Cortical and subcortical functional specificity associated with response inhibition.

Is motor response inhibition supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation.

Impairment of manual but not saccadic response inhibition following acute alcohol intoxication.

BACKGROUND: Alcohol impairs response inhibition; however, it remains contested whether such impairments affect a general inhibition system, or whether affected inhibition systems are embedded in, and specific to, each response modality. Further, alcohol-induced impairments have not been disambiguated between proactive and reactive inhibition mechanisms, and nor have the contributions of action-updating impairments to behavioural 'inhibition' deficits been investigated. METHODS: Forty Participants (25 female) completed both a manual and a saccadic stop-signal reaction time (SSRT) task before and after a 0.8g/kg dose of alcohol and, on a separate day, before and after a placebo. Blocks in which participants were required to ignore the signal to stop or make an additional 'dual' response were included to obtain measures of proactive inhibition as well as updating of attention and action. RESULTS: Alcohol increased manual but not saccadic SSRT. Proactive inhibition was weakly reduced by alcohol, but increases in the reaction times used to baseline this contrast prevent clear conclusions regarding response caution. Finally, alcohol also increased secondary dual response times of the dual task uniformly as a function of the delay between tasks, indicating an effect of alcohol on action-updating or execution. CONCLUSIONS: The modality-specific effects of alcohol favour the theory that response inhibition systems are embedded within response modalities, rather than there existing a general inhibition system. Concerning alcohol, saccadic control appears relatively more immune to disruption than manual control, even though alcohol affects saccadic latency and velocity. Within the manual domain, alcohol affects multiple types of action updating, not just inhibition.

Enhanced awareness followed reversible inhibition of human visual cortex: a combined TMS, MRS and MEG study.

This series of experiments investigated the neural basis of conscious vision in humans using a form of transcranial magnetic stimulation (TMS) known as continuous theta burst stimulation (cTBS). Previous studies have shown that occipital TMS, when time-locked to the onset of visual stimuli, can induce a phenomenon analogous to blindsight in which conscious detection is impaired while the ability to discriminate 'unseen' stimuli is preserved above chance. Here we sought to reproduce this phenomenon using offline occipital cTBS, which has been shown to induce an inhibitory cortical aftereffect lasting 45-60 minutes. Contrary to expectations, our first experiment revealed the opposite effect: cTBS enhanced conscious vision relative to a sham control. We then sought to replicate this cTBS-induced potentiation of consciousness in conjunction with magnetoencephalography (MEG) and undertook additional experiments to assess its relationship to visual cortical excitability and levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA; via magnetic resonance spectroscopy, MRS). Occipital cTBS decreased cortical excitability and increased regional GABA concentration. No significant effects of cTBS on MEG measures were observed, although the results provided weak evidence for potentiation of event related desynchronisation in the ß band. Collectively these experiments suggest that, through the suppression of noise, cTBS can increase the signal-to-noise ratio of neural activity underlying conscious vision. We speculate that gating-by-inhibition in the visual cortex may provide a key foundation of consciousness.

The timing and neuroanatomy of conscious vision as revealed by TMS-induced blindsight.

Following damage to the primary visual cortex, some patients exhibit "blindsight," where they report a loss of awareness while retaining the ability to discriminate visual stimuli above chance. Transient disruption of occipital regions with TMS can produce a similar dissociation, known as TMS-induced blindsight. The neural basis of this residual vision is controversial, with some studies attributing it to the retinotectal pathway via the superior colliculus whereas others implicate spared projections that originate predominantly from the LGN. Here we contrasted these accounts by combining TMS with visual stimuli that either activate or bypass the retinotectal and magnocellular (R/M) pathways. We found that the residual capacity of TMS-induced blindsight occurs for stimuli that bypass the R/M pathways, indicating that such pathways, which include those to the superior colliculus, are not critical. We also found that the modulation of conscious vision was time and pathway dependent. TMS applied either early (0-40 msec) or late (280-320 msec) after stimulus onset modulated detection of stimuli that did not bypass R/M pathways, whereas during an intermediate period (90-130 msec) the effect was pathway independent. Our findings thus suggest a prominent role for the R/M pathways in supporting both the preparatory and later stages of conscious vision. This may help resolve apparent conflict in previous literature by demonstrating that the roles of the retinotectal and geniculate pathways are likely to be more nuanced than simply corresponding to the unconscious/conscious dichotomy.

Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation.

OBJECTIVES: Past research has largely neglected to investigate mild adverse effects (MAEs) to transcranial magnetic stimulation (TMS), including headache and nausea. Here we explored the relationship between MAEs, participant characteristics (age and gender) and protocol parameters, including mode of application, coil geometry, stimulated brain region, TMS frequency, TMS intensity, and active vs. sham stimulation. METHODS: Data from 1270 standard post-monitoring forms was obtained from 113 healthy participants. Analyses aimed to identify the risk factors associated with MAE reports and specific symptoms. RESULTS: The overall rate of MAEs across TMS sessions was ∼5%, with ∼78% of symptoms occurring post-session. Initial TMS sessions were followed by a higher MAE incidence rate relative to later testing sessions. No associations between participant characteristics, TMS frequency, or intensity were observed. CONCLUSIONS: TMS-related MAEs are relatively common and may be exacerbated by initial expectations or anxieties of participants. A significant proportion of MAEs may reflect reporting of coincidental phenomena that are unrelated to TMS. Recommendations for future safety studies are proposed and monitoring documentation is provided. SIGNIFICANCE: Our findings illustrate the importance of standardized monitoring of MAEs. Such research aids our understanding of how MAEs arise and may lead to interventions for reducing their incidence.

Is delayed foveal feedback critical for extra-foveal perception?

Recent neuroimaging evidence suggests that visual inputs arising beyond the fovea can be 'fed back' to foveal visual cortex to construct a new retinotopic representation. However, whether these representations are critical for extra-foveal perception remains unclear. Using transcranial magnetic stimulation we found that relatively late (350-400 msec) disruption of foveal retinotopic cortex impaired perceptual discrimination of objects in the periphery. These results are consistent with the hypothesis that feedback to the foveal retinotopic cortex is crucial for extra-foveal perception, and provide additional evidence for 'constructive' feedback in human vision.

Tumor-related immunity in prostate cancer patients treated with human recombinant granulocyte monocyte-colony stimulating factor (GM-CSF).

BACKGROUND: Granulocyte monocyte-colony stimulating factor (GM-CSF) supports the survival, expansion, and differentiation of lymphoid and myeloid derived dendritic cells (DCs). We hypothesized that systemic therapy with GM-CSF in prostate cancer patients could augment prostate cancer-related immunity and induce clinical response. METHODS: Eligible patients were randomly assigned to receive either 125 or 250 microg/m(2) GM-CSF subcutaneously three times a week until clinical progression. Prostate-specific antigen (PSA) T cell precursor frequencies were determined by a flow cytometric method. RESULTS: We were able to show, for the first time, a statistically significant correlation between pre-treatment PSA level and PSA-specific CD4(+) T cell precursors and a trend between pre-treatment PSA level and PSA-specific CD8(+) T cell precursors (P<0.0001 and P=0.059, respectively). CONCLUSIONS: These results suggest that existent immunity to PSA in prostate cancer patients may be a promising target for future immunotherapeutic approaches to prostate cancer.

Impaired cytolytic activity in peripheral blood T cells from renal cell carcinoma patients.

Classic T lymphocyte cytotoxicity is mediated through the T cell receptor (TCR). Defects in TCR signal transduction and cytolytic activity have been reported in tumor infiltrating T lymphocytes. We hypothesized that impaired cytotoxicity occurs in peripheral blood T cells from renal cell carcinoma (RCC) that can be reversed by exposure to rhIL-2. Peripheral blood mononuclear cells (PBMC) from 29 RCC patients and 29 healthy volunteers were isolated and cultured in the absence or presence of 10 IU/ml rhIL-2. A redirected cytotoxicity assay that requires TCR signal transduction was used with chromium-labeled P815 target cells, effector PBMC and anti-CD3 antibody. Target cell lysis was measured in "lytic units" (LU). Mean LU from RCC patients was lower than that of healthy volunteers (105.8 LU vs. 194.6 LU, P = 0.025). Exposure to rhIL-2 increased T cell-mediated lysis in both groups. Disruption of T cell cytotoxicity in RCC patients can be overcome by exposure to rhIL-2.

Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma.

PURPOSE: The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. RESULTS: One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. CONCLUSION: This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.

Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial.

PURPOSE: This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). PATIENTS AND METHODS: Eligibility requirements were resected locally advanced (LA; T3b-4 or N1-3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. RESULTS: Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P =.73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P =.38). Analysis including metastasectomy patients made no difference in DFS or overall survival. CONCLUSION: One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.