Frontal Cortical Lesions Research Articles

P34.10 Transformation to Small Cell Lung Cancer from an Adenocarcionma EGFR+ as Resistance Mechanism. Utility of Liquid Biopsy in Treatment Selection

Tyrosine kinase inhibitors (TKIs) have been shown to be effective in advanced lung cancer with mutation of the EGFR gene. Several mechanisms of resistance to TKIs have been identified, such as: point mutation of the EGFR T790M within exon 205.6, amplification of the MET and Her2 gene, secondary mutations in BRAF-12 and very rarely the histological transformation to small cell lung cancer (SCLC). Case Report CLINICAL CASE : 51-year-old, former tobacco user, diagnosed in 2013 with left locally advanced lung adenocarcinoma, Stage IIIB, EGFR mutated (L858R) by liquid biopsy (LB) because the lake of histological material was not enough to study EGFR in tumoral tissue. Initially received gefitinib 250 mg/day. After 4 years she progressed in 2017, with increase of lung tumor mass with bone compromise. The histological diagnose of lesion showed: Poorly differentiated lung carcinoma with features of SCLC confirmed by Immunohistochemistry, a 2nd LB was performed and informed EGFR L858R mutation in circulating DNA (cDNA). The therapeutic plan was Radiation therapy in rib cage and 6 cycles of chemotherapy platin based plus etoposide, after complete treatment response assessment (RA) showed stable disease. In March 2019 a 3rd LB was performed, an EGFR L858R + in cDNA was still present; so patient restart Gefitinib. A 6-month tomography control informed stable lung images with new liver metastases and a brain CT scan performed because neurological symptoms showed a right frontal cortical lesion of 16 mm x 19 mm. She received whole brain radiotherapy. She archived complete response in CNS by images and significant clinical improvement, but progression, with multiples nodule in the lung and liver . The new liver biopsy demonstrated an infiltration of SCLC, and a 4th LB showed EGFR + L858R mutation. Based in this information it was decided to continue with gefitinib and start a second line chemotherapy, with taxanes, in a concurrent way. At the moment of this report, the patient is still alive with stable disease, after three cycles of chemotherapy, whitout any severe adverse effects, except mild diarrhea and dermatitis. LB has demonstrated in this patient the coexistence of L858 Mutation in blood and SCLC in tumor tissue. The transformation to SCLC in histological tissue biopsy is a very rare mechanism of resistance to TKIs, about 3 % of the cases of the patients with EGFR mutations. LB allows us to select the best treatment for this patient and could detect the absence of other mechanism of resistance, like mutation of the EGFR T790M. At the moment of the presentation of this abstract, there are very few cases and reports about the right treatment of the patient with this uncommon condition in the literature. One of this reports describe a patient with the T 790 M in LB and a transformation to SCLC in tumor tissue, treated with osimertinib plus chemotherapy. A larger number of patients could provide a strong evidence on this issue.

Clinical and Radiological Features of Adult Onset Bilateral Medial Frontal Cerebral Cortical Encephalitis With Anti-myelin Oligodendrocyte Glycoprotein Antibody.

Objective: To clarify the clinical and radiological features of adult onset anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated bilateral medial frontal cerebral cortical encephalitis (BFCCE).Methods: We systematically reviewed the literature for patients with anti-MOG antibody-associated BFCCE. Patients who were also positive for other encephalitis-related autoantibodies were excluded from the study. The frequency of several characteristic neurological symptoms and lesion distributions were analyzed.Results: We identified six patients with anti-MOG antibody-associated BFCCE. Among them, 6/6 had headache, 4/6 had fever, 3/6 had seizure, 2/6 had paraparesis, 2/6 had lethargy, and 2/6 had memory disturbance. CSF pleocytosis was observed in 5/6 patients, while CSF myelin basic protein was not elevated in any of the six patients. On brain MRI, 6/6 had bilateral medial frontal cortical lesions, 3/6 had corpus callosum lesions, and 3/6 had leptomeningeal enhancements. Most of the lesions were distributed in the territory of the anterior cerebral artery (ACA).Conclusion: Our results indicate that anti-MOG antibody-associated BFCCE presents with characteristic clinical symptoms and MRI findings, which might reflect lesion formation in the ACA territory.

Neurocysticercosis in a 14-year-old Nigerian: A case report and review of the literature

Neurocysticercosis (NCC), an infection of the brain by the larval form of Taenia solium tapeworm, has been described as the most common cause of acquired adult seizure and epilepsy in regions of the world where the worm infestation is endemic. It is acquired following ingestion of raw or partially cooked pork-containing cysts of T. solium. We report the case of a 14-year-old male patient, who presented with recurrent tonic–clonic partial seizures of 3 months duration, seizures, and progressive weakness of the left limb, while being fully conscious. He had a left facioparesis of the upper motor neuron type with plastic left hemiparesis. An impression of a right frontal cortical lesion was made. The laboratory investigations as well as the chest radiograph were reported as being essentially unremarkable. The magnetic resonance image of the brain revealed a circumscribed right parietal lesion which was circumscribed. A provisional diagnosis of intracranial tumor was then made. Surgery involved an en bloc resection of a cystic right parietal mass. The gelatinous fluid contained within was submitted for cytological examination. The latter revealed the presence of a cysticercus comprising the scolex, spiral canal, and the bladder wall. A diagnosis of NCC was made, and the patient was thereafter commenced on antihelminthics. The patient made an appreciable recovery thereafter. This report is to emphasize the continued existence of this disease, the need to improve diagnostic suspicion, and skill. This report further supports the proposal to declare NCC an international reportable disease.

Anti-myelin oligodendrocyte glycoprotein antibody associated encephalitis

The recent development of a cell-based assay that can detect specific autoantibodies revealed the clinical features of diseases associated with the anti-myelin oligodendrocyte glycoprotein (MOG) antibody. The anti-MOG antibody associated diseases may include inflammatory demyelinating central nervous system diseases such as neuromyelitis optica spectrum disorders, optic neuritis, myelitis, atypical multiple sclerosis, and encephalitis. Among them, anti-MOG antibody associated cortical encephalitis may develop seizure as one of the primary symptoms, present unique lateral or bilateral medial frontal cortical lesions on brain MRI FLAIR images. In acute phase, steroid pulse therapy and anti-epileptic drugs are required. In chronic phase, immunosuppressive drugs are often required to prevent relapses.

Individual-Level Lesion-Network Mapping to Visualize the Effects of a Stroke Lesion on the Brain Network: Connectograms in Stroke Syndromes.

Background and PurposeSimilar-sized stroke lesions at similar locations can have different prognoses in clinical practice. Lesion-network mapping elucidates network-level effects of lesions that cause specific neurologic symptoms and signs, and also provides a group-level understanding. This study visualized the effects of stroke lesions on the functional brain networks of individual patients.MethodsWe enrolled patients with ischemic stroke who were hospitalized within 1 week of the stroke occurrence. Resting-state functional magnetic resonance imaging was performed 3 months after the index stroke. For image preprocessing, acute stroke lesions were visually delineated based on diffusion-weighted images obtained at admission, and the lesion mask was drawn using MRIcron software. Correlation matrices were calculated from 280 brain regions using the Brainnetome Atlas, and connectograms were visualized using in-house MATLAB code.ResultsWe found characteristic differences in connectograms between pairs of patients who had comparable splenial, frontal cortical, cerebellar, and thalamocapsular lesions. Two representative patients with bilateral thalamic infarctions showed significant differences in their reconstructed connectograms. The cognitive function had recovered well at 3 months after stroke occurrence in patients with well-maintained interhemispheric and intrahemispheric connectivities.ConclusionsThis pilot study has visualized the effects of stroke lesions on the functional brain networks of individual patients. Consideration of the neurobiologic mechanisms underlying the differences between their connectograms has yielded new hypotheses about differences in the effects of stroke lesions.

The Diagnostic Role of Brain MRI in Detection of Multiple Sclerosis Related Cognitive Impairment

Background: Cognitive impairment (CI) is a common manifestation of multiple sclerosis (MS), which can severely affect patients’ and their families’ life. Early suspicion and detection of CI can improve general medical management of MS patients. Objectives: To correlate MS related CI to cortical brain lesions using brain magnetic resonance imaging (MRI). Materials and Methods: Cognitive impairment was detected using mini mental state examination (MMSE); Neurological examination and brain MRI were performed for all patients. Correlation was calculated between disease cortical burden detected by MRI and CI. Results: Fifty-three patients with proven MS were scanned by brain MRI; 69.8% of them had cognitive impairment diagnosed with MMSE. The presence and severity of cognitive impairment was correlated to cortical brain lesion. Cognitive impairment was not correlated with non-cortical brain lesions or neurological physical disability measured by Expanded Disability Status Scale (EDSS). Conclusions: Presence of brain frontal cortical lesions detected by MRI in MS patients can predict subsequent development of MS-related CI.

Fatal Curvularia brain abscess in a heart and kidney transplant recipient

A 42-year-old woman with history of heart failure status post orthotopic heart transplant and end stage renal disease presented to the hospital with decompensated heart failure that progressed to cardiogenic shock. She underwent a new orthotopic heart transplant and cadaveric donor kidney transplant. Three weeks later, she experienced right facial droop and right upper extremity weakness. Computed tomography showed a left frontal cortical lesion with vasogenic edema and a central hemorrhagic component. Given the concern for an angioinvasive mold infection, she was started on voriconazole and amphotericin B. Brain biopsy was performed and histopathology revealed septated hyphae with acute angle branching. Mycology culture isolated Curvularia sp. Unfortunately, her mental status deteriorated with subsequent development of multiorgan failure that led to death.

Supra-Tentorial Cortical Ependymoma in an Adult: Case Report and Review of the Literature

Supratentorial cortical ependymoma is a rare primary brain tumor in adults. Only 50 cases are reported in the literature including pediatric and adult patients. We report a 30-year-old male with sensory-type seizures who was found to have a right posterior frontal cortical lesion with large cystic component. The lesion was resected completely and histopathology and immunohistochemistry examinations confirmed anaplastic ependymoma WHO grade III. The patient received radiotherapy treatment post-surgery, and he was tumor free one year after treatment.

Infusions of Nerve Growth Factor Into the Developing Frontal Cortex Leads to Deficits in Behavioral Flexibility and Increased Perseverance.

In the pursuit of further establishing a neurodevelopmental animal model to investigate the mechanisms underlying impaired executive function, a core and severely debilitating symptom of schizophrenia, we sought to characterize the deficits in behavioral flexibility in adult rats following neonatal infusions of nerve growth factor (NGF) into the medial part of the developing frontal cortex. Our previous studies using this neonatal frontal cortical lesion model have shown that it leads to adult-onset positive and negative symptom-like features, and several neuropathological abnormalities of schizophrenia. In the present study, we used operant conditioning-based paradigms to investigate set-shifting ability and reversal learning performance in adult rats that received infusions of NGF into the developing frontal cortex on post-natal day 1. NGF-infusion caused apoptosis of cells in the subplate layer. Adult rats that received neonatal infusions of NGF showed decreased grey matter thickness, and decreased levels of parvalbumin in prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC). NGF-treated rats had difficulty completing the set-shifting and reversal learning tasks due to increased perseverance (ie, a failure to disengage from the previously-learned strategy once the rule contingencies were changed) compared to the control group. Collectively, these results identify the crucial role of the frontal cortical subplate layer in the structural and functional development of the mPFC relevant to schizophrenia. Furthermore, the present findings substantially advance the face and construct validity of this putative preclinical model of schizophrenia based on developmental disruption of the frontal cortical subplate.

Preconditioning of Spatial and Auditory Cues: Roles of the Hippocampus, Frontal Cortex, and Cue-Directed Attention.

Loss of function of the hippocampus or frontal cortex is associated with reduced performance on memory tasks, in which subjects are incidentally exposed to cues at specific places in the environment and are subsequently asked to recollect the location at which the cue was experienced. Here, we examined the roles of the rodent hippocampus and frontal cortex in cue-directed attention during encoding of memory for the location of a single incidentally experienced cue. During a spatial sensory preconditioning task, rats explored an elevated platform while an auditory cue was incidentally presented at one corner. The opposite corner acted as an unpaired control location. The rats demonstrated recollection of location by avoiding the paired corner after the auditory cue was in turn paired with shock. Damage to either the dorsal hippocampus or the frontal cortex impaired this memory ability. However, we also found that hippocampal lesions enhanced attention directed towards the cue during the encoding phase, while frontal cortical lesions reduced cue-directed attention. These results suggest that the deficit in spatial sensory preconditioning caused by frontal cortical damage may be mediated by inattention to the location of cues during the latent encoding phase, while deficits following hippocampal damage must be related to other mechanisms such as generation of neural plasticity.

A case of marchiafava bignami disease with frontal cortex involvement and late onset, long-lasting psychiatric symptoms

AimsTo describe the case and management of a patient with marchiafava bignami disease (MBD) with frontal cortical lesions, no specific symptoms at first referral to the emergency room, and late onset of atypical psychiatric symptoms.MethodsWe report the case of a 44-year-old patient with a history of chronic alcohol abuse, eventually diagnosed with MBD.ResultsMagnetic resonance showed lesions in the splenium and in the body of corpus callosum and bilateral lesions of the frontal cortex. The patient showed late-onset atypical psychiatric symptoms, which were drug resistant.ConclusionsThe case we describe seems to support the existing few ones describing cortical involvement in MBD, which suggest that this is associated with a poorer prognosis. Psychiatric symptoms may be challenging to treat because of drug resistance. The involvement of psychiatrists together with neurologists and radiologists, with a consultation–liaison approach has proved important for the achievement of diagnosis and of the most appropriate management and treatment for this patient.Disclosure of interestThe authors have not supplied their declaration of competing interest.

A clinical study on closing-in in focal brain-damaged individuals

In visuo-constructional assessment, brain-damaged individuals may copy figures near to or superimposed on the model, showing the Closing-in (CI). CI has been largely investigated in dementia, and often ascribed to impairments of the attention/executive abilities (“Attraction hypothesis”). Only a few dated studies investigated frequency of CI in brain-damaged individuals, without clarifying the genesis of the phenomenon. We aimed at testing the “Attraction hypothesis” in 27 individuals with focal frontal cortical or sub-cortical brain lesions by a dual-task experimental paradigm. The participants underwent a neuropsychological battery and a copying task to be performed alone (single task condition), or concurrently with a simple or a complex verbal secondary task (dual-task conditions). CI was found in 66% of frontal-damaged individuals, who scored significantly lower than healthy adults on all neuropsychological measures; brain-damaged individuals showing CI performed worse than frontal-damaged individuals without CI on frontal and visuo-constructional measures. In the dual-task condition with the complex secondary task CI was significantly enhanced, with a weaker tendency to self-correction, in individuals with CI compared to individuals without CI. These findings would confirm that the CI in brain-damaged individuals is related to reduction of attentional resources, consistently with the “Attraction hypothesis”.

Seizure Outcomes and Predictors of Recurrent Post-Stroke Seizure: A Retrospective Observational Cohort Study.

BackgroundSeizure is a common complication after stroke (termed “post-stroke seizure,” PSS). Although many studies have assessed outcomes and risk factors of PSS, no reliable predictors are currently available to determine PSS recurrence. We compared baseline clinical characteristics and post-stroke treatment regimens between recurrent and non-recurrent PSS patients to identify factors predictive of recurrence.MethodsConsecutive PSS patients admitted to our stroke center between January 2011 and July 2013 were monitored until February 2014 (median 357 days; IQR, 160–552) and retrospectively evaluated for baseline clinical characteristics and PSS recurrence. Cumulative recurrence rates at 90, 180, and 360 days post-stroke were estimated by Kaplan—Meier analysis. Independent predictors of recurrent PSS were identified by Cox proportional-hazards analysis.ResultsA total of 104 patients (71 men; mean age, 72.1 ± 11.2 years) were analyzed. PSS recurred in 31 patients (30%) during the follow-up. Factors significantly associated with PSS recurrence by log-rank analysis included previous PSS, valproic acid (VPA) monotherapy, polytherapy with antiepileptic drugs (AEDs), frontal cortical lesion, and higher modified Rankin Scale score at discharge (all p < 0.05). Independent predictors of recurrent PSS were age <74 years (HR 2.38, 95% CI 1.02–5.90), VPA monotherapy (HR 3.86, 95% CI 1.30–12.62), and convulsions on admission (HR 3.87, 95% CI 1.35–12.76).ConclusionsApproximately one-third of PSS patients experienced seizure recurrence within one year. The predictors of recurrent PSS were younger age, presence of convulsions and VPA monotherapy. Our findings should be interpreted cautiously in countries where monotherapy with second-generation AEDs has been approved because this study was conducted while second-generation AEDs had not been officially approved for monotherapy in Japan.

The Utilization of Cranial Models Created Using Rapid Prototyping Techniques in the Development of Models for Navigation Training

Navigation in neurosurgery has expanded rapidly; however, suitable models to train end users to use the myriad software and hardware that come with these systems are lacking. Utilizing three-dimensional (3D) industrial rapid prototyping processes, we have been able to create models using actual computed tomography (CT) data from patients with pathology and use these models to simulate a variety of commonly performed neurosurgical procedures with navigation systems. To assess the possibility of utilizing models created from CT scan dataset obtained from patients with cranial pathology to simulate common neurosurgical procedures using navigation systems. Three patients with pathology were selected (hydrocephalus, right frontal cortical lesion, and midline clival meningioma). CT scan data following an image-guidance surgery protocol in DIACOM format and a Rapid Prototyping Machine were taken to create the necessary printed model with the corresponding pathology embedded. The ability in registration, planning, and navigation of two navigation systems using a variety of software and hardware provided by these platforms was assessed. We were able to register all models accurately using both navigation systems and perform the necessary simulations as planned. Models with pathology utilizing 3D rapid prototyping techniques accurately reflect data of actual patients and can be used in the simulation of neurosurgical operations using navigation systems.

Right frontal cortical lesions disrupt anger mimicry

The current study investigates the neural substrates of facial expression mimicry by assessing individuals with right and left lateralised frontal cortical lesions. Electromyography was used to measure spontaneous changes in electrical activity over the corrugator supercilii (brow) and zygomaticus major (cheek) muscle regions in response to happy and angry facial expressions. Individuals with right (n=4) and left (n=5) frontal cortical lesions and demographically matched controls (n=9) were compared. It was shown that while all three groups mimic happy facial expressions, only controls and individuals with left frontal lesions mimic angry expressions. These data are consistent with evidence for right frontal cortical specialisation for the processing of anger.

Attention-modulating effects of cognitive enhancers

Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H 3 antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.

Embolie gazeuse cérébrale iatrogène d’origine veineuse sans signe respiratoire : un mécanisme rétrograde ?

Introduction Air embolism is a rare complication of various invasive medical procedures. Venous cerebral air embolism is usually the consequence of paradoxical embolism. We report a case of isolated cerebral air embolism resulting from a non-paradoxical mechanism. Case report A few minutes after his central venous catheter had been accidentally disconnected, a 63-year-old man developed left-sided rhythmic jerking movements followed by left hemiplegia. There were no associated cardiologic or pulmonary signs. Brain CT showed air bubbles in the right frontal cortical sulci. The brain MRI DWI and FLAIR sequences showed a high intensity right frontal cortical lesion without reduction in ADC. Transesophageal echocardiogram did not find a patent foramen ovale. Conclusions In this case of venous cerebral air embolism, the lack of any cardiopulmonary manifestation, the lack of a patent foramen ovale and the neuroradiological findings are not in favor of the hypothesis of paradoxical embolism. The hypothesis of retrograde venous cerebral air embolism is discussed.

Primary central nervous system lymphoma with cortical laminar hemorrhage

Here we report a case of primary central nervous system (CNS) lymphoma with cortical laminar hemorrhage. The present case showed an acute onset of focal neurologic signs and bilateral cortical lesions surrounded by peripheral white matter edema on magnetic resonance imaging. A part of the left frontal cortical lesion was hyperintense on T1-weighted images and hypointense on T2-weighted and T2⁎-weighted gradient-echo images, suggesting subacute laminar hemorrhage. The patient was initially diagnosed with multiple hemorrhagic infarctions, but a biopsy specimen revealed diffuse large B-cell lymphoma with hemosiderin deposits. Immunohistochemical studies revealed that the tumor cell cytoplasm and membrane stained positively for anti-vascular endothelial growth factor antibody. The present case reconfirms the danger of making a specific lymphoma diagnosis based on magnetic resonance imaging findings alone and that histopathologic examination following brain biopsy is necessary for a correct diagnosis. Vascular endothelial growth factor expression might be associated with the intratumoral hemorrhage.

Dissociable effects of prefrontal and anterior temporal cortical lesions on stereotypical gender attitudes

Clinical observations of patients with ventral frontal and anterior temporal cortical lesions reveal marked abnormalities in social attitudes. A previous study in seven patients with ventral prefrontal lesions provided the first direct experimental evidence for abnormalities in social attitudes using a well-established measure of gender stereotypes, the Implicit Association Test (IAT). Here, we were able to test whether these first findings could be reproduced in a larger sample of 154 patients with penetrating head injuries, and to determine the differential effects of ventromedial prefrontal (vmPFC) and ventrolateral prefrontal (vlPFC) cortical lesions on IAT performance. In addition, we investigated the role of the superior anterior temporal lobe (aTL), recently shown to represent conceptual social knowledge. First, we used a linear regression model to identify the role of each of the three regions, while controlling for the extent of damage to other regions. We found that larger lesions in either the vmPFC or the superior aTL were associated with increased stereotypical attitudes, whereas larger lesions in the vlPFC were associated with decreased stereotypical attitudes. Second, in a confirmatory analysis, we grouped patients by lesion location and compared their performance on the IAT with that of healthy volunteers. Compared to controls, patients with lesions in either the vmPFC or the superior aTL showed increased stereotypical attitudes, whereas patients with lesions in the vlPFC showed decreased stereotypical attitudes. The functional contributions of these regions in social attitudes are discussed.

Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: Persisting effects on locomotor activity, learning and nicotine self-administration

Dopaminergic innervation of the frontal cortex in adults is important for a variety of cognitive functions and behavioral control. However, the role of frontal cortical dopaminergic innervation for neurobehavioral development has received little attention. In the current study, rats were given dopaminergic lesions in the frontal cortex with local micro-infusions of 6-hydroxydopamine (6-OHDA) at 1 week of age. The long-term behavioral effects of neonatal frontal cortical 6-OHDA lesions were assessed in a series of tests of locomotor activity, spatial learning and memory, and i.v. nicotine self-administration. In addition, neurochemical indices were assessed with tissue homogenization and HPLC in the frontal cortex, striatum, and nucleus accumbens of neonatal and adult rats after neonatal 6-OHDA lesions. In neonatal rats, frontal 6-OHDA lesions as intended caused a significant reduction in frontal cortical dopamine without effects on frontal cortical 5-HT and norepinephrine. The frontal cortical dopamine depletion increased 5-HT and norepinephrine levels in the nucleus accumbens. Locomotor activity assessment during adulthood in the figure-8 maze showed that lesioned male rats were hyperactive relative to sham-lesioned males. Locomotor activity of female rats was not significantly affected by the neonatal frontal 6-OHDA lesion. Learning and memory in the radial-arm maze was also affected by neonatal frontal 6-OHDA lesions. There was a general trend toward impaired performance in early maze acquisition and a paradoxical improvement at the end of cognitive testing. Nicotine self-administration showed significant lesion×sex interactions. The sex difference in nicotine self-administration with females self-administering significantly more nicotine than males was reversed by neonatal 6-OHDA frontal cortical lesions. Neurochemical studies in adult rats showed that frontal cortical dopamine and DOPAC levels significantly correlated with nicotine self-administration in the 6-OHDA-lesioned animals but not in the controls. Frontal cortical 5-HT and 5HIAA showed inverse correlations with nicotine self-administration in the 6-OHDA-lesioned animals but not in the controls. These results show that interfering with normal dopamine innervation of the frontal cortex during early postnatal development has persisting behavioral effects, which are sex-specific.