to rTMS and 5 to TBS) opted to continue their treatment beyond session 36. The treatment protocol allowed personalization in target, TMS protocol, as well as number of pulses and sessions as clinically indicated. Sustained response and remission using Hamilton Rating Scale for Depression, 17-items (HAMD-17) was the primary outcome. RESULTS: The average number of overall treatment sessions was 70.54 ± 16.73 for the sample. Overall, there was a 53.57% response rate and a 32.14% remission rate. Response and remission rates rose as the number of sessions increased and there did not appear to be a plateau in response over time. CONCLUSION: Our results support the idea that subpopulation of TMS patients are late responders. Continuation of TMS up to 72 treatments among those patients who do not meet response criteria by session 36 may improve overall response rates. While the number of subjects and study design limit generalization, given the fact that these patients were medication refractory and had failed initial course of TMS, the result of this study is encouraging.

Electroconvulsive therapy effects on anhedonia and reward circuitry anatomy: A dimensional structural neuroimaging approach.

BACKGROUND: Anhedonia is a core symptom of major depressive disorder (MDD) resulting from maladaptive reward processing. Electroconvulsive therapy (ECT) is an effective treatment for patients with MDD. No previous neuroimaging studies have taken a dimensional approach to assess whether ECT-induced volume changes are specifically related to improvements in anhedonia and positive valence emotional constructs. We aimed to assess the relationship between ECT-induced brain volumetric changes and improvement in anhedonia and reward processing in patients with MDD. METHODS: We evaluated 15 patients with MDD before and after ECT. We used magnetic resonance imaging, clinical scales (i.e., Quick Inventory of Depressive Symptomatology for syndromal depression severity and Snaith-Hamilton Pleasure Scale for anhedonia) and the Temporal Experience of Pleasure Scale for anticipatory and consummatory experiences of pleasure. We identified 5 regions of interest within the reward circuit and a 6th control region relevant for MDD but not core to the reward system (Brodmann Area 25). RESULTS: Anhedonia, anticipatory and consummatory reward processing improved after ECT. Volume increases within the right reward system separated anhedonia responders and non-responders. Improvement in anticipatory (but not consummatory) reward correlated with increases in volume in hippocampus, amygdala, ventral tegmental area and nucleus accumbens. LIMITATIONS: We evaluated a modest sample size of patients with concurrent pharmacological treatment using a subjective psychometric assessment. CONCLUSIONS: We highlight the importance of a dimensional and circuit-based approach to understanding target engagement and the mechanism of action of ECT, with the goal to define symptom- and circuit-specific response biomarkers for device neuromodulation therapies.

Psychiatric Applications of Repetitive Transcranial Magnetic Stimulation.

Transcranial magnetic stimulation (TMS) is an increasingly popular noninvasive brain stimulation modality. In TMS, a pulsed magnetic field is used to noninvasively stimulate a targeted brain region. Repeated stimulation produces lasting changes in brain activity via mechanisms of synaptic plasticity similar to long-term potentiation. Local application of TMS alters activity in distant, functionally connected brain regions, indicating that TMS modulates activity of cortical networks. TMS has been approved by the U.S. Food and Drug Administration for the treatment of major depressive disorder, obsessive-compulsive disorder, and smoking cessation, and a growing evidence base supports its efficacy in the treatment of other neuropsychiatric conditions. TMS is rapidly becoming part of the standard of care for treatment-resistant depression, where it yields response rates of 40%-60%. TMS is generally safe and well tolerated; its most serious risk is seizure, which occurs very rarely. This review aims to familiarize practicing psychiatrists with basic principles of TMS, including target localization, commonly used treatment protocols and their outcomes, and safety and tolerability. Practical considerations, including evaluation and monitoring of patients undergoing TMS, device selection, treatment setting, and insurance reimbursement, are also reviewed.

Intranasal Ketorolac for Acute Pain in Adult Emergency Department Patients.

Pain is a common complaint in the emergency department. An alternative to opioids is desirable. Oral medications are not feasible with gastrointestinal disorders or NPO. Intravenous medications require skill and time. Intravenous/intramuscular medications are painful with potential needlestick injury. Intranasal medications have rapid onset, easy administration, do not need skilled providers, and no risk of needlestick injury. A total of 28 adults with acute pain (numeric rating scale ≥ 4) received intranasal ketorolac. Numeric rating scale decreased in all: 32% complete pain relief, median (interquartile range) decrease -5 (-6.8 to -4) (p < .001). Pain relief onset was median [interquartile range] 5 (2.3, 15.0) min. Vital signs remained normal. There were no nasal mucosal changes, no complications. Minor side effects, mostly nasal burning, in 43%, resolved within 5 min. Patients and nurses were satisfied with intranasal ketorolac, and would use it again. Intranasal ketorolac had a rapid onset, was effective, safe, well tolerated with minor side effects that resolved quickly.

White matter markers and predictors for subject-specific rTMS response in major depressive disorder.

Repetitive transcranial magnetic stimulation (rTMS) has established therapeutic efficacy for major depressive disorder (MDD). While translational research has focused primarily on understanding the mechanism of action of TMS on functional activation and connectivity, the effects on structural connectivity remain largely unknown especially when rTMS is applied using subject-specific brain targets. This study aims to use novel diffusion magnetic resonance imaging (dMRI) analysis to examine microstructural changes related to rTMS treatment response using a unique cohort of 21 patients with MDD treated using rTMS with subject-specific targets. White matter dMRI microstructural measures and clinical scores were captured before and after the full course of treatment. We defined disease-relevant fiber bundles connected to different subregions of the left prefrontal cortex and analyzed changes in diffusion properties as well as correlations between the changes of dMRI measures and the changes in Hamilton Depression Rating Scale (HAMD). No significant changes were observed in tracts connected to the TMS targets. rTMS significantly increased the extra-axonal free-water volume, fractional anisotropy and decreased the radial diffusivity in anterior-medial prefrontal fiber bundles but did not lead to raw changes in lateral prefrontal tracts. That said, the microstructural changes in the lateral prefrontal white matter were significantly correlated with treatment response. Moreover, pre-rTMS dMRI measures of the dorsal anterior cingulate cortex and lateral prefrontal cortex connections are correlated with changes in HAMD scores. Microstructural changes in the anterior-medial and lateral prefrontal white matter are potentially involved in treatment response to TMS, though further investigation is needed using larger datasets.

Anxious attachment is associated with heightened responsivity of a parietofrontal cortical network that monitors peri-personal space.

BACKGROUND: Attachment, or affiliative bonding among conspecifics, is thought to involve neural mechanisms underlying behavioral responses to threat and reward-related social signals. However, attachment-oriented responses may also rely on basic sensorimotor processes. One sensorimotor system that may play a role in attachment is the parietofrontal cortical network that responds to stimuli that are near or approaching the body, the peripersonal space (PPS) monitoring system. We hypothesized that this network may vary in responsivity to such potentially harmful stimuli, particularly those with social salience, based on individual differences in attachment styles. METHODS: Young adults viewed images of human faces or cars that appeared to move towards or away from them, while functional magnetic resonance imaging data were collected. Correlations between each of four adult attachment styles, measured using the Relationship Questionnaire, and responses of the PPS network to approaching (versus withdrawing) stimuli were measured. RESULTS: A region-of-interest (ROI) analysis, focused on six cortical regions of the PPS network that showed significant responses to approaching versus withdrawing face stimuli in an independent sample (n = 80), revealed that anxious attachment style (but not the other 3 attachment styles) was significantly positively correlated with responses to faces (but not to cars) in all six ROIs (r = 0.33-0.49, p = 0.01-0.0001, n = 50). CONCLUSIONS: These findings suggest that anxious attachment is associated with over-responsivity of a sensorimotor network involved in attending to social stimuli near the body.

Topical Refrigerant Spray for IVs: Patient/Provider Responses - Prospective, Double-blind, Randomized Study.

Painful procedures are common. Patients prefer analgesia for painful procedures. Studies indicate that use of a topical refrigerant spray (TRS) prior to needlestick procedures decreases needlestick pain. TRS is easy to apply, inexpensive, has fast onset, and avoids needlestick pain and anxiety, and needlestick injury risk. Patient and health care provider (HCP) acceptance of any technique is essential before it is adopted. This study evaluated the decrease in pain with TRS and the patient and HCP satisfaction and acceptance of TRS for peripheral intravenous (PIV) placement. Adults (N = 300) randomized to placebo or TRS and HCPs (N = 300) placing PIVs answered questionnaires. Patients had significantly less pain than with prior PIVs, and were satisfied with and would use TRS in the future (P < 0.001). HCP felt that patients had significantly (P < 0.001) less pain with TRS than the placebo, and were satisfied with the TRS, and would use TRS in the future.Registered at Clinicaltrials.gov NCT01670487.

Elevated Amygdala Activity in Young Adults With Familial Risk for Depression: A Potential Marker of Low Resilience.

BACKGROUND: Amygdala overactivity has been frequently observed in patients with depression, as well as in nondepressed relatives of patients with depression. A remaining unanswered question is whether elevated amygdala activity in those with familial risk for depression is related to the presence of subthreshold symptoms or to a trait-level vulnerability for illness. METHODS: To examine this question, functional magnetic resonance imaging data were collected in nondepressed young adults with (family history [FH+]) (n = 27) or without (FH-) (n = 45) a first-degree relative with a history of depression while they viewed images of "looming" or withdrawing stimuli (faces and cars) that varied in salience by virtue of their apparent proximity to the subject. Activation of the amygdala and 2 other regions known to exhibit responses to looming stimuli, the dorsal intraparietal sulcus (DIPS) and ventral premotor cortex (PMv), were measured, as well as levels of resilience, anxiety, and psychotic and depressive symptoms. RESULTS: Compared with the FH- group, the FH+ group exhibited significantly greater responses of the amygdala, but not the dorsal intraparietal sulcus or ventral premotor cortex, to looming face stimuli. Moreover, amygdala responses in the FH+ group were negatively correlated with levels of resilience and unrelated to levels of subthreshold symptoms of psychopathology. CONCLUSIONS: These findings indicate that elevated amygdala activity in nondepressed young adults with a familial history of depression is more closely linked to poor resilience than to current symptom state.

Patient and Health Care Provider Responses from a Prospective, Double-Blind, Randomized Controlled Trial Comparing Vapocoolant Spray versus Placebo Spray in Adults Undergoing Venipuncture in the Emergency Department.

BACKGROUND: Painful medical procedures are common. Topical anesthetics are easily applied, rapid onset, inexpensive, and avoid injection pain and needlestick injury. The aims of this study, using patient and health care provider questionnaires, were to answer the following questions: (1) Does vapocoolant spray decrease venipuncture pain? (2) Would patients be satisfied with and use a vapocoolant spray in the future? (3) Would providers be satisfied with and use a vapocoolant spray in the future? DESIGN: Adults (18-80 years) in a hospital emergency department (ED) were randomly assigned to sterile water placebo spray (S) (N = 50) or vapocoolant spray (V) (N = 50) before venipuncture. Questionnaires were completed by patients undergoing venipuncture (N = 100) and the health care providers (N = 100) who performed the venipuncture (total questionnaires = 200) as part of a prospective, double-blind, randomized controlled trial comparing the efficacy and safety of vapocoolant spray compared with placebo spray in patients undergoing venipuncture in the ED. RESULTS: Patient and venipuncture variables were not significantly different for the two groups (S vs. V). Responses to the questionnaires were significantly different for the S versus V groups for both the patients and the health care providers. Patient questionnaires: Did you have less pain with spray? S 14%, V 76% (p < .001). Compared with previous blood draws, the spray was much more painful/more painful: S 10%, V 6%; same: S 76%, V 16%; less painful/much less painful: S 14%, V 78% (p < .001). How satisfied were you with the spray? Satisfied/very satisfied: S 20%, V 74% (p < .001). Would you use this spray in future? Yes S 20%, V 80% (p < .001). Provider results: The patient had less pain with the use of the spray: S 14%, V 78% (p < .001). How satisfied were you with the use of the spray? Satisfied/very satisfied: S 12%, V 82% (p < .001). Would you use this spray in the future? Yes S 24%, V 84% (p < .001). CONCLUSIONS: The use of a vapocoolant spray in adult ED patients undergoing venipuncture significantly decreased venipuncture pain, was associated with high patient and provider satisfaction, and both patients and providers would use a vapocoolant spray in the future for venipuncture and other painful procedures.

fMRI responses to emotional faces in children and adolescents at genetic risk for psychiatric illness share some of the features of depression.

BACKGROUND: Fronto-limbic regions of the brain including the sub-genual (sgPFC) and medial prefrontal (mPFC) cortices are central to processing emotionally salient and hedonic stimuli (Mayberg, 2009) and implicated in depression. The relevance of cortico-limbic models of emotion and reward processing in children with genetic risk for psychiatric disorders has not been assessed. METHODS: Here we studied adolescents at risk for schizophrenia (HRS) and controls (HC) using an event-related fMRI continuous affective appraisal task. HRS were divided into sub-groups based on the presence or absence of negative symptoms (Miller et al., 2003), HRS_NS+ and HRS_NS- respectively. Brain responses to positive, negative and neutral emotional stimuli were estimated. RESULTS: Consistent with observations in the depressive phenotype, for positively valenced stimuli, HRS_NS+ (relative to HC and HRS_NS-) were characterized by hypo-responsivity of the sgPFC and the mPFC, but hyper-responsivity of the mid-brain. sgPFC and mPFC signals were coupled across groups. LIMITATIONS: Such studies can benefit from larger sample sizes, though our observed effect sizes were in the moderate to large range. CONCLUSIONS: Children and adolescents at risk for psychiatric illness and who evince reliably present negative symptoms show brain responses to socially rewarding stimuli similar to those observed in depression. Studies in at-risk children and adolescents may be important in understanding how early manifestations of depression-like characteristics impact brain function.