Effects of neurological music therapy on behavioural and emotional recovery after traumatic brain injury: A randomized controlled cross-over trial.

Traumatic brain injury (TBI) causes deficits in executive function (EF), as well as problems in behavioural and emotional self-regulation. Neurological music therapy may aid these aspects of recovery. We performed a cross-over randomized controlled trial where 40 persons with moderate-severe TBI received a 3-month neurological music therapy intervention (2 times/week, 60 min/session), either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. The evidence from this RCT previously demonstrated that music therapy enhanced general EF and set shifting. In the current study, outcome was assessed with self-report and caregiver-report questionnaires performed at baseline, 3-month, 6-month, and 18-month stages. The results showed that the self-reported Behavioural Regulation Index of the Behaviour Rating Inventory of Executive Function (BRIEF-A) improved more in the AB than BA group from baseline to 3-month stage and the effect was maintained in the 6-month follow-up. No changes in mood or quality of life questionnaires were observed. However, a qualitative content analysis of the feedback revealed that many participants experienced the intervention as helpful in terms of emotional well-being and activity. Our results suggest that music therapy has a positive effect on everyday behavioural regulation skills after TBI.

Resting-State Network Plasticity Induced by Music Therapy after Traumatic Brain Injury.

Traumatic brain injury (TBI) is characterized by a complex pattern of abnormalities in resting-state functional connectivity (rsFC) and network dysfunction, which can potentially be ameliorated by rehabilitation. In our previous randomized controlled trial, we found that a 3-month neurological music therapy intervention enhanced executive function (EF) and increased grey matter volume in the right inferior frontal gyrus (IFG) in patients with moderate-to-severe TBI (N = 40). Extending this study, we performed longitudinal rsFC analyses of resting-state fMRI data using a ROI-to-ROI approach assessing within-network and between-network rsFC in the frontoparietal (FPN), dorsal attention (DAN), default mode (DMN), and salience (SAL) networks, which all have been associated with cognitive impairment after TBI. We also performed a seed-based connectivity analysis between the right IFG and whole-brain rsFC. The results showed that neurological music therapy increased the coupling between the FPN and DAN as well as between these networks and primary sensory networks. By contrast, the DMN was less connected with sensory networks after the intervention. Similarly, there was a shift towards a less connected state within the FPN and SAL networks, which are typically hyperconnected following TBI. Improvements in EF were correlated with rsFC within the FPN and between the DMN and sensorimotor networks. Finally, in the seed-based connectivity analysis, the right IFG showed increased rsFC with the right inferior parietal and left frontoparietal (Rolandic operculum) regions. Together, these results indicate that the rehabilitative effects of neurological music therapy after TBI are underpinned by a pattern of within- and between-network connectivity changes in cognitive networks as well as increased connectivity between frontal and parietal regions associated with music processing.

Music Therapy Enhances Executive Functions and Prefrontal Structural Neuroplasticity after Traumatic Brain Injury: Evidence from a Randomized Controlled Trial.

Traumatic brain injury (TBI) causes lifelong cognitive deficits, particularly impairments of executive functioning (EF). Musical training and music-based rehabilitation have been shown to enhance cognitive functioning and neuroplasticity, but the potential rehabilitative effects of music in TBI are still largely unknown. The aim of the present crossover randomized controlled trial (RCT) was to determine the clinical efficacy of music therapy on cognitive functioning in TBI and to explore its neural basis. Using an AB/BA design, 40 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. Neuropsychological and motor testing and magnetic resonance imaging (MRI) were performed at baseline and at the 3-month and 6-month stage. Thirty-nine subjects who participated in baseline measurement were included in an intention-to-treat analysis using multiple imputation. Results showed that general EF (as indicated by the Frontal Assessment Battery [FAB]) and set shifting improved more in the AB group than in the BA group over the first 3-month period and the effect on general EF was maintained in the 6-month follow-up. Voxel-based morphometry (VBM) analysis of the structural MRI data indicated that gray matter volume (GMV) in the right inferior frontal gyrus (IFG) increased significantly in both groups during the intervention versus control period, which also correlated with cognitive improvement in set shifting. These findings suggest that neurological music therapy enhances EF and induces fine-grained neuroanatomical changes in prefrontal areas.

Identification of Depression and Screening for Work Disabilities among Long-Term Unemployed People.

The study explores whether clinical screening targeted at work disabilities among long-term unemployed people reveals eligible individuals for a disability pension and the importance of depression in granting the disability pensions. A total of 364 participants of the screening project were considered as eligible to apply for disability pension. Among them, 188 were diagnosed as clinically depressed. They were classified into those with earlier depression diagnosis (n = 85), those whose depression had not been diagnosed earlier (n = 103), and those without diagnosed depression (n = 176). The association of this ‘Depression identification pattern’ with being granted a disability pension was explored by logistic regression analyses. Compared to those with earlier diagnosis, those whose depression had not been diagnosed earlier were granted disability pension more commonly (72% vs. 54% OR 2.2, p = 0.012). Corresponding figures of the undepressed were 73%, OR 2.3, p = 0.002. The adjustments did not affect the results. Clinical examination of the long-term unemployed people in terms of work disability seems to be worthwhile. In particular, the examination reveals new depression diagnoses, which contribute more to the award of disability pension than depression diagnosed earlier by regular health care. Novel ways to detect depression among the unemployed should be implemented in the health and employment services.

Identification of major depressive disorder among the long-term unemployed.

PURPOSE: Depression is a common mental health disorder among the unemployed, but research on identifying their depression in health care is scarce. The present study aimed to explore the identification of major depressive disorder (MDD) in health care on long-term unemployed and find out if the duration of unemployment correlates with the risk for unidentified MDD. METHODS: The study sample consisted the patient files of long-term unemployed people (duration of unemployment 1-35 years, median 11 years), who in a screening project diagnosed with MDD (n = 243). The MDD diagnosis was found in the health care records of 101. Binomial logistic regression models were used to explore the effect of the duration of unemployment, as a discrete variable, to the identification of MDD in health care. RESULTS: MDD was appropriately identified in health care for 42% (n = 101) of the participants with MDD. The odds ratio for unidentified MDD in health care was 1.060 (95% confidence interval 1.011; 1.111, p = 0.016) per unemployment year. When unemployment had continued, for example, for five years the odds ratio for having unidentified MDD was 1.336. The association remained significant throughout adjustments for the set of background factors (gender, age, occupational status, marital status, homelessness, criminal record, suicide attempts, number of health care visits). CONCLUSIONS: This study among depressed long-term unemployed people indicates that the longer the unemployment period has lasted, the more commonly these people suffer from unidentified MDD. Health services should be developed with respect to sensitivity to detect signs of depression among the long-term unemployed.

Long-Term Paired Associative Stimulation Enhances Motor Output of the Tetraplegic Hand.

A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38-68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0-5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 ± 0.17 points (p < 0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 ± 29%, p = 0.046, n = 5 patients). Long-term PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted.

Oral motor functions, speech and communication before a definitive diagnosis of amyotrophic lateral sclerosis.

The aim of this study was to explore the cranial nerve symptoms, speech disorders and communicative effectiveness of Finnish patients with diagnosed or possible amyotrophic lateral sclerosis (ALS) at their first assessment by a speech-language pathologist. The group studied consisted of 30 participants who had clinical signs of bulbar deterioration at the beginning of the study. They underwent a thorough clinical speech and communication examination. The cranial nerve symptoms and ability to communicate were compared in 14 participants with probable or definitive ALS and in 16 participants with suspected or possible ALS. The initial type of ALS was also assessed. More deterioration in soft palate function was found in participants with possible ALS than with diagnosed ALS. Likewise, a slower speech rate combined with more severe dysarthria was observed in possible ALS. In both groups, there was some deterioration in communicative effectiveness. In the possible ALS group the diagnostic delay was longer and speech therapy intervention actualized later. The participants with ALS showed multidimensional decline in communication at their first visit to the speech-language pathologist, but impairments and activity limitations were more severe in suspected or possible ALS. The majority of persons with bulbar-onset ALS in this study were in the latter diagnostic group. This suggests that they are more susceptible to delayed diagnosis and delayed speech therapy assessment. It is important to start speech therapy intervention during the diagnostic processes particularly if the person already shows bulbar symptoms.

Long-term paired associative stimulation can restore voluntary control over paralyzed muscles in incomplete chronic spinal cord injury patients.

Emerging therapeutic strategies for spinal cord injury aim at sparing or restoring at least part of the corticospinal tract at the acute stage. Hence, approaches that strengthen the weak connections that are spared or restored are crucial. Transient plastic changes in the human corticospinal tract can be induced through paired associative stimulation, a noninvasive technique in which transcranial magnetic brain stimulation is synchronized with electrical peripheral nerve stimulation. A single paired associative stimulation session can induce transient plasticity in spinal cord injury patients. It is not known whether paired associative stimulation can strengthen neuronal connections persistently and have therapeutic effects that are clinically relevant. We recruited two patients with motor-incomplete chronic (one para- and one tetraplegic) spinal cord injuries. The patients received paired associative stimulation for 20-24 weeks. The paraplegic patient, previously paralyzed below the knee level, regained plantarflexion and dorsiflexion of the ankles of both legs. The tetraplegic patient regained grasping ability. The newly acquired voluntary movements could be performed by the patients in the absence of stimulation and for at least 1 month after the last stimulation session. In this unblinded proof-of-principle demonstration in two subjects, long-term paired associative stimulation induced persistent and clinically relevant strengthening of neural connections and restored voluntary movement in previously paralyzed muscles. Further study is needed to confirm whether long-term paired associative stimulation can be used in rehabilitation after spinal cord injury by itself and, possibly, in combination with other therapeutic strategies.

Identification of alcohol abuse and transition from long-term unemployment to disability pension.

AIMS: The aim of the study was to reveal potential gaps and inconsistencies in the identification of alcohol abuse in health care and in employment services and to analyse the granting of disability pensions with respect to the alcohol abuse identification pattern. METHODS: The material consisted of documentary information on 505 long-term unemployed subjects with low employability sent to the development project entitled 'Eligibility for a Disability Pension' in 2001-2006 in Finland. The dichotomous variables 'Alcohol abuse identified in employment services' and 'Alcohol abuse identified in health care' were cross-tabulated to obtain a four-class variable 'Alcohol abuse identification pattern'. Logistic regression analyses were conducted to ascertain the association of alcohol abuse identification pattern with the granting of disability pensions. RESULTS: Alcohol abuse was detected by both health care and employment services in 47% of those identified as abusers (41% of examinees). Each service systems also identified cases that the other did not. When alcohol abuse was identified in health care only, the OR for a disability pension being granted was 2.8 (95% CI 1.5-5.2) compared with applicants without identified alcohol abuse. The result remained the same and statistically significant after adjusting for confounders. CONCLUSIONS: Alcohol abuse identified in health care was positively associated with the granting of a disability pension. Closer co-operation between employment services and health care could help to identify those long-term unemployed individuals with impaired work ability in need of thorough medical examination.

The use of F-response in defining interstimulus intervals appropriate for LTP-like plasticity induction in lower limb spinal paired associative stimulation.

BACKGROUND: In spinal paired associative stimulation (PAS), orthodromic volleys are induced by transcranial magnetic stimulation (TMS) in upper motor neurons, and antidromic volleys by peripheral nerve stimulation (PNS) in lower motor neurons of human corticospinal tract. The volleys arriving synchronously to the corticomotoneuronal synapses induce spike time-dependent plasticity in the spinal cord. For clinical use of spinal PAS, it is important to develop protocols that reliably induce facilitation of corticospinal transmission. Due to variability in conductivity of neuronal tracts in neurological patients, it is beneficial to estimate interstimulus interval (ISI) between TMS and PNS on individual basis. Spinal root magnetic stimulation has previously been used for this purpose in spinal PAS targeting upper limbs. However, at lumbar level this method does not take into account the conduction time of spinal nerves of the cauda equina in the spinal canal. NEW METHOD: For lower limbs spinal PAS, we propose estimating appropriate ISIs on the basis of F-response and motor-evoked potential (MEP) latencies. The use of navigation in TMS and ensuring correct PNS electrode placement with F-response recording enhances the precision of the method. RESULTS: Our protocol induced 186±17% (mean±STE) MEP amplitude facilitation in healthy subjects, being effective in all subjects and nerves tested. COMPARISON WITH EXISTING METHOD: We report for the first time the individual estimation of ISIs in spinal PAS for lower limbs. CONCLUSIONS: Estimation of ISI on the basis of F and MEP latencies is sufficient to effectively enhance corticospinal transmission by lower limb spinal PAS in healthy subjects.

Necessity of monitoring after negative head CT in acute head injury.

OBJECTIVE: The main objective of this study was to evaluate the incidence of delayed complications in acute head injury (HI) patients with an initial normal head computed tomography (CT). MATERIALS AND METHODS: This retrospective study included 3023 consecutive patients who underwent head CT due to an acute HI at the Emergency Department (ED) of Tampere University Hospital (August 2010-July 2012). Regardless of clinical injury severity, the patients with a normal head CT were selected (n=2444, 80.9%). The medical records of these patients were reviewed to identify the individuals with a serious clinically significant complication related to the primary HI. The time window considered was the following 72h after the primary head CT. A repeated head CT in the hospital ward, death, or return to the ED were indicative of a possible complication. RESULTS: The majority (n=1811, 74.1%) of the patients with a negative head CT were discharged home and 1.1% (n=27) of these patients returned to ED within 72h post-CT. A repeated head CT was performed on 12 (44.4%) of the returned patients and none of the scans revealed an acute lesion. Of the 632 (25.9%) CT-negative patients admitted to the hospital ward from the ED, a head CT was repeated in 46 (7.3%) patients within 72h as part of routine practice. In the repeated CT sample, only one (0.2%) patient had a traumatic intracranial lesion. This lesion did not need neurosurgical intervention. The overall complication rate was 0.04%. CONCLUSION: In the present study, which includes head injuries of all severity, the probability of delayed life-threatening complications was negligible when the primary CT scan revealed no acute traumatic lesions.

Assessing the state of chronic spinal cord injury using diffusion tensor imaging.

The aim of this study was to quantify the association between diffusion tensor imaging (DTI) parameters of the cervical spinal cord and neurological disability in patients with chronic traumatic spinal cord injury (SCI). A cervical spinal cord 3T magnetic resonance imaging (MRI) with DTI sequences was performed on 28 patients with chronic traumatic SCI and 40 healthy control subjects. DTI metrics, including fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD), were calculated within the normal-appearing spinal cord area at levels C2 or C3. Clinical assessment of the patients was performed according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the motor subscale of the Functional Independence Measure (FIM). The FA values of the patients with SCI were significantly lower than those of healthy control subjects (p<0.000001). In contrast, the ADC and RD values of these patients were significantly higher than those of control subjects (ADC p<0.0001, RD p<0.00001). In patients with SCI, the FA values were positively correlated with the motor (pr=0.56, p<0.01) and sensory (pr=0.66, p<0.001) scores of ISNCSCI and with the motor subscale of FIM (pr=0.51, p<0.01). DTI revealed spinal cord pathology, which was undetectable using conventional MRI. DTI changes in regions that were remote from the site of primary injury were most likely the result of secondary degeneration of white matter tracts. Decreased FA values were correlated with poorer motor and sensory function, as well as a lack of independence in daily living. DTI is a promising quantitative and objective tool that may be used in the clinical assessment of patients with SCI.

[Update on current care guidelines: spinal cord injury]. / Selkäydinvamma.

Traumatic spinal cord injury is most common among men between 16 and 30 years. Prevention should be targeted both on traffic safety and individual behaviour Key issues in patient care are safe transfer from the place of injury to a hospital, diagnostic imaging (primarily CT, MRI if needed) and assessment of neurological injury by AIS-questionnaire, early surgical decompression and stabilisation for most cases, and treatment and rehabilitation starting from the emergency room and extending to life-long care carried out by a multi-professional team.

Persistent symptoms in mild to moderate traumatic brain injury associated with executive dysfunction.

In order to improve detection of subtle cognitive dysfunction and to shed light on the etiology of persistent symptoms after mild-to-moderate traumatic brain injury (TBI), we employed an experimental executive reaction time (RT) test, standardized neuropsychological tests, and diffusion tensor imaging (DTI). The Executive RT-Test, an Executive Composite Score from standardized neuropsychological tests, and DTI-indices in the midbrain differentiated between patients with persistent symptoms from those fully recovered after mild-to-moderate TBI. We suggest that persistent symptoms in mild-to-moderate TBI may reflect disrupted fronto-striatal network involved in executive functioning, and the Executive RT-Test provides an objective and novel method to detect it.

Intranasal administration of human IL-6 increases the severity of chemically induced seizures in rats.

Here we study the role of a pleiotropic pro-inflammatory cytokine, interleukin-6 (IL-6), in epilepsy. To examine this problem, we used human recombinant IL-6 applied intranasally (400 ng/40 microl) to rats 1h before seizures induced by systemic injection of pentylenenetrazole (PTZ, 75 mg/kg). Overall, compared to the saline-treated control animals (n = 11 in each group), IL-6-treated rats demonstrated elevated levels of IL-6 in the frontal lobe (measured by ELISA) and increased severity of PTZ-induced seizures (shorter latency, longer duration and higher mortality). Our findings show that IL-6 plays a pro-convulsant role in the brain and suggest that the IL-6 system may be a novel target for the development of anticonvulsant drugs.

Long-term functional consequences of transient occlusion of the middle cerebral artery in rats: a 1-year follow-up of the development of epileptogenesis and memory impairment in relation to sensorimotor deficits.

Post-stroke seizures occur in 5-20% of patients. Modeling of stroke-induced seizures in animals provides a useful tool for investigating the molecular basis of epileptogenesis and for developing therapies for stroke patients at increased risk for epileptogenesis. The questions addressed in the study were: (1) Do rats develop spontaneous seizures after transient occlusion of the middle cerebral artery (MCAO)? (2) Is epileptogenesis associated with impaired hippocampus-dependent spatial learning and memory? (3) Are the functional abnormalities linked to axonal plasticity in the dentate gyrus? (4) Does the sensorimotor impairment induced by MCAO predict the risk of epileptogenesis? Adult male Sprague-Dawley rats were subjected to MCAO for 120 min. Development of spontaneous seizures was monitored by 1 week of continuous video-electroencephalographic (EEG) recordings at 3, 7, and 12 months after MCAO. Spontaneous seizures were not detected during 1-year follow-up in ischemic rats. Animals were, however, impaired in the spatial memory task (P<0.001), which was not associated with altered hippocampal LTP or abnormal mossy fiber sprouting (Timm staining). Animals also had a long-lasting sensorimotor deficit (P<0.05). The present study indicates that MCAO causes long-lasting sensorimotor and spatial memory impairment, but does not induce epileptogenesis or spontaneous seizures.

3-D reconstructed magnetic resonance imaging in localization of subdural EEG electrodes. Case illustration.

We report an illustrative case of presurgical evaluation for epilepsy surgery, where the three-dimensional reconstructed magnetic resonance imaging played a pivotal role in determining the exact location of the subdural strip electrodes in temporomesial area. The tip of one the frontal strip electrodes was actually recording the temporopolar ictal activity. This contributed conclusively to the decision for surgical treatment and to the excellent outcome.

Intrinsic synaptic circuitry of the amygdala.

The present study is part of an ongoing project aimed at understanding the electrophysiologic properties of single amygdaloid neurons and their correlations with the morphology of the somata as well as axonal and dendritic trees. The axonal morphology of 14 three-dimensional, reconstructed spiny neurons (4 in the lateral and 10 in the basal nucleus) that were filled in vivo with intracellular injections of biocytin is described. Three-dimensional reconstruction was performed using Neurolucida software (MicroBrightField). Sholl analysis was used to assess the axonal length as well as the number of axonal varicosities and endings within concentric spherical shells placed at 50- micro m intervals from the soma. These data indicate that the same neuron can innervate several amygdaloid nuclear divisions or nuclei and extra-amygdaloid regions. This finding suggests that the same neuron can modulate various brain areas in parallel. Both the presumed intra-amygdaloid (all axonal branches within the amygdala) and extra-amygdaloid (axons also outside the amygdala) projection neurons have dense perisomatic axonal arborizations, and consequently, the intra-amygdaloid and extra-amygdaloid projection neurons are difficult to differentiate based on the analysis of perisomatic axonal morphology. Furthermore, the same extra-amygdaloid neuron can drive many neurons both locally as well as at extra-amygdaloid projection areas within a relatively short time. Finally, the axonal morphology of spiny neurons located in the lateral or basal nuclei was similar. These data provide baseline quantitative information about the axonal dimensions of amygdaloid neurons and can form the anatomic basis for modeling amygdaloid neuronal circuits when more quantitative data regarding neuronal numbers, size, and dendritic morphology become available.

Atipamezole, an alpha2-adrenoceptor antagonist, augments the effects of L-DOPA on evoked dopamine release in rat striatum.

The effects of atipamezole, an alpha(2)-adrenoceptor antagonist, L-3,4-dihydroxyphenylalanine (L-DOPA) and the combination of these drugs on dopamine overflow were studied in dopaminergic presynaptic terminals of rat caudate and nucleus accumbens. Dopamine overflow evoked by 100 pulses of electrical stimulation of the medial forebrain bundle at a low (20 Hz) and high (50 Hz) frequency was measured by in vivo voltammetry. L-DOPA (15 mg/kg) increased dopamine overflow in the caudate nucleus, but this dose had no effects in the nucleus accumbens. Atipamezole (300 microg/kg) had no effects on its own on dopamine overflow, but it did increase the size of the readily releasable storage pool and the effects of L-DOPA treatment in both structures. The combination of the drugs increased dopamine overflow to a larger extent at high compared to low stimulation frequencies. We conclude that the rat caudate nucleus is more sensitive than the nucleus accumbens to the effects of L-DOPA, and the effects of L-DOPA treatment might be effectively enhanced by antagonism of alpha(2)-adrenoceptors.

Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade and cognitive deficits in ovariectomized mice.

Estrogen is implicated in hippocampus-dependent spatial learning as well as structural organization and electrophysiological properties of the rat hippocampus but little is known about its mechanisms of action in mice. In this study, we investigated pharmacologically whether estrogen interacts with the hippocampal N-methyl-D-aspartate (NMDA) receptors in ovariectomized mice as postulated for rats. Female C57BL/6J mice were ovariectomized at 5 months, and 2 weeks before testing at 12 months, half of them received subcutaneous estrogen pellets containing 0.18 mg of 17 beta-estradiol. The competitive NMDA-antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), was administered at 5.0 and 10.0 microM to block induction of long-term potentiation (LTP) in the hippocampal slice and intraperitoneally at 0.5, 2.0, and 5.0 mg/kg to impair spatial learning in the water maze. Estrogen treatment shifted the dose-response curve to CPP in both experiments. First, 10 microM CPP blocked the initiation of LTP in all mice, but 5 microM only in ovariectomized non-estrogen-treated mice. Second, final level of acquisition and probe trial performance in the water maze were less affected by high doses of CPP in the estrogen-treated ovariectomized mice than in non-treated group. In control tests for motor side effects, estrogen treatment did not reduce the tendency of CPP to decrease locomotor activity in the open field and impair balance on a rotating rod, and estrogen by itself decreased swimming speed as did CPP, but these effects did not interact. Our findings support the notion that estrogen treatment increases the number of active NMDA-receptors in the mouse hippocampus.