Good functional outcome following bilateral external capsule hemorrhage mimicking bilateral basal ganglia hemorrhage in a coma patient.

Simultaneous spontaneous bilateral external capsule hemorrhage is a rare clinical entity with extremely poor outcome. However, knowledge on the effective management of this fatal disease is limited. Herein,we described a case of a 42-year-old man with acute coma and quadriplegia as well as respiratory failure related to the disease. The patient underwent minimally invasive surgery plus local thrombolysis. Consequently, he recovered with satisfactory neurological function recovery on the 180th day of follow-up.

Could pure agraphia be the only sign of stroke? Lessons from two case reports.

Agraphia is defined as the disruption of the previously intact writing skills due to an acquired brain damage. Stroke remains the most common cause of language impairment; however, writing disorders, including agraphia, are underestimated in patients with stroke. In this regard, we report two patients presenting with pure agraphia as an early symptom of stroke. Both patients complained of at least two difficulties in visualizing letter formation beforehand, the frequent need for verbal cues, misuse of lines and margins, poorly legible signature, and writing and thinking at the same time (e.g., creative thinking and taking notes). They underwent brain magnetic resonance imaging which revealed a small lacunar infarction of the left insula and external capsule (patient 1) and a small hemorrhagic lesion in the posterior limb of the left internal capsule (patient 2). To our knowledge, this is the first report on pure agraphia as the presenting symptom of stroke. We suggest that all patients with acute agraphia, even when presenting as an isolated symptom, should be evaluated for stroke, in order to better facilitate its diagnosis and treatment.

A fixel-based analysis of micro- and macro-structural changes to white matter following adult traumatic brain injury.

Diffusion tensor imaging is often used to assess white matter (WM) changes following traumatic brain injury (TBI), but is limited in voxels that contain multiple fibre tracts. Fixel-based analysis (FBA) addresses this limitation by using a novel method of analysing high angular resolution diffusion-weighted imaging (HARDI) data. FBA examines three aspects of each fibre tract within a voxel: tissue micro-structure (fibre density [FD]), tissue macro-structure (fibre-bundle cross section [FC]) and a combined measure of both (FD and fibre-bundle cross section [FDC]). This study used FBA to identify the location and extent of micro- and macro-structural changes in WM following TBI. A large TBI sample (Nmild = 133, Nmoderate-severe = 29) and control group (healthy and orthopaedic; N = 107) underwent magnetic resonance imaging with HARDI and completed reaction time tasks approximately 7 months after their injury (range: 98-338 days). The TBI group showed micro-structural differences (lower FD) in the corpus callosum and forceps minor, compared to controls. Subgroup analyses revealed that the mild TBI group did not differ from controls on any fixel metric, but the moderate to severe TBI group had significantly lower FD, FC and FDC in multiple WM tracts, including the corpus callosum, cerebral peduncle, internal and external capsule. The moderate to severe TBI group also had significantly slower reaction times than controls, but the mild TBI group did not. Reaction time was not related to fixel findings. Thus, the WM damage caused by moderate to severe TBI manifested as fewer axons and a reduction in the cross-sectional area of key WM tracts.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

Asymptomatic Striatocapsular slit-like Hemorrhage as a Severity Marker in Patients with Hypertensive Angiopathy.

BACKGROUND: Concomitant asymptomatic striatocapsular slit-like hemorrhage (SSH) is occasionally found in patients of spontaneous intracerebral hemorrhage (ICH), but was seldomly described in the literature. In this study, we described the clinico-radiological features of asymptomatic SSH in ICH patients with hypertensive microangiopathy. METHODS AND RESULTS: 246 patients with strictly deep or mixed deep and lobar ICH/microbleeds were included. SSH was defined as hypointense lesions involving the lateral aspect of lentiform nucleus or external capsule in slit shape (>1.5 cm) on susceptibility-weighted imaging without history of associated symptoms. Demographics and neuroimaging markers were compared between patients with SSH and those without. Patients with SSH (n=24, 10%) and without SSH had comparable age (62.0 ± 12.6 vs. 62.3 ± 13.5, p = 0.912) and vascular risk factor profiles including the diagnosis of chronic hypertension, diabetes, and dyslipidemia (all p>0.05). SSH was associated with more common lobar microbleeds (79.2% vs 48.2%, p = 0.005), lacunes (75% vs. 41.4%, p = 0.002) and higher white matter hyperintensity (WMH) volumes (24.1 [10.4-46.3] vs. 13.9 [7.0-24.8] mL, p = 0.012) on MRI, as well as more frequent left ventricular hypertrophy (LVH) (50.0% vs. 20.5%, p = 0.004) and albuminuria (41.7% vs. 19.4%, p = 0.018). In multivariable analyses, SSH remains independently associated with LVH (p = 0.017) and albuminuria (p = 0.032) after adjustment for age, sex, microbleed, lacune and WMH volume. CONCLUSIONS: Asymptomatic SSH is associated with more severe cerebral small vessel disease-related change on brain MRI, and hypertensive cardiac and renal injury, suggesting a more advanced stage of chronic hypertension.

Prospective memory impairment in patients with white matter lesions.

OBJECTIVE: A vast majority of the episodic memory literature in white matter lesions (WML) had focused on "retrospective memory (RM)", little was known about prospective memory (PM) in WML patients. The aim of our study was to investigate the effect of WML patients on event-based prospective memory (EBPM) and time-based prospective memory (TBPM). In addition, our study attempted to understand the possible mechanisms of PM damage in WML patients. METHODS: A total of 42 WML patients and 40 age and education level matched healthy controls were included. EBPM (an action whenever particular words were presented) and TBPM (an action at certain times) were performed to test the involvement of PM in WML. The extent of WML within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). RESULTS: A significant difference was found in the performance of Montreal Cognitive Assessment (MOCA) (21.8 ± 3.9 vs. 26.6 ± 1.7, p < 0.05) and TBPM (2.88 ± 1.21 vs. 4.27 ± 0.78, p < 0.05), but not Mini-Mental State Examination (MMSE) (26.9 ± 2.8 vs. 27.3 ± 1.2, p > 0.05) and EBPM (3.62 ± 1.25 vs.4.47 ± 1.11, p > 0.05) in WML patients compared with the healthy controls. Moreover, TBPM and MOCA scores were negatively correlated with CHIPS scores. CONCLUSIONS: WML patients were impaired in TBPM but not in EBPM, supporting that EBPM and TBPM have different neural mechanisms. Our results demonstrated that WML are involved in the TBPM probably by affecting the central cholinergic pathway.

Individual differences in social desirability are associated with white-matter microstructure of the external capsule.

Humans tend to present themselves in a positive light to gain social approval. This behavioral trait, termed social desirability, is important for various types of social success. Surprisingly, investigation into the neural underpinnings of social desirability has been limited and focused only on interindividual differences in dopamine receptor binding. These studies revealed reduced dopamine receptor binding in the striatum of individuals who are high in trait social desirability. Interestingly, high dopamine signaling has been associated with low white-matter integrity, irrespective of social desirability. Based on these findings, we hypothesized that a positive association exists between trait social desirability and the white-matter microstructure of the external capsule, which carries fibers to the striatum from the prefrontal cortex. To test this hypothesis, we collected diffusion tensor imaging data and examined the relationship between fractional anisotropy of the external capsule and participants' social desirability-our analysis revealed a positive association. As a second exploratory step, we examined the association between social desirability and white-matter microstructure throughout the whole brain. Our whole-brain analysis revealed associations within multiple major white-matter tracts, demonstrating that socially desirable behavior relies on connectivity between distributed brain regions.

A diffusion spectrum imaging-based tractographic study into the anatomical subdivision and cortical connectivity of the ventral external capsule: uncinate and inferior fronto-occipital fascicles.

PURPOSE: The inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus (UF) are major fronto-capsular white matter pathways. IFOF connects frontal areas of the brain to parieto-occipital areas. UF connects ventral frontal areas to anterior temporal areas. Both fascicles are thought to subserve higher language and emotion roles. Controversy pertaining to their connectivity and subdivision persists in the literature, however. METHODS: High-definition fiber tractography (HDFT) is a non-tensor tractographic method using diffusion spectrum imaging data. Its major advantage over tensor-based tractography is its ability to trace crossing fiber pathways. We used HDFT to investigate subdivisions and cortical connectivity of IFOF and UF in 30 single subjects and in an atlas comprising averaged data from 842 individuals. A per-subject aligned, atlas-based approach was employed to seed fiber tracts and to study cortical terminations. RESULTS: For IFOF, we observed a tripartite arrangement corresponding to ventrolateral, ventromedial, and dorsomedial frontal origins. IFOF volume was not significantly lateralized to either hemisphere. UF fibers arose from ventromedial and ventrolateral frontal areas on the left and from ventromedial frontal areas on the right. UF volume was significantly lateralized to the left hemisphere. The data from the averaged atlas was largely in concordance with subject-specific findings. IFOF connected to parietal, occipital, but not temporal, areas. UF connected predominantly to temporal poles. CONCLUSION: Both IFOF and UF possess subdivided arrangements according to their frontal origin. Our connectivity results indicate the multifunctional involvement of IFOF and UF in language tasks. We discuss our findings in context of the tractographic literature.

Anodal Transcranial Direct Current Stimulation Provokes Neuroplasticity in Repetitive Mild Traumatic Brain Injury in Rats.

Repetitive mild traumatic brain injury (rmTBI) provokes behavioral and cognitive changes. But the study about electrophysiologic findings and managements of rmTBI is limited. In this study, we investigate the effects of anodal transcranial direct current stimulation (tDCS) on rmTBI. Thirty-one Sprague Dawley rats were divided into the following groups: sham, rmTBI, and rmTBI treated by tDCS. Animals received closed head mTBI three consecutive times a day. Anodal tDCS was applied to the left motor cortex. We evaluated the motor-evoked potential (MEP) and the somatosensory-evoked potential (SEP). T2-weighted magnetic resonance imaging was performed 12 days after rmTBI. After rmTBI, the latency of MEP was prolonged and the amplitude in the right hind limb was reduced in the rmTBI group. The latency of SEP was delayed and the amplitude was decreased after rmTBI in the rmTBI group. In the tDCS group, the amplitude in both hind limbs was increased after tDCS in comparison with the values before rmTBI. Anodal tDCS after rmTBI seems to be a useful tool for promoting transient motor recovery through increasing the synchronicity of cortical firing, and it induces early recovery of consciousness. It can contribute to management of concussion in humans if further study is performed.

Therapeutic benefit of lentiviral-mediated neonatal intracerebral gene therapy in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) is an inherited lysosomal storage disease caused by ß-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in central nervous system (CNS) tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model. A single injection of LV.GALC in the external capsule of Twitcher neonates resulted in robust transduction of neural cells with minimal and transient activation of inflammatory and immune response. Importantly, we documented a proficient transduction of proliferating and post-mitotic oligodendroglia, a relevant target cell type in GLD. GALC activity (30-50% of physiological levels) was restored in the whole CNS of treated mice as early as 8 days post-injection. The early and stable enzymatic supply ensured partial clearance of storage and reduction of psychosine levels, translating in amelioration of histopathology and enhanced lifespan. At 6 months post-injection in non-affected mice, LV genome persisted exclusively in the injected region, where transduced cells overexpressed GALC. Integration site analysis in transduced brain tissues showed no aberrant clonal expansion and preferential targeting of neural-specific genes. This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology, with the final aim of providing an effective and timely treatment of these global disorders.

Behavioral and neurophysiological evidence that lateral paracapsular GABAergic synapses in the basolateral amygdala contribute to the acquisition and extinction of fear learning.

The lateral/basolateral amygdala (BLA) is crucial to the acquisition and extinction of Pavlovian fear conditioning, and synaptic plasticity in this region is considered to be a neural correlate of learned fear. We recently reported that activation of BLA ß3-adrenoreceptors (ß3-ARs) selectively enhances lateral paracapsular (LPC) feed-forward GABAergic inhibition onto BLA pyramidal neurons, and that intra-BLA infusion of a ß3-AR agonist reduces measures of unconditioned anxiety-like behavior. Here, we utilized a combination of behavioral and electrophysiological approaches to characterize the role of BLA LPCs in the acquisition of fear and extinction learning in adult male Long-Evans rats. We report that intra-BLA microinjection of ß3-AR agonists (BRL37344 or SR58611A, 1µg/0.5µL/side) prior to training fear conditioning or extinction blocks the expression of these behaviors 24h later. Furthermore,ex vivo low-frequency stimulation of the external capsule (LFS; 1Hz, 15min), which engages LPC synapses, induces LTP of BLA fEPSPs, while application of a ß3-AR agonist (SR58611A, 5µM) induces LTD of fEPSPs when combined with LFS. Interestingly, fEPSP LTP is not observed in recordings from fear conditioned animals, suggesting that fear learning may engage the same mechanisms that induce synaptic plasticity at this input. In support of this, we find that LFS produces LTD of inhibitory postsynaptic currents (iLTD) at LPC GABAergic synapses, and that this effect is also absent following fear conditioning. Taken together, these data provide preliminary evidence that modulation of LPC GABAergic synapses can influence the acquisition and extinction of fear learning and related synaptic plasticity in the BLA.

Changes of White Matter Diffusion Anisotropy in Response to a 6-Week iPad Application-Based Occupational Therapy Intervention in Children with Surgically Treated Hydrocephalus: A Pilot Study.

Objective Our aims were (1) to test whether diffusion tensor imaging (DTI) could detect underlying white matter (WM) changes after a 6-week iPad application-based occupational therapy (OT) intervention in children with surgically treated hydrocephalus (HCP); and (2) to explore the association between WM changes and performance outcomes. Methods Five children (age range: 6.05-9.10 years) with surgically treated HCP completed an intensive iPad-based OT intervention targeting common domains of long-term deficits in children with HCP. The intervention included 6 weekly sessions in an OT clinic supplementing home-based program (1 hour/day, 4 days/week). DTI and neuropsychological assessments were performed before and after the intervention. Observation After the therapy, significant increases in fractional anisotropy (FA) and/or decreases in radial diffusivity were found in extensive WM areas. All participants demonstrated an increased perceptual reasoning index (PRI, Wechsler Abbreviated Scale of Intelligence: 2nd edition, PRI gains = 14.20 ± 7.56, p = 0.014). A significant positive correlation was found between PRI increase and the increase of FA in the right posterior limb of the internal capsule and the right external capsule (both p < 0.05). Conclusion This study provides initial evidence of DTI's sensitivity to detect subtle WM changes associated with performance improvements in response to a 6-week OT intervention in children with HCP.

Tractography of the external capsule and cognition: A diffusion MRI study of cholinergic fibers.

INTRODUCTION: White matter changes (WMC) in the cholinergic tracts contribute to executive dysfunction in the context of cognitive aging. WMC in the external capsule have been associated with executive dysfunction. The objectives of this study were to: 1) Characterize the lateral cholinergic tracts (LCT) and the superior longitudinal fasciculus (SLF). 2) Evaluate the association between diffusion measures within those tracts and cognitive performance. METHODS: Neuropsychological testing and high angular resolution diffusion imaging (HARDI) of 34 healthy elderly participants was done, followed by anatomically constrained probabilistic tractography reconstruction robust to crossing fibers. The external capsule was manually segmented on a mean T1 image then merged with an atlas, allowing extraction of the LCT. Diffusion tensor imaging (DTI) and HARDI-based measures were obtained. RESULTS: Correlations between diffusion measures in the LCT and the time of completion of Stroop (left LCT radial and medial diffusivity), the Symbol Search score (right LCT apparent fiber density) and the motor part of Trail-B (left LCT axial and radial diffusivity) were observed. Correlations were also found with diffusion measures in the SLF. WMC burden was low, and no correlation was found with diffusion measures or cognitive performance. DISCUSSION: DTI and HARDI, with isolation of strategic white matter tracts for cognitive functions, represent complimentary tools to better understand the complex process of brain aging.

Clinicoradiological Profile of Superficial Middle Cerebral Vein Thrombosis.

BACKGROUND: The diagnosis of isolated cortical vein thrombosis (ICVT) involving superficial middle cerebral vein (SMCV) remains challenging even in the present era of modern MRI protocols. OBJECTIVE: The purpose of this study is to review the clinical and radiological characteristics of SMCV thrombosis in our hospital. METHODS: Chart review of cases of SMCV thrombosis admitted in a tertiary care university hospital in South India during a 1-year period from September 2015 to August 2016. RESULTS: Five SMCV thrombosis patients were identified and presented with focal seizures. Neuroimaging showed edema (with or without hemorrhage) of cortex and white matter of inferior frontal gyrus, temporal pole, superior temporal gyrus, insular cortex, and external capsule. The thrombosis of SMCV was demonstrated by Spin echo T1-weighted, GRE-weighted axial, and postcontrast T1-weighted images in coronal and sagittal planes, with a slice thickness of <3 mm. Four received anticoagulation and all improved rapidly and completely. CONCLUSION: SMCV thrombosis should be considered in patients having recent onset seizures in appropriate setting based on MRI evidence of parenchymal edema and/or hemorrhage in the perisylvian region along with evidence of thrombosed vein in that region. Appropriate imaging sequences help in confirmation of diagnosis.

Microneuroanatomy of the Anterior Frontal Laser Trajectory to the Insula.

BACKGROUND: Magnetic resonance imaging-guided laser interstitial thermal therapy (LITT) is an emerging minimally invasive procedure for the treatment of deep intracranial lesions. Insular lesions are challenging to treat because of the risk of damaging important surrounding structures. The precise knowledge of the neural structures that are at risk along the trajectory and during the ablation is essential to reduce associated complications. This study aims to describe the relevant anatomy of the anterior frontal LITT trajectory to the insular region by using sectional anatomy and fiber dissection technique. METHODS: Three silicone-injected cadaveric heads were used to implant laser catheters bilaterally to the insular region by using a frameless stereotactic technique from a frontal approach. Sections were cut in both the oblique axial plane parallel to the trajectory and in the coronal plane. White matter fiber dissections were used to establish the tracts related to the laser trajectory from lateral to medial and medial to lateral. RESULTS: Supraorbital regions were selected as entry points. After crossing the frontal bone, the track intersected the inferior frontal lobe. The catheter was illustrated reaching the insular region medial to the inferior fronto-occipital fasciculus and insular cortex, and superior to the uncinate fasciculus. The uncinate fasciculus, extreme capsule, claustrum, external capsule, and putamen were traversed, preserving the major vascular structures. CONCLUSIONS: Independent of the insular area treated, an understanding of the neuroanatomy related to the anterior frontal laser trajectory is essential to improve the ability to perform LITT of this challenging region.

Electrically induced verbal perseveration: A striatal deafferentation model.

OBJECTIVE: The present study aimed to elucidate the neural correlates of the deafferentation cognitive model of verbal perseveration (VP) by analyzing the connectomics of the sites where electric stimulation elicited VP during awake left glioma surgery. METHODS: We retrospectively reviewed the anatomic sites that generated VP when electrically stimulated in a series of 21 patients operated on while awake for a left glioma. Each stimulation point was manually located on the postoperative MRI and then registered to the Montreal Neurological Institute template. Connectomics of these sites were further analyzed with Tractotron and disconnectome maps. RESULTS: VP stimulation sites were located within the white matter surrounding the posterosuperior head of the caudate nucleus, as well as within the white matter of the external capsule and the superolateral wall of the temporal horn of the ventricle. Furthermore, Tractotron and disconnectome maps revealed the connectome of these stimulation sites: the inferior fronto-occipital fasciculus, frontostriatal tract, and anterior thalamic radiations. CONCLUSION: On the basis of these results and other data, we propose the following anatomic implementation of the deafferentation cognitive model: the lexico-semantic system, comprising different areas linked together through direct cortico-cortical connections, sends information to the striatum; the striato-thalamic system acts as a tunable filter of this lexico-semantic input; and the thalamus projects back to the lexico-semantic system, amplifying the targeted response and inhibiting its competitors.

A stable and easily reproducible model of focal white matter demyelination.

BACKGROUND: Demyelination is the end product of numerous pathological processes, and also is one of the main causes of neurological disability in Multiple sclerosis (MS). Research into the pathogenesis of MS is hampered by the conventional rodent models' inability to produce stable demyelination. NEW METHOD: Focal demyelinating lesions were stereotactically targeted to the corpus callosum with a two-point injection of lysophosphatidylcholine (LPC-2) in mice. Three groups were analyzed (n = 8, each) and water maze, sensorimotor test, and compound action potential were included in functional tests. Electron microscopy was used for morphological analyses while western blot and immunohistochemistry were included for molecular detection. RESULTS: Ten days after the LPC-2 injection, the expression of myelin basic protein (MBP) was reduced, while non-phosphorylated neurofilament (SMI-32) was increased. The amplitude of the N1 segment decreased and less well-defined myelin sheaths was found. Behavioral tests showed increased latency to escape and reduced time spent in target quadrant. Four weeks later, MBP expression still reduced, SMI-32 expression was increased, both spatial learning (D24-D27) and spatial memory (D28) were still significantly impaired in LPC-2 injection mice. COMPARISON WITH EXISTING METHOD(S): Compared with the classic single-point LPC-injection model, our studies showed that the two-point LPC-injection not only could induce demyelination in a short-term manner, but also could cause demyelination in a long-term manner with little remyelination in the mouse corpus callosum. CONCLUSIONS: We established a simple, reliable, and inexpensive model of demyelination in the corpus callosum in mice, with functional and morphological reproducibility, and good validity.

Chronic Intermittent Ethanol Exposure Modulation of Glutamatergic Neurotransmission in Rat Lateral/Basolateral Amygdala is Duration-, Input-, and Sex-Dependent.

The basolateral amygdala (BLA) controls numerous behaviors, like anxiety and reward seeking, via the activity of glutamatergic principal neurons. These BLA neurons receive excitatory inputs primarily via two major anatomical pathways - the external capsule (EC), which contains afferents from lateral cortical structures, and the stria terminalis (ST), containing synapses from more midline brain structures. Chronic intermittent ethanol (CIE) exposure/withdrawal produces distinct alterations in these pathways. Specifically, 10 days of CIE (via vapor inhalation) increases presynaptic function at ST synapses and postsynaptic function at EC synapses. Given that 10-day CIE/withdrawal also increases anxiety-like behavior, we sought to examine the development of these alterations at these inputs using an exposure time-course in both male and female rats. Specifically, using 3, 7, and 10 days CIE exposure, we found that all three durations increase anxiety-like behavior in the elevated plus maze. At BLA synapses, increased presynaptic function at ST inputs required shorter exposure durations relative to post-synaptic alterations at EC inputs in both sexes. But, synaptic alterations in females required longer ethanol exposures compared to males. These data suggest that presynaptic alteration at ST-BLA afferents is an early neuroadaptation during repeated ethanol exposures. And, the similar patterns of presynaptic-then-postsynaptic facilitation across the sexes suggest the former may be required for the latter. These cooperative interactions may contribute to the increased anxiety-like behavior that is observed following CIE-induced withdrawal and may provide novel therapeutic targets to reverse withdrawal-induced anxiety.