Safety of intracranial electrodes in an MRI environment: a technical report.

INTRODUCTION: Intracranial electroencephalography (iEEG) involves placing intracranial electrodes to localise seizures in patients with medically refractory epilepsy. While magnetic resonance imaging (MRI) enables visualisation of electrodes within patient-specific anatomy, the safety of these electrodes must be confirmed prior to routine clinical utilisation. Therefore, the purpose of this study was to evaluate the safety of iEEG electrodes from a particular manufacturer in a 3.0-Tesla (3.0T) MRI environment. METHODS: Measurements of magnetically induced displacement force and torque were determined for each of the 10 test articles using standardised techniques. Test articles were subsequently evaluated for radiofrequency-induced heating using a Perspex phantom in both open and 'fault' conditions. Additionally, we assessed radiofrequency (RF)-induced heating with all test articles placed into the phantom simultaneously to simulate an implantation, again in both open and 'fault' conditions. Finally, each test article was evaluated for MRI artefacts. RESULTS: The magnetically induced displacement force was found to be less than the force on the article due to gravity for all test articles. Similarly, the maximum magnetically induced torque was less than the worst-case torque due to gravity for all test articles apart from the 8-contact strip - for which it was 11% greater - and the depthalon cap. The maximum temperature change for any portion of any test article assessed individually was 1.7°C, or 1.2°C for any device component meant to be implanted intracranially. In the implantation configuration, the maximum recorded temperature change was 0.7°C. CONCLUSIONS: MRI may be safely performed for localising iEEG electrodes at 3.0T under certain conditions.

Anatomic Variations of Foramen Ovale as a Predictor of Successful Cannulation in Percutaneous Trigeminal Rhizotomies.

BACKGROUND AND OBJECTIVES: Percutaneous trigeminal rhizotomies are common treatment modalities for medically refractory trigeminal neuralgia (TN). Failure of these procedures is frequently due to surgical inability to cannulate the foramen ovale (FO) and is thought to be due to variations in anatomy. The purpose of this study is to characterize the relationships between anatomic features surrounding FO and investigate the association between anatomic morphology and successful cannulation of FO in patients undergoing percutaneous trigeminal rhizotomy. METHODS: A retrospective analysis was conducted of all patients undergoing percutaneous trigeminal rhizotomy for TN at our academic center between January 1, 2010, and July 31, 2022. Preoperative 1-mm thin-cut computed tomography head imaging was accessed to perform measurements surrounding the FO, including inlet width, outlet width, interforaminal distance (a representation of the lateral extent of FO along the middle fossa), and sella-sphenoid angle (a representation of the coronal slope of FO). Mann-Whitney U tests assessed the difference in measurements for patients who succeeded and failed cannulation. RESULTS: Among 37 patients who met inclusion criteria, 34 (91.9%) successfully underwent cannulation. Successful cannulation was associated with larger inlet widths (median = 5.87 vs 3.67 mm, U = 6.0, P = .006), larger outlet widths (median = 7.13 vs 5.10 mm, U = 14.0, P = .040), and smaller sella-sphenoid angles (median = 52.00° vs 111.00°, U = 0.0, P < .001). Interforaminal distances were not associated with the ability to cannulate FO surgically. CONCLUSION: We have identified morphological characteristics associated with successful cannulation in percutaneous rhizotomies for TN. Preoperative imaging may optimize surgical technique and predict cannulation failure.

No change in network connectivity measurements between separate rsfMRI acquisition times.

The role of resting state functional MRI (rsfMRI) is increasing in the field of epilepsy surgery because it is possible to interpolate network connectivity patterns across the brain with a high degree of spatial resolution. Prior studies have shown that by rsfMRI with scalp electroencephalography (EEG), an epileptogenic network can be modeled and visualized with characteristic patterns of connectivity that are relevant to both seizure-related and neuropsychological outcomes after surgery. The aim of this study is to show that a 5-min acquisition time provides reproducible results related to the relevant connectivity metrics when compared to a separately acquired 5-min scan. Fourteen separate rsfMRI sessions from ten different patients were used for comparison, comprised of patients with temporal lobe epilepsy both pre- and post-operation. Results showed that there was no significant difference in any of the connectivity metrics when comparing both 5-min scans to each other. These data support the continued use of a 5-min scan for epileptogenic network modeling in future studies because the inter-scan variability is sufficiently low as not to alter the output metrics characterizing the network connectivity.

Deep brain stimulation for chronic pain: a systematic review and meta-analysis.

Background: Deep brain stimulation (DBS) has shown promise in effectively treating chronic pain. This study aimed to assess the efficacy of DBS in this context. Methods: We conducted a systematic literature search using PubMed, Scopus, and Web of Science, following the PRISMA guidelines. A well-constructed search strategy was utilized. Our literature search identified two groups of subjects: one group underwent DBS specifically for chronic pain treatment (DBS-P), while the second group received DBS for other indications (DBS-O), such as Parkinson's disease or dystonia, with pain perception investigated as a secondary outcome in this population. Meta-analysis was performed using R version 4.2.3 software. Heterogeneity was assessed using the tau^2 and I^2 indices, and Cochran's Q-test was conducted. Results: The analysis included 966 patients in 43 original research studies with chronic pain who underwent DBS (340 for DBS-P and 625 for DBS-O). Subgroup analysis revealed that DBS-P exhibited a significant effect on chronic pain relief, with a standardized mean difference (SMD) of 1.65 and a 95% confidence interval (CI) of [1.31; 2.00]. Significant heterogeneity was observed among the studies, with an I^2 value of 85.8%. However, no significant difference was found between DBS-P and DBS-O subgroups. Subgroup analyses based on study design, age, pain diseases, and brain targets demonstrated varying levels of evidence for the effectiveness of DBS across different subgroups. Additionally, meta-regression analyses showed no significant relationship between age or pain duration and DBS effectiveness for chronic pain. Conclusion: These findings significantly contribute to the expanding body of knowledge regarding the utility of DBS in the management of chronic pain. The study underscores the importance of conducting further research to enhance treatment outcomes and elucidate patient-specific factors that are associated with treatment response. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=428442, identifier CRD42023428442.

Necessity and feasibility of remote tele-programming of deep brain stimulation systems in Parkinson's disease.

INTRODUCTION: Outcomes after deep brain stimulation (DBS) therapy are dependent on good surgical placement in the target nucleus and optimized stimulation parameters through multiple programming sessions. This often requires frequent travel to a specialized DBS center, which presents a challenge for those with limited access. Recently, the FDA approved a remote tele-programming solution for DBS. To determine if remote tele-programming of DBS systems is beneficial and useful for Parkinson's Disease (PD) patients, Parkinson's Foundation hosted a survey in collaboration with Abbott Labs. METHODS: The survey was conducted to assess the need for telemedicine among PD patients with DBS and the usability of the telehealth interface for DBS teleprogramming. The survey included two validated instruments: The Effective Accessibility and Accommodation survey (EAA) and the Telehealth Usability Questionnaire (TUQ). RESULTS: 47 patients completed the EAA and 41 completed the TUQ. Results from the EAA revealed more than a third of PD patients cannot easily get to a clinic for various reasons, and more than a quarter reported difficulty contacting their clinic for advice. Results from the TUQ revealed overall satisfaction with the DBS remote programming telehealth interface and care provided. The majority of respondents reported that remote tele-programming visits are similar in quality to in-person visits. CONCLUSION: This study provides support for the use of telehealth and tele-programming for DBS management in PD patients. The ability to use remote technologies for care will increase access to DBS and mitigate the disparities that currently prevent access to care.

Clinical outcomes of globus pallidus deep brain stimulation for Parkinson disease: a comparison of intraoperative MRI- and MER-guided lead placement.

OBJECTIVE: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance. METHODS: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters. RESULTS: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery. CONCLUSIONS: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

Long-Term Outcomes of Endoscopic Third Ventricle Colloid Cyst Resection: Case Series With a Proposed Grading System.

BACKGROUND: Endoscopic resection of colloid cysts has gained recent widespread practice. However, reported complication and recurrence rates are variable, possibly, in part, because of a lack of consistency with reporting of the extent of cyst capsule removal. OBJECTIVE: To present the long-term outcomes of endoscopic resection of third ventricle colloid cysts without complete capsule removal and propose a grading system to allow consistent description of surgical outcomes. METHODS: A retrospective review of 74 patients who underwent endoscopic resection of symptomatic third ventricle colloid cysts between 1995 and 2018 was performed. Kaplan-Meier analyses were used to assess recurrence-free survival rates. RESULTS: Median patient age and cyst diameter were 48.0 (13.0-80.0) yr and 12.0 (5.0-27.0) mm, respectively. Complete emptying of cyst contents with capsule coagulation was achieved in 73 (98.6%) patients. All patients improved or remained stable postoperatively, with a median follow-up duration of 10.3 (0.3-23.7) yr. Radiographic recurrence occurred in 6 (8.1%) patients after their initial surgery, 5 (6.8%) of whom underwent redo endoscopic resection. No major complications or mortality was encountered at primary or recurrence surgery. CONCLUSION: Endoscopic resection of third ventricle colloid cysts without emphasizing complete capsule removal is a viable option for successfully treating colloid cysts of the third ventricle. Long-term follow-up demonstrates that it is associated with low risks of complications, morbidity, mortality, and recurrence. The proposed extent of the resection grading scheme will permit comparison between the different surgical approaches and facilitate the establishment of treatment guidelines for colloid cysts.

Seizure Freedom After Epilepsy Surgery and Higher Baseline Cognition May Be Associated With a Negatively Correlated Epilepsy Network in Temporal Lobe Epilepsy.

Background: Brain regions positively correlated with the epileptogenic zone in patients with temporal lobe epilepsy vary in spread across the brain and in the degree of correlation to the temporal lobes, thalamus, and limbic structures, and these parameters have been associated with pre-operative cognitive impairment and seizure freedom after epilepsy surgery, but negatively correlated regions have not been as well studied. We hypothesize that connectivity within a negatively correlated epilepsy network may predict which patients with temporal lobe epilepsy will respond best to surgery. Methods: Scalp EEG and resting state functional MRI (rsfMRI) were collected from 19 patients with temporal lobe epilepsy and used to estimate the irritative zone. Using patients' rsfMRI, the negatively correlated epilepsy network was mapped by determining all the brain voxels that were negatively correlated with the voxels in the epileptogenic zone and the spread and average connectivity within the network was determined. Results: Pre-operatively, connectivity within the negatively correlated network was inversely related to the spread (diffuseness) of that network and positively associated with higher baseline verbal and logical memory. Pre-operative connectivity within the negatively correlated network was also significantly higher in patients who would go on to be seizure free. Conclusion: Patients with higher connectivity within brain regions negatively correlated with the epilepsy network had higher baseline memory function, narrower network spread, and were more likely to be seizure free after surgery.

Clinical outcomes of pallidal deep brain stimulation for dystonia implanted using intraoperative MRI.

OBJECTIVE: Lead placement for deep brain stimulation (DBS) using intraoperative MRI (iMRI) relies solely on real-time intraoperative neuroimaging to guide electrode placement, without microelectrode recording (MER) or electrical stimulation. There is limited information, however, on outcomes after iMRI-guided DBS for dystonia. The authors evaluated clinical outcomes and targeting accuracy in patients with dystonia who underwent lead placement using an iMRI targeting platform. METHODS: Patients with dystonia undergoing iMRI-guided lead placement in the globus pallidus pars internus (GPi) were identified. Patients with a prior ablative or MER-guided procedure were excluded from clinical outcomes analysis. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed preoperatively and at 6 and 12 months postoperatively. Other measures analyzed include lead accuracy, complications/adverse events, and stimulation parameters. RESULTS: A total of 60 leads were implanted in 30 patients. Stereotactic lead accuracy in the axial plane was 0.93 ± 0.12 mm from the intended target. Nineteen patients (idiopathic focal, n = 7; idiopathic segmental, n = 5; DYT1, n = 1; tardive, n = 2; other secondary, n = 4) were included in clinical outcomes analysis. The mean improvement in BFMDRS score was 51.9% ± 9.7% at 6 months and 63.4% ± 8.0% at 1 year. TWSTRS scores in patients with predominant cervical dystonia (n = 13) improved by 53.3% ± 10.5% at 6 months and 67.6% ± 9.0% at 1 year. Serious complications occurred in 6 patients (20%), involving 8 of 60 implanted leads (13.3%). The rate of serious complications across all patients undergoing iMRI-guided DBS at the authors' institution was further reviewed, including an additional 53 patients undergoing GPi-DBS for Parkinson disease. In this expanded cohort, serious complications occurred in 11 patients (13.3%) involving 15 leads (10.1%). CONCLUSIONS: Intraoperative MRI-guided lead placement in patients with dystonia showed improvement in clinical outcomes comparable to previously reported results using awake MER-guided lead placement. The accuracy of lead placement was high, and the procedure was well tolerated in the majority of patients. However, a number of patients experienced serious adverse events that were attributable to the introduction of a novel technique into a busy neurosurgical practice, and which led to the revision of protocols, product inserts, and on-site training.

Use of a Subtemporal Approach for a Salvage Placement of a Trigeminal Ganglion Stimulating Electrode for the Treatment of Trigeminal Neuropathic Pain.

BACKGROUND: Trigeminal ganglion stimulation can be effective for trigeminal neuralgia. For patients who respond well to neurostimulation delivered percutaneously through the foramen ovale but require extensive revision and removal of instrumentation, a subtemporal approach for stimulation of the trigeminal ganglion is an alternative option as a salvage procedure. CASE DESCRIPTION: We report on a 47-year-old woman who responded well to neurostimulation for trigeminal neuropathic pain over a 1-year period from 2008 to 2009. Her preoperative pain on the numerical rating scale (NRS) was between 7 and 8 out of 10, which decreased to 2 out of 10 postoperatively. However, she developed lead migration because of a motor vehicle accident. After revision surgeries to correct this, she continued to experience pain relief until 2011. At follow-up, signs of infection prompted removal of instrumentation and subsequent return of her pain. She continued to experience persistent and severe pain (NRS score 7 of 10), which was intractable to pharmacologic treatment over 5 years. She returned in 2016 to discuss neurosurgical options, and the original approach was ruled out because of her history of lead migration, erosion, and scarring. A subtemporal approach was pursued as a salvage option, which provided several advantages for this patient. CONCLUSIONS: The subtemporal approach for salvage placement of the trigeminal ganglion stimulating electrode was effective in this patient and minimized risks given her history of erosion and multiple operations. This suggests that the subtemporal approach is a viable salvage operation for trigeminal ganglion stimulation for trigeminal neuropathic pain.

A neurosurgeon`s view: Laser interstitial thermal therapy of mesial temporal lobe structures.

Stereotactic laser ablation of mesial temporal structures is a promising new surgical intervention for patients with mesial temporal lobe epilepsy (MTLE). Since this procedure was first used to treat MTLE in 2010, the literature contains reports of 37 patients that underwent MR-guided stereotactic laser amygdalohippocampotomy (SLAH) using Laser Interstitial Thermal Therapy (LITT) with at least 1year of follow-up. This early body of data suggests that SLAH is a safe and effective treatment for MTLE in properly selected patients. Moreover, SLAH is substantially less invasive when compared with open surgical procedures including standard anterior temporal lobectomy and its more selective variants, results in immediate destruction of tissue in contrast to radiosurgical treatments for MTLE, and can more readily ablate larger volumes of tissue than is possible with techniques employing radiofrequency ablation. Finally, evidence is accruing that SLAH is associated with lower overall risk of neuropsychological deficits compared to open surgery. Thus, LITT constitutes a novel minimally invasive tool in the neurosurgeon's armamentarium for managing medically refractory seizures that may draw eligible patients to consider surgical interventions to manage their seizures.

Occipital Nerve Stimulation for the Treatment of Refractory Occipital Neuralgia: A Case Series.

BACKGROUND: Occipital neuralgia is a chronic pain syndrome characterized by sharp, shooting pains in the distribution of the occipital nerves. Although relatively rare, it associated with extremely debilitating symptoms that drastically affect a patient's quality of life. Furthermore, it is extremely difficult to treat as the symptoms are refractory to traditional treatments, including pharmacologic and procedural interventions. A few previous case studies have established the use of a neurostimulation of the occipital nerves to treat occipital neuralgia. OBJECTIVE: The following expands on that literature by retrospectively reviewing the results of occipital nerve stimulation in a relatively large patient cohort (29 patients). METHODS: A retrospective review of 29 patients undergoing occipital nerve stimulation for occipital neuralgia from 2012 to 2017 at a single institution with a single neurosurgeon. RESULTS: Of those 29 patients, 5 were repair or replacement of previous systems, 4 did not have benefit from trial stimulation, and 20 saw benefit to their trial stage of stimulation and went on to full implantation. Of those 20 patients, even with a history of failed procedures and pharmacological therapies, there was an overall success rate of 85%. The average preoperative 10-point pain score dropped from 7.4 ± 1.7 to a postoperative score of 2.9 ± 1.7. However, as with any peripheral nerve stimulation procedure, there were complications (4 patients), including infection, hardware erosion, loss of effect, and lead migration, which required revision or system removal. CONCLUSION: Despite complications, the results suggest, overall, that occipital nerve stimulation is a safe and effective procedure for refractory occipital neuralgia and should be in the neurosurgical repertoire for occipital neuralgia treatment.

High frequency stimulation of the infralimbic cortex induces morphological changes in rat hippocampal neurons.

BACKGROUND: Although a significant subset of patients with major depressive disorder (MDD) fail to respond to medical or behavioural therapy, deep brain stimulation (DBS) applied to the subgenual cingulate cortex (SCC; sg25) has been shown to reduce depressive symptoms in a subset of patients. This area receives projections from neurons in the CA1 region and subiculum of the hippocampus (HC), a brain region implicated in the pathobiology and treatment of MDD. OBJECTIVE: To assess whether high frequency stimulation (HFS) of the infralimbic cortex is associated with changes in cellular morphology in the HC. METHODS: Rats were subjected to either infralimbic HFS or sham-stimulation. Measures of cellular morphology, including dendritic length and complexity, were assessed in pyramidal neurons in the CA1 region of the HC by means of the Golgi-Cox histological stain. RESULTS: Dendritic length (p = 0.013) and number of branch points (p = 0.004) were significantly increased across the entire dendritic tree in animals subjected to HFS. Subsequent Scholl analysis revealed that for dendritic length these effects were localized to the region between 80 and 160 µm from the soma (p < 0.001 for either 40 µm interval) in the basal dendritic tree, while branch point number was predominantly increased between 120 and 160 µm from the soma (p < 0.001) in the apical dendritic tree. CONCLUSIONS: High-frequency stimulation of the infralimbic cortex increases the complexity of apical dendrites and the length of basal dendritic trees of pyramidal neurons located in the CA1 hippocampal subfield relative to sham-stimulated animals.

Endoscopic third ventriculostomy for treatment of adult hydrocephalus: long-term follow-up of 163 patients.

OBJECTIVE The efficacy of endoscopic third ventriculostomy (ETV) for the treatment of pediatric hydrocephalus has been extensively reported in the literature. However, ETV-related long-term outcome data are lacking for the adult hydrocephalus population. The objective of the present study was to assess the role of ETV as a primary or secondary treatment for hydrocephalus in adults. METHODS The authors performed a retrospective chart review of all adult patients (age ≥ 18 years) with symptomatic hydrocephalus treated with ETV in Calgary, Canada, over a span of 20 years (1994-2014). Patients were dichotomized into a primary or secondary ETV cohort based on whether ETV was the initial treatment modality for the hydrocephalus or if other CSF diversion procedures had been previously attempted respectively. Primary outcomes were subjective patient-reported clinical improvement within 12 weeks of surgery and the need for any CSF diversion procedures after the initial ETV during the span of the study. Categorical and actuarial data analysis was done to compare the outcomes of the primary versus secondary ETV cohorts. RESULTS A total of 163 adult patients with symptomatic hydrocephalus treated with ETV were identified and followed over an average of 98.6 months (range 0.1-230.4 months). All patients presented with signs of intracranial hypertension or other neurological symptoms. The primary ETV group consisted of 112 patients, and the secondary ETV consisted of 51 patients who presented with failed ventriculoperitoneal (VP) shunts. After the initial ETV procedure, clinical improvement was reported more frequently by patients in the primary cohort (87%) relative to those in the secondary ETV cohort (65%, p = 0.001). Additionally, patients in the primary ETV group required fewer reoperations (p < 0.001), with cumulative ETV survival time favoring this primary ETV cohort over the course of the follow-up period (p < 0.001). Fifteen patients required repeat ETV, with all but one experiencing successful relief of symptoms. Patients in the secondary ETV cohort also had a higher incidence of complications, with one occurring in 8 patients (16%) compared with 2 in the primary ETV group (2%; p = 0.010), although most complications were minor. CONCLUSIONS ETV is an effective long-term treatment for selected adult patients with hydrocephalus. The overall ETV success rate when it was the primary treatment modality for adult hydrocephalus was approximately 87%, and 99% of patients experience symptomatic improvement after 2 ETVs. Patients in whom VP shunt surgery fails prior to an ETV have a 22% relative risk of ETV failure and an almost eightfold complication rate, although mostly minor, when compared with patients who undergo a primary ETV. Most ETV failures occur within the first 7 months of surgery in patients treated with primary ETV, but the time to failure is more prolonged in patients who present with failed previous shunts.

Neuron somal size is decreased in the lateral amygdalar nucleus of subjects with bipolar disorder.

OBJECTIVE: Morphometric studies of postmortem brains from subjects with mood disorders have reported altered density of glial cells in the amygdala; however, the nuclear regions have not been examined individually. METHODS: We assessed the size and density of both neuronal and glial cells in discrete amygdalar nuclei in postmortem sections from subjects with major depressive disorder, bipolar disorder (BD) and schizophrenia and from nonpsychiatric control subjects. Three adjacent Nissl-stained sections were examined from each individual. RESULTS: We report significantly decreased neuron somal size in the lateral amygdalar nucleus (LAN) and the accessory basal parvocellular nucleus (ABPC) in subjects with BD, relative to control subjects. These changes in cellular morphology were most prominent in the LAN in sections obtained from the left hemisphere. CONCLUSIONS: These findings add to increasing evidence for neuropathological changes in the amygdala of subjects with BD and specifically implicate the LAN and ABPC in this disorder.

Decreased expression of insulin-like growth factor binding protein 2 in the prefrontal cortex of subjects with bipolar disorder and its regulation by lithium treatment.

Insulin-like growth factors (IGFs) regulate cellular proliferation and death, and their bioactivity is controlled by IGF binding proteins (IGFBPs). Since IGFBP-2 is the major brain resident IGFBP, and we have demonstrated lithium-mediated changes in its mRNA and protein levels in neuronal cultures, we examined IGFBP-2 expression in prefrontal cortex postmortem brain tissue from subjects with mood disorders. We found decreased IGFBP-2 expression in bipolar disorder patients compared with controls; this was especially pronounced in subjects not treated with lithium. These results suggest a role for IGFBPs in the etiology and pharmacotherapy of mood disorders.

Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia.

Impairment of neuroplasticity is considered to play a role in the pathogenesis of psychiatric disorders. To further characterize the impairment of neuroplasticity in psychiatric disorders, expression of the neuronal plasticity marker 43 kDa growth-associated protein (GAP-43) was detected in postmortem hippocampal sub-regions from psychiatric patients including major depressive disorder, bipolar disorder and schizophrenia subjects, and matched control subjects. We found that GAP-43 protein levels in the hippocampal hilar region were significantly lower in bipolar disorder and schizophrenia subjects than in control subjects. We also found that GAP-43 protein levels in the inner molecular layer of the dentate gyrus and the stratum radiatum of CA2 region were reduced in a trend in bipolar disorder and schizophrenia subjects when compared with control subjects. These results suggest that impairment of neuroplasticity may occur in the hippocampus of bipolar disorder and schizophrenia patients.

Insulin-like growth factor binding protein-2 expression is decreased by lithium.

Lithium has been shown to possess cytoprotective properties in both cellular and animal models. Moreover, previous studies indicate that lithium treatment alters the expression of insulin-like growth factor binding protein-1 (IGFBP-1), a critical modulator of insulin-like growth factor bioactivity. Given the critical roles played by insulin-like growth factors in cellular mitogenesis, differentiation, and cell death, and that IGFBP-2 is the major brain resident IGFBP, we assessed IGFBP-2 expression in primary cortical neuroncultures subsequent to lithium treatment. We report that 7 days of lithium treatment at therapeutically relevant doses attenuates the expression of IGFBP-2 mRNA and protein in a dose and time-dependent manner. Therefore, these results suggest a possible role for the insulin-like growth factor system in lithium's mechanism of action.

Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder with a strong genetic component, and may involve autoimmune processes. Support for this latter hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), with onset of OCD symptoms following streptococcal infections. Genes involved in immune response therefore represent possible candidate genes for OCD, including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune system. Four polymorphisms in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat (MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were investigated for the possibility of association with OCD using 160 nuclear families with an OCD proband. We examined the transmission of alleles of these four polymorphisms with the transmission disequilibrium test (TDT). A biased transmission of the 459-bp allele (allele 2: chi2 = 5.255, P = 0.022) of MOG4 was detected, while MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype 1.13.2.2 (chi2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the family-based association test (FBAT) was significant for MOG4 in total Yale-Brown Obsessive-Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further investigations combining genetic, pathological, and pharmacological strategies, are warranted.

Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment.

BACKGROUND: Signal transduction abnormalities have been identified in patients with bipolar (BD) and major depressive (MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream target for signal transduction pathways is the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Therefore, we measured the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional processing and important in the pathophysiology of both BD and MDD. METHODS: Human postmortem amygdala sections were generously provided by the Stanley Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative to total cell number. RESULTS: There were no differences between diagnostic groups--control subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained cells were found in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. CONCLUSIONS: These results suggest that CREB activity may be an important factor in the neurobiology of suicide and the well-documented antisuicidal effect of lithium.