A Prospective Study of Publicly Funded Molecular Testing of Indeterminate Thyroid Nodules: Canada's Experience.

CONTEXT: Indeterminate thyroid nodules (ITNs) lead to diagnostic surgeries in many countries. Use of molecular testing (MT) is endorsed by several guidelines, but costs are limitative, especially in public healthcare systems like in Canada. OBJECTIVES: Primary objective: evaluate the clinical value of Thyroseq® v3 (TSv3) using benign call rate (BCR) in a real-world practice. Secondary objective: assess cost-effectiveness of MT. DESIGN: This is a multicentric prospective study. SETTING: This study was conducted in 5 academic centers in Quebec, Canada. PATIENTS OR OTHER PARTICIPANTS: 500 consecutive patients with Bethesda III (on 2 consecutive cytopathologies) or IV and TIRADS 3 or 4 nodules measuring 1 to 4 cm were included. INTERVENTION: MT was performed between November 2021 and November 2022. Patients with a positive TSv3 were referred to surgery. Patients with a negative TSv3 were planned for follow-up by ultrasonography for a minimum of 2 years. MAIN OUTCOME MEASURE: The BCR, corresponding to the proportion of ITNs with negative TSv3 results, was assessed. RESULTS: 500 patients underwent TSv3 testing, with a BCR of 72.6% (95% CI: 68.5-76.5; p<0.001). 99.7% of patients with a negative result avoided surgery. The positive predictive value of TSv3 was 68.2% (95% CI: 58.5-76.9). The cost-benefit analysis identified that the implementation of MT would yield cost savings of $6.1 million over the next 10 years. CONCLUSIONS: Use of MT (TSv3) in a well-selected population with ITNs led to a BCR of 72.6%. It is cost-effective and prevents unnecessary surgeries in a public healthcare setting.

Inhibition of the CCR6-CCL20 axis prevents regulatory T cell recruitment and sensitizes head and neck squamous cell carcinoma to radiation therapy.

BACKGROUND:  Radioresistance of HNSCCs remains a major challenge for effective tumor control. Combined radiotherapy (RT) and immunotherapy (IT) treatment improved survival for a subset of patients with inflamed tumors or tumors susceptible to RT-induced inflammation. To overcome radioresistance and improve treatment outcomes, an understanding of factors that suppress anti-tumor immunity is necessary. In this regard, regulatory T cells (Tregs) are critical mediators of immune suppression in HNSCCs. In this study, we investigated how radiation modulates Treg infiltration in tumors through the chemokine CCL20. We hypothesized that radiation induces CCL20 secretion resulting in Treg infiltration and suppression of anti-tumor immunity. METHODS:  Human and mouse HNSCC cell lines with different immune phenotypes were irradiated at doses of 2 or 10 Gy. Conditioned media, RNA and protein were collected for assessment of CCL20. qPCR was used to determine CCL20 gene expression. In vivo, MOC2 cells were implanted into the buccal cavity of mice and the effect of neutralizing CCL20 antibody was determined alone and in combination with RT. Blood samples were collected before and after RT for analysis of CCL20. Tumor samples were analyzed by flow cytometry to determine immune infiltrates, including CD8 T cells and Tregs. Mass-spectrometry was performed to analyze proteomic changes in the tumor microenvironment after anti-CCL20 treatment. RESULTS:  Cal27 and MOC2 HNSCCs had a gene signature associated with Treg infiltration, whereas SCC9 and MOC1 tumors displayed a gene signature associated with an inflamed TME. In vitro, tumor irradiation at 10 Gy significantly induced CCL20 in Cal27 and MOC2 cells relative to control. The increase in CCL20 was associated with increased Treg migration. Neutralization of CCL20 reversed radiation-induced migration of Treg cells in vitro and decreased intratumoral Tregs in vivo. Furthermore, inhibition of CCL20 resulted in a significant decrease in tumor growth compared to control in MOC2 tumors. This effect was further enhanced after combination with RT compared to either treatment alone. CONCLUSION:  Our results suggest that radiation promotes CCL20 secretion by tumor cells which is responsible for the attraction of Tregs. Inhibition of the CCR6-CCL20 axis prevents infiltration of Tregs in tumors and suppresses tumor growth resulting in improved response to radiation.

Anosmie et dysgueusie associées à l'infection au SRAS-CoV-2: étude cas­témoins appariée selon l'âge.

CONTEXTE: On a signalé l'anosmie et la dysgueusie comme symptômes potentiels de la maladie à coronavirus 2019. Cette étude visait à confirmer si ces symptômes sont caractéristiques chez les personnes ayant eu un résultat positif au dépistage du coronavirus du syndrome respiratoire aigu sévère 2 (SRAS-CoV-2). MÉTHODES: Nous avons réalisé une étude cas­témoins appariée selon l'âge dans la région des Cantons-de-l'Est, au Québec, entre le 10 et le 23 mars 2020. Nous avons inclus les adultes (18 ans et plus) ayant obtenu un résultat positif au dépistage du SRAS-CoV-2 par test d'amplification en chaîne par polymérase couplée à une transcription inverse. Les cas ont été appariés (1:1) par tranche d'âge de 5 ans avec des témoins sélectionnés aléatoirement parmi tous les patients ayant eu un résultat négatif au dépistage pendant la même période. Les données démographiques et de laboratoire ont été récupérées dans les dossiers médicaux. Les symptômes cliniques et les comorbidités associés à l'anosmie et à la dysgueusie ont été notés lors d'entrevues téléphoniques faites au moyen d'un questionnaire standardisé. RÉSULTATS: Parmi les 2883 personnes soumises au dépistage du SRAS-CoV-2, nous avons recensé 134 cas positifs (70 femmes [52,2 %] et 64 hommes [47,8 %]; âge médian 57,1 ans [intervalle interquartile 41,2­64,5 ans]). Les symptômes indépendamment associés à l'infection confirmée au SRAS-CoV-2 dans une analyse de régression logistique conditionnelle étaient les suivants : anosmie et/ou dysgueusie (rapport de cotes [RC] ajusté 62,9; intervalle de confiance [IC] de 95 % 11,0­359,7), myalgie (RC ajusté 7,6; IC de 95 % 1,9­29,9), vision trouble (RC ajusté 0,1; IC de 95 % 0,0­0,8) et douleur thoracique (RC ajusté 0,1; IC de 95 % 0,0­0,6). INTERPRÉTATION: Nous avons observé un lien étroit entre les symptômes olfactifs et gustatifs et la positivité au SRAS-CoV-2. Ces symptômes devraient être considérés comme une caractéristique fréquente et distinctive de l'infection au SRAS-CoV-2 et devraient servir d'indication de dépistage, et même de répétition du dépistage chez les personnes dont le résultat initial est négatif.

Anosmia and dysgeusia associated with SARS-CoV-2 infection: an age-matched case-control study.

BACKGROUND: Anosmia and dysgeusia have been reported as potential symptoms of coronavirus disease 2019. This study aimed to confirm whether anosmia and dysgeusia are specific symptoms among those who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted an age-matched case-control study in the Eastern Townships region of Quebec between Mar. 10 and Mar. 23, 2020. We included adults (age ≥ 18 yr) who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction. Cases were matched (1:1) according to 5-year age groups with control patents selected randomly from among all patients who tested negative for SARS-CoV-2 during the same period. Demographic and laboratory information was collected from medical records. Clinical symptoms and comorbidities associated with anosmia and dysgeusia were obtained by telephone interview with a standardized questionnaire. RESULTS: Among 2883 people tested for SARS-CoV-2, we identified 134 positive cases (70 women [52.2%] and 64 men [47.8%]; median age 57.1 [interquartile range 41.2-64.5] yr). The symptoms independently associated with SARS-CoV-2 positivity in conditional logistic regression were anosmia or dysgeusia or both (adjusted odds ratio [OR] 62.9, 95% confidence interval [CI] 11.0-359.7), presence of myalgia (adjusted OR 7.6, 95% CI 1.9-29.9), blurred vision (adjusted OR 0.1, 95% CI 0.0-0.8) and chest pain (adjusted OR 0.1, 95% CI 0.0-0.6). INTERPRETATION: We found a strong association between olfactory and gustatory symptoms and SARS-CoV-2 positivity. These symptoms should be considered as common and distinctive features of SARS-CoV-2 infection and should serve as an indication for testing and possible retesting of people whose first test result is negative.

The infraclavicular pedicled flap in head and neck reconstruction: applications and outcomes.

BACKGROUND: An infraclavicular pedicled flap (ICPF) was recently described in the literature. This anatomical region is attractive for the restoration of head and neck oncological defects. This paper is a review of our experience with this versatile flap. METHODS: A retrospective study was conducted by reviewing the records of all the patients operated in a tertiary-care center between August 2013 and January 2019 whose surgery involved an ICPF. RESULTS: Forty-four patients received an ICPF for various indications, including large vessel coverage in neck/parotid recontouring (34.1%), postlaryngectomy reconstruction (34.1%), and fistula closure (25.0%). All flaps survived. Thirteen patients experienced a postoperative complication (29.5%), six of whom (13.9%) required a repeat procedure under general anesthesia. CONCLUSION: ICPF is suitable for several indications and is a useful adjunctive tool in head and neck reconstruction. It proved to have a high survival rate, with complication rates similar to other regional flaps.

[Cognitive-behavioral therapy at the Pavillon Albert-Prévost's specialized outpatient clinics during the last 50 years: innovations and evolution]. / La thérapie cognitivo-comportementale dans les cliniques spécialisées du Pavillon Albert-Prévost dans les 50 dernières années : innovations et évolution.

The Pavillon Albert-Prévost (PAP) has played a leading role in the development of modern psychiatry in the province of Québec. It has also been, in the francophone milieu, the teaching hospital that was the most deeply influenced by psychoanalytic theories. The arrival of somatic approaches, particularly biofeedback and relaxation, in the Psychosomatic medicine and consultation-liaison service, as introduced by Dr. Jacques Monday in the 1970s, was initially greeted with great scepticism by the majority of his colleagues at PAP. In the 1980s and 1990s, Dr. Camille Laurin, then head of the department, invited Dr. Louis Chaloult to offer a clinical supervision seminar to mental health professionals. Drs. Chaloult and Monday trained generations of clinicians in cognitive behavior therapy and relaxation therapy as, over time, these approaches both practical, efficient and effective became more widely practiced and recommended by practice guidelines in psychiatry. Dr. Chaloult with the help of Dr. Jean Goulet developed a CBT teaching curriculum for residents in psychiatry and other health care professionals, wrote an influential textbook on CBT, co-developped a widely consulted website www.tccmontreal.com providing CBT practice guides for clinicians and patients alike, became one of the first psychiatrists acting as a psychiatre répondant in CLSCs (teaching CBT to other members of the team in order to provide CBT in primary care), co-developed the Centre de Psychothérapie at the PAP to promote cross theoretical training in psychotherapy for residents in psychiatry and interns of other mental healthcare disciplines. In this spirit, Dre. Thanh-Lan Ngô contributed to these endeavors and co-created with Dr. Jean Leblanc and Dre. Magalie Lussier-Valade another website www.psychopap.com dedicated to the transfer of knowledge in CBT as well as other forms of psychotherapy in order to celebrate 100 years of teaching in psychiatry at the PAP. Following the creation of specialised outpatient clinics in 1994, CBT was more widely offered and developed as a standard of care. These influential programs include those of three psychologists Dr Michel Dugas' Generalised anxiety disorder model, Pascale Brillon's teaching of trauma focussed CBT (with three books on the subject, Dr Richard Fleet's research on emergency room presentation of panic disorder. This collaborative teaching and research program included Dre. Julie Turcotte and Dr. Pierre Savard, both specialised in CBT and instrumental in training generations of psychiatrists in evidence-based treatments for severe refractory disorders. At the Early psychosis clinic, an innovative program of CBT modules adapted to the functional and symptomatic impairment level of the heterogeneous clientele was developed by Pierre Fortier and Dr. Jean-Pierre Mottard. At the Readaptation for Psychosis program, France Bérubé and Jocelyne St-Onge, offered auditory hallucinations group, metacognitive therapy, the integrated psychotherapy programme. At the Personality disorder clinic, dialectical behavior therapy groups were offered by Julie Jomphe who trained many cohorts of residents, offered adaptations to families (Family connections), adolescents, and children (in schools). At the Psychosomatic service Donald Bouthillier treated somatisation disorders with affective-cognitive behavioral therapy for somatization disorder. And finally, at the Mood disorder clinic, Drs. Ngô, Bernard Gauthier, Léon Maurice Larouche, Anne-Sophie Boulanger along with Manon Quesnel, Renée Leblanc and colleagues offered a sequential program of CBT approaches to treat severe and refractory mood disorders.

Evaluation of PACE4 isoforms as biomarkers in thyroid cancer.

BACKGROUND: To date, no single molecular marker has been demonstrated as clinically useful in differentiating malignant from benign thyroid nodules when a fine needle aspiration falls in the "unknown significance" categories of the Bethesda Classification. PACE4, a member of the proprotein convertase family of enzymes, has been shown to play a major role in the pathogenesis of prostate cancer, through the formation of an oncogenic isoform named PACE4-altCT. PACE4 isoforms have also been suggested to play a role in other cancers, including thyroid cancer, but have never been investigated in a detailed manner. Our objective is to compare the histochemical distribution of the two major PACE4 isoforms in benign and malignant thyroid nodules, in order to determine their potential usefulness as discriminatory biomarkers. METHODS: Thyroid tissues of patients who underwent thyroidectomy were classified according to final pathology. Corresponding tissue sections were immunostained, using two previously validated antibodies raised against the C-terminal end of the two PACE4 isoforms, namely the full-length PACE4 protein (PACE4-FL) and its alternative isoform (PACE4-altCT). Nodules were compared with adjacent normal parenchyma and immunostaining was rated as "low" or "high" by a head and neck pathologist. RESULTS: Non-lesional thyroid parenchyma did not express PACE4-FL (p = 0.002). As a group, malignant (n = 17) nodules expressed PACE4-FL significantly more than benign (n = 24) nodules (percentage of high immunostaining: 52.9% vs 4.2%; p = 0.001). Reciprocally, there was a statistically lower expression of PACE4-altCT in malignant nodules than in adjacent non-lesional parenchyma (p = 0.014). The specificity of a high PACE4-FL immunostaining in determining malignancy was 95.8% (95% CI, 78.9% to 99.9%). CONCLUSION: This study supports the previously described relationship between PACE4-FL and PACE4-altCT through alternative splicing. It also suggests that PACE4-FL is a promising biomarker for thyroid malignancy. Its high specific expression for malignancy could make it an interesting "rule in" test for thyroid cancer. Further prospective, quantitative studies are currently being designed to address how measurements of PACE4 isoforms could be used in a clinical setting. TRIAL REGISTRATION: This study does not report the results of a health care intervention on human participants. It was nonetheless registered on ClinicalTrials.gov under reference number NCT03160482 .

Comparison of mechanisms for contrast-invariance of orientation selectivity in simple cells.

The simple cells of the visual cortex respond over a narrow range of stimulus orientations, and this tuning is invariant to the contrast at which the stimulus is presented. The inputs to a single cell derive from a population of thalamic cells that provide a bell-shaped tuning width and offset that increases with stimulus contrast. Synaptic depression, noise and inhibition have been proposed as feedforward mechanisms to explain why these increases do not appear in simple cells. The extent to which these three mechanisms contribute to contrast-invariant orientation tuning is unknown. Consequently, the aim was to test the hypothesis that these mechanisms do not contribute equally. Unlike previous studies, all mechanisms were examined using the same network model based on Banitt et al. (2007). The results showed that thalamocortical synaptic noise was essential and sufficient to widen tuning widths at low contrasts to that of higher contrasts but could not counteract the offset at higher contrasts. Thalamocortical synaptic depression could only be used to counteract a small fraction of the offset otherwise the relationship between contrast and response rate was disrupted. Only broadly tuned simple and complex cell inhibition could counteract the remaining offset for all stimulus contrasts but complex cell inhibition reduced the gain of the response. These results suggest unequal contributions of these feedforward mechanisms with thalamic synaptic noise widening tuning widths for low contrasts, synaptic depression counteracting a small component of the offset and synaptic inhibition completely removing the remaining offset to produce contrast-invariant orientation tuning.

Postsecondary academic achievement and first-episode psychosis: A mixed-methods study.

BACKGROUND: Postsecondary academic achievement as an area of functional recovery for young adults living with mental illness has received little research attention. PURPOSE: This study had three purposes: to compare rates of participation, performance, and satisfaction in postsecondary education between young adults with first-episode psychosis and closely matched young adults; to identify characteristics associated with academic participation; and to explore the processes associated with educational experiences. METHOD: One hundred young adults ages 18 to 30 participated in the study. Quantitative data on academic engagement, performance, and satisfaction, and qualitative data (n = 52) on academic experiences were integrated through pattern analyzes. FINDINGS: Young adults with psychosis were significantly less likely to be engaged in postsecondary education. No difference appeared for the extent of engagement, but performance and satisfaction were lower among participants with psychosis. Participants engaged in reflexive decision making to access postsecondary education and to maintain adequate academic performance. Strategies used by successful students with mental illness were identified. IMPLICATIONS: Assessment and intervention focused on educational needs and skills should become landmark practices for psychiatric rehabilitation practitioners, including occupational therapists.

A challenging case of squamous metaplasia in a pleomorphic adenoma: diagnostic and clinical pitfalls.

Squamous metaplasia in a pleomorphic adenoma (PA) has been reported, but rarely has it been documented as being extensive enough to cause significant misdiagnosis. We present a case of a 37-year-old man presenting with a 1.7-cm minor salivary gland PA of the palate. It exhibited extensive squamous metaplasia mimicking a squamous cell carcinoma (SCC) on multiple preoperative biopsies. The final diagnosis was only made after a complete oncological excision with margins and free flap reconstruction. Florid squamous metaplasia in a PA, although rare, should be recognized and distinguished from SCC. Failure to differentiate these entities can lead to patient overtreatment.

Effects of reflux laryngitis on non-nutritive swallowing in newborn lambs.

Reflux laryngitis in infants may be involved not only in laryngeal disorders, but also in disorders of cardiorespiratory control through its impact on laryngeal function. Our objective was to study the effect of reflux laryngitis on non-nutritive swallowing (NNS) and NNS-breathing coordination. Two groups of six newborn lambs, randomized into laryngitis and control groups, were surgically instrumented for recording states of alertness, swallowing and cardiorespiratory variables without sedation. A mild to moderate reflux laryngitis was induced in lambs from the experimental group. A significant decrease in the number of NNS bursts and apneas was observed in the laryngitis group in active sleep (p=0.03). In addition, lower heart and respiratory rates, as well as prolonged apnea duration (p<0.0001) were observed. No physiologically significant alterations in NNS-breathing coordination were observed in the laryngitis group. We conclude that a mild to moderate reflux laryngitis alters NNS burst frequency and autonomous control of cardiac activity and respiration in lambs.

Influence of asymmetric attenuation of single and paired dendritic inputs on summation of synaptic potentials and initiation of action potentials.

Previous studies revealed mechanisms of dendritic inputs leading to action potential initiation at the axon initial segment and backpropagation into the dendritic tree. This interest has recently expanded toward the communication between different parts of the dendritic tree which could preprocess information before reaching the soma. This study tested for effects of asymmetric voltage attenuation between different sites in the dendritic tree on summation of synaptic inputs and action potential initiation using the NEURON simulation environment. Passive responses due to the electrical equivalent circuit of the three-dimensional neuron architecture with leak channels were examined first, followed by the responses after adding voltage-gated channels and finally synaptic noise. Asymmetric attenuation of voltage, which is a function of asymmetric input resistance, was seen between all pairs of dendritic sites but the transfer voltages (voltage recorded at the opposite site from stimulation among a pair of dendritic sites) were equal and also summed linearly with local voltage responses during simultaneous stimulation of both sites. In neurons with voltage-gated channels, we reproduced the observations where a brief stimulus to the proximal ascending dendritic branch of a pyramidal cell triggers a local action potential but a long stimulus triggers a somal action potential. Combined stimulation of a pair of sites in this proximal dendrite did not alter this pattern. The attraction of the action potential onset toward the soma with a long stimulus in the absence of noise was due to the higher density of voltage-gated sodium channels at the axon initial segment. This attraction was, however, negligible at the most remote distal dendritic sites and was replaced by an effect due to high input resistance. Action potential onset occurred at the dendritic site of higher input resistance among a pair of remote dendritic sites, irrespective of which of these two sites received the synaptic input. Exploration of the parameter space showed how the gradient of voltage-gated channel densities and input resistances along a dendrite could draw the action potential onset away from the stimulation site. The attraction of action potential onset toward the higher density of voltage-gated channels in the soma during stimulation of the proximal dendrite was, however, reduced after the addition of synaptic noise.

Housing and home-leaving experiences of young adults with psychotic disorders: a comparative qualitative study.

Housing stability is a key component of rehabilitation for individuals with severe mental illnesses but remains a challenge for mental health service providers, particularly with young adults experiencing early mental health difficulties. The aim of this study is to explore perceptions of housing and home-leaving processes among young adults with emerging psychotic disorders and to compare it to the perceptions of young adults without psychotic disorders. A qualitative, grounded theory based, multiple case study was conducted among 52 adults aged 18-30 years old. Two core categories emerged in relation with perception of housing: choice/control over the residential environment, and housing opportunities over time. Difference between the groups include more coerced home-leaving for young adults with first-episode psychosis and low levels of choice, control and opportunities for a sub-group of participants living in group homes. The housing situation of young adults is analyzed and discussed from a systemic perspective.

Transitions to adulthood in first-episode psychosis: a comparative study.

AIM: The first aim of this study is to compare attainment of five markers of transition to adulthood between young adults with first-episode psychosis and young adults without any psychopathology. The second aim is to examine if the association between age group and transition to adulthood is similar for individuals who experience first-episode psychosis versus those who do not. METHODS: Participants were 50 young adults with first-episode schizophrenia aged between 18 and 30 years old, and 50 volunteers without any psychopathology matched for sex and age. Participants were assessed with the Quality of Life Scale and a questionnaire on markers of transition to adulthood. RESULTS: Significant differences appear between the groups for three of the five markers of transition to adulthood, namely: residential/financial independence, educational attainment and involvement in a romantic relationship. The effect of age on several markers is significant for the comparison group only. CONCLUSION: Rehabilitation interventions should be informed by a developmental perspective on community functioning for young adults with first-episode schizophrenia. Vocational rehabilitation should be extended to focus more extensively on supported education and not only on supported employment, and interventions targeting residential independence should be granted more attention.

Effects of simulated reflux laryngitis on laryngeal chemoreflexes in newborn lambs.

It has been suggested that reflux laryngitis (RL) is involved in apneas-bradycardias of the newborn. The aim of the present study was to develop a unique RL model in newborn lambs to test the hypothesis that RL enhances the cardiorespiratory components of the laryngeal chemoreflexes (LCR) in the neonatal period. Gastric juice surrogate (2 ml of normal saline solution with HCl pH 2 + pepsin 300 U/ml) (RL group, n = 6) or normal saline (control group, n = 6) was repeatedly injected onto the posterior aspect of the larynx, 3 times a day for 6 consecutive days, via a retrograde catheter introduced into the cervical esophagus. Lambs instilled with gastric juice surrogate presented clinical signs of RL, as well as moderate laryngitis on histological observation. Laryngeal chemoreflexes were thereafter induced during sleep by injection of 0.5 ml of HCl (pH 2), ewe's milk, distilled water or saline into the laryngeal vestibule via a chronic, transcutaneous supraglottal catheter. Overall, RL led to a significantly greater respiratory inhibition compared with the control group during LCR, including longer apnea duration (P = 0.01), lower minimal respiratory rate (P = 0.002), and a more prominent decrease in arterial hemoglobin saturation (SpO(2)) (P = 0.03). No effects were observed on cardiac variables. In conclusion, 1) our unique neonatal ovine model presents clinical and histological characteristics of RL; and 2) the presence of RL in newborn lambs increases the respiratory inhibition observed with LCR, at times leading to severe apneas and desaturations.

Effects of electrical coupling among layer 4 inhibitory interneurons on contrast-invariant orientation tuning.

Simulations of orientation selectivity in visual cortex have shown that layer 4 complex cells lacking orientation tuning are ideal for providing global inhibition that scales with contrast in order to produce simple cells with contrast-invariant orientation tuning (Lauritzen and Miller in J Neurosci 23:10201-10213, 2003). Inhibitory cortical cells have been shown to be electrically coupled by gap junctions (Fukuda and Kosaka in J Neurosci 120:5-20, 2003). Such coupling promotes, among other effects, spike synchronization and coordination of postsynaptic IPSPs (Beierlein et al. in Nat Neurosci 3:904-910, 2000; Galarreta and Hestrin in Nat Rev Neurosci 2:425-433, 2001). Consequently, it was expected (Miller in Cereb Cortex 13:73-82, 2003) that electrical coupling would promote nonspecific functional responses consistent with the complex inhibitory cells seen in layer 4 which provide broad inhibition in response to stimuli of all orientations (Miller et al. in Curr Opin Neurobiol 11:488-497, 2001). This was tested using a mechanistic modeling approach. The orientation selectivity model of Lauritzen and Miller (J Neurosci 23:10201-10213, 2003) was reproduced with and without electrical coupling between complex inhibitory neurons. Although extensive coupling promotes uniform firing in complex cells, there were no detectable improvements in contrast-invariant orientation selectivity unless there were coincident changes in complex cell firing rates to offset the untuned excitatory component that grows with contrast. Thus, changes in firing rates alone (with or without coupling) could improve contrast-invariant orientation tuning of simple cells but not synchronization of complex inhibitory neurons alone.