CSF GABA is reduced in first-episode psychosis and associates to symptom severity.

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls.

Although cerebellar involvement across a wide range of cognitive and neuropsychiatric phenotypes is increasingly being recognized, previous large-scale studies in schizophrenia (SZ) have primarily focused on supratentorial structures. Hence, the across-sample reproducibility, regional distribution, associations with cerebrocortical morphology and effect sizes of cerebellar relative to cerebral morphological differences in SZ are unknown. We addressed these questions in 983 patients with SZ spectrum disorders and 1349 healthy controls (HCs) from 14 international samples, using state-of-the-art image analysis pipelines optimized for both the cerebellum and the cerebrum. Results showed that total cerebellar grey matter volume was robustly reduced in SZ relative to HCs (Cohens's d=-0.35), with the strongest effects in cerebellar regions showing functional connectivity with frontoparietal cortices (d=-0.40). Effect sizes for cerebellar volumes were similar to the most consistently reported cerebral structural changes in SZ (e.g., hippocampus volume and frontotemporal cortical thickness), and were highly consistent across samples. Within groups, we further observed positive correlations between cerebellar volume and cerebral cortical thickness in frontotemporal regions (i.e., overlapping with areas that also showed reductions in SZ). This cerebellocerebral structural covariance was strongest in SZ, suggesting common underlying disease processes jointly affecting the cerebellum and the cerebrum. Finally, cerebellar volume reduction in SZ was highly consistent across the included age span (16-66 years) and present already in the youngest patients, a finding that is more consistent with neurodevelopmental than neurodegenerative etiology. Taken together, these novel findings establish the cerebellum as a key node in the distributed brain networks underlying SZ.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis.

OBJECTIVE: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients. METHOD: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer. RESULTS: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. CONCLUSION: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

Time course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat.

Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time-resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long-term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9-14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X-ray diffraction analyses demonstrate that myosin can bind to actin in an ATP-dependent manner even after 9-14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post-translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long-term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.

[Use of social and health primary care services for older people with complex needs: Comparison of three types of gerontological coordination]. / Utilisation des services d'aide et de soins à domicile pour les personnes âgées en situations complexes : comparaison entre trois types de coordination gérontologique.

BACKGROUND: Older people with complex needs live mainly at home. Several types of gerontological coordinations have been established on the French territory to meet their needs and to implement social and primary health care services. But we do not have any information on the use of these services at home as a function of the coordination method used. METHODS: We compared the use of home care services for older people with complex needs in three types of coordination with 12 months' follow-up. The three coordinations regrouped a gerontological network with case management (n=105 persons), a nursing home service (SSIAD) with a nurse coordination (n=206 persons) and an informal coordination with a non-professional caregiver (n=117 persons). RESULTS: At t0, the older people addressed to the gerontological network had less access to the services offered at home; those followed by the SSIAD had the highest number of services and of weekly interventions. Hours of weekly services were two-fold higher in those with the informal coordination. At t12, there was an improvement in access to services for the network group with case management and an overall increase in the use of professional services at home with no significant difference between the three groups. CONCLUSION: The use of social and primary health care services showed differences between the three gerontological coordinations. The one-year evolution in the use of home services was comparable between the groups without an explosion in the number of services in the network group with case management.

Air breathing in Magadi tilapia Alcolapia grahami, under normoxic and hyperoxic conditions, and the association with sunlight and reactive oxygen species.

Observations of the Magadi tilapia Alcolapia grahami in hot, highly alkaline Lake Magadi revealed that they air breathe not only during hypoxia, as described previously, but also during normoxia and hyperoxia. Air breathing under these latter conditions occurred within distinct groupings of fish (pods) and involved only a small proportion of the population. Air breathing properties (duration and frequency) were quantified from video footage. Air breathing within the population followed a diel pattern with the maximum extent of pod formation occurring in early afternoon. High levels of reactive oxygen species (ROS) in the water may be an irritant that encourages the air-breathing behaviour. The diel pattern of air breathing in the field and in experiments followed the diel pattern of ROS concentrations in the water which are amongst the highest reported in the literature (maximum daytime values of 2.53 ­ 8.10 µM H2O2). Interlamellar cell masses (ILCM) occurred between the gill lamellae of fish from the lagoon with highest ROS and highest oxygen levels, while fish from a normoxic lagoon with one third the ROS had little or no ILCM. This is the first record of air breathing in a facultative air-breathing fish in hyperoxic conditions and the first record of an ILCM in a cichlid species.

Addition of heart score to high-sensitivity troponin T versus conventional troponin T in risk stratification of patients with chest pain at the coronary emergency rooms.

Patients with chest pain have a large impact on available resources in coronary emergency rooms (CER). Clinical judgement, ECG, risk scores and biomarkers guide in risk stratification. We investigated if high-sensitivity troponin T (HsT) and the HEART Score could contribute to risk stratification at the CER. All patients with chest pain, without elevated conventional troponin levels at presentation, were included. HsT levels were determined at admission (T1), at 4-6 h (T2) and 8-10 h after symptom onset (T3). The HEART Score was calculated as risk score for the occurrence of a major adverse cardiac event (MACE). Thirty days after discharge, occurrence of MACE was registered. Eighty-nine patients were included (overall mean age 61 years (range 20-90)). At presentation, 68 patients (76 %) had a HsT below cut-off value of 14 ng/l (mean HEART Score 3.7, range 1-9). Thirty-one of these 68 patients had a HEART Score between 1-3, no MACE occurred in this group. For 3 patients (4 %) HsT levels increased above 14 ng/l. These 3 patients had a HEART Score between 4-6. The majority of patients with chest pain can be safely discharged within 4-6 h after onset of symptoms using HsT and the HEART Score. In contrast, patients with initially normal HsT but a high HEART Score need longer follow-up and repeat HsT determination.

17 years' experience of surgical management of thoracic outlet syndrome at a district general hospital.

INTRODUCTION: Thoracic outlet syndrome (TOS) is caused by compression of the neurovascular structures passing through the thoracic inlet. It is categorised into three subtypes: neurogenic TOS (NTOS), venous TOS (VTOS) and arterial TOS (ATOS). This study evaluates the outcomes of patients who underwent first rib resection (FRR) for TOS during a period of 17 years at a single district general hospital. METHODS: Retrospective review of patient notes of individuals treated with FRR from August 2004 to August 2021. RESULTS: A total of 62 FRRs were performed on 51 individual patients. Indications for FRR included 42 NTOS (68%), 6 VTOS (10%) and 14 ATOS (23%). Thirty-four patients (64%) were female and the mean age at time of surgery was 39 years (range 27 to 64 years). Eleven patients (21%) underwent bilateral FRR and seven cases of cervical ribs were observed. The mean time from initial symptoms to diagnosis was 18 months (range 2 to 60 months). Overall, outcomes after surgery were positive across all subtypes of TOS. Based on Derkash's classification, 52 patients (84%) reported excellent/good, 8 (13%) reported fair and 2 (3%) reported poor resolution of symptoms at 6 month follow-up. Complications included four (9%) pneumothorax, two (4%) wound infections, two (4%) haematoma, one (2%) haemothorax, three (5%) phrenic nerve complications and one (2%) brachial neuropraxia. CONCLUSIONS: FRR for TOS can be performed safely and effectively in a district general hospital environment with excellent patient clinical outcomes.

The efficacy and safety of rotavirus vaccines in countries in Africa and Asia with high child mortality.

Rotavirus remains a leading cause of diarrhoeal morbidity and mortality in young children and rotavirus vaccines are critical for reducing global disease burden. This report addresses the performance of rotavirus vaccines in countries with high child mortality. We performed a sensitivity analysis as part of a systematic review on rotavirus vaccines to inform development of World Health Organization vaccine recommendations. The efficacy of four prequalified vaccines against severe rotavirus gastroenteritis was similar across high mortality settings in Asia and Africa. Within the first year following vaccination, vaccine efficacy for the four vaccines ranged from 48% to 57% while in the second year, efficacy ranged from 29% to 54%. The four vaccines showed no increase in intussusception risk in these settings. All four vaccines appear to prevent significant numbers of severe rotavirus gastroenteritis episodes with no measurable increase in intussusception risk in high mortality settings in Africa and Asia.

Quality of life during the course of cancer treatment in older newly diagnosed patients. Results of a prospective pilot study.

BACKGROUND: The aim of this prospective study was to report the quality of life (QoL) of older cancer patients during the first year after diagnosis and factors influencing QoL. PATIENTS AND METHODS: Newly diagnosed patients aged ≥65 years were recruited for a pilot prospective cohort study at the Jewish General Hospital, Montreal, Canada. Participants were interviewed at baseline, and at 1.5, 3, 4.5, 6, and 12 months. QoL was assessed at each interview using the European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire with 30 items. Logistic regression was conducted to determine which sociodemographic, health, and functional status characteristics were associated with decline in global health status/QoL between baseline and 12-month follow-up. RESULTS: There were 112 participants at baseline (response rate 72%), median age of 74.1, and 70% were women. Between baseline and 12-month follow-up (n=78), 18 participants (23.1%) declined ≥10 points in global health status/QoL, while 34 participants (43.6%) remained stable and 23 participants (33.3%) improved ≥10 points. None of the sociodemographic, health, and functional status variables were associated with decline in logistic regression analyses. CONCLUSION: Almost 25% of older adults experienced clinically relevant decline in their QoL. Further research is needed on which factors influence decline in QoL in older adults.

Where is the nerve? Review of operation note documentation practice for inguinal hernia repair.

INTRODUCTION: Careful identification and management of inguinal nerves during inguinal hernia repair is important to avoid iatrogenic injury. Documentation of this practice may inform postoperative clinical management. We set out to investigate how often surgeons identify inguinal nerves and document findings and management in their operation notes. METHODS: We carried out a retrospective review of operation notes at a single district general hospital. We analysed operation notes for documentation of identification and intraoperative management (preservation or sacrifice) of the inguinal nerves (iliohypogastric, ilioinguinal, genital branch of genitofemoral nerve). We collected data on the baseline characteristics of the patients, hernia characteristics and primary operating surgeons for subgroup analysis. RESULTS: A total of 100 patients were included in the analysis. Identification of any inguinal nerves (generic 'nerve') was documented in 17% of operation notes. Documentation in the operation notes of named individual nerves was limited. No documentation of intraoperative management of inguinal nerves was found in 83% of operation notes. Preservation of the inguinal nerves (generic 'nerve') was recorded in 8% and sacrifice recorded in 9% of cases. Subgroup analysis revealed similar incidence of documentation of identification and management of inguinal nerves across grades of primary surgeon, with overall incidence low for all grades. CONCLUSION: This study reveals a lack of appreciation of the importance of documenting identification and management of inguinal nerves in operation notes. Further consideration of the potential implications of poor documentation would be beneficial to improve standards.

A Qualitative Study of Health Care Providers' Views on Integrating Oral Health into Prenatal Care.

OBJECTIVE: Providing preventive oral health during prenatal care is a recognized strategy for improving pregnant women's access to oral health care. This study sought to qualitatively explore the views of health care providers in British Columbia (BC), Canada, on strategies for integrating preventive oral health into prenatal care. METHODS: Twenty-four purposefully selected health care providers (13 oral health and 11 prenatal care providers) in Vancouver and Surrey BC participated in audio-recorded semistructured interviews. Interviews lasted from 31 to 61 min, were transcribed verbatim, and were analyzed using an inductive thematic analysis with N-Vivo software. Study validity was ensured via memoing, fieldnotes, member checking, and external audit. RESULTS: Thematic analysis revealed 5 major themes: perception of integrated care, relevance of integrated prenatal oral health, strategies for achieving integrated prenatal oral health, drivers of the integration process, and barriers to integrating oral health during pregnancy. Interprofessional collaboration based on information sharing and communication was identified as a critical factor for integrated care. Oral health checks should be a component of prenatal assessments for achieving integrated prenatal oral health. Participants recommended that prenatal providers should offer oral health education and use screening questions to identify the pregnant woman's oral health needs. The establishment of referral systems was advocated, while dental assessments and oral prophylaxis via the medical services plan were proposed. The inclusion of dental providers in prenatal teams and educating health care providers on interprofessional collaboration were also supported. CONCLUSION: Oral health and prenatal providers in BC are positively disposed to adopting integrated preventive prenatal oral health care based on interprofessional collaborative practices. The inclusion of oral health providers in prenatal teams was suggested. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by policymakers for advocacy and decision making when planning care delivery programs for women during pregnancy. Including the suggested strategies could lead to increased access to, and utilization of, oral health services among pregnant women.

Modulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations.

Βeta oscillatory activity (human: 13-35 Hz; primate: 8-24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson's disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson's following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks.

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.

Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.

Dependence of cortical plasticity on correlated activity of single neurons and on behavioral context.

It has not been possible to analyze the cellular mechanisms underlying learning in behaving mammals because of the difficulties in recording intracellularly from awake animals. Therefore, in the present study of neuronal plasticity in behaving monkeys, the net effect of a single neuron on another neuron (the "functional connection") was evaluated by cross-correlating the times of firing of the two neurons. When two neurons were induced to fire together within a short time window, the functional connection between them was potentiated, and when simultaneous firing was prevented, the connection was depressed. These modifications were strongly dependent on the behavioral context of the stimuli that induced them. The results indicate that changes in the temporal contingency between neurons are often necessary, but not sufficient, for cortical plasticity in the adult monkey: behavioral relevance is required.