The diagnosis and evaluation of dementia and mild cognitive impairment with emphasis on SPECT perfusion neuroimaging.

As the world population ages, the incidence of dementing illnesses will dramatically increase. The number of people afflicted with dementia is expected to quadruple in the next 50 years. Since the neuropathology of the dementias precedes clinical symptoms often by several years, earlier detection and intervention could be key steps to mitigating the progression and burden of these diseases. This review will explore methods of evaluating, differentiating, and diagnosing the multiple forms of dementia. Particular emphasis will be placed on the diagnosis of mild cognitive impairment-the precursor to dementia. Anatomical imaging; cerebrospinal fluid markers; functional neuroimaging, such as positron emission tomography and single photon emission tomography; and molecular imaging, such as amyloid marker imaging, will be assessed in terms of sensitivity and specificity. Cost will also be a consideration, as the growing population afflicted with dementia represents an increasingly large financial encumbrance to the healthcare systems of every nation. In the face of expensive new markers and limited availability of cyclotrons, single photon emission computer tomography (SPECT) provides relatively high sensitivity and specificity at a comparatively low overall cost.

Increased Asymmetric Perfusion of the Cerebral Cortices and Thalamus Indicates Individuals at Risk for Bipolar Disorder: A Family Cohort Single Photon Emission Computed Tomography Neuroimaging Study.

Bipolar disorder is a significant mental illness affecting over 4 million people in North America and approximately 46 million worldwide. While the onset of bipolar disorder is typically in late adolescence and early adulthood, the correct diagnosis can be delayed for several years. This delay can result in inappropriate pharmaceutical interventions, loss of career or productivity, suicide, family hardship, and unnecessary expense. Moreover, prolonged untreated or inappropriately treated bipolar disorder may cause damage to the brain. Early diagnosis is a critical need to circumvent the damage, suffering, and expense caused by the current delay. Brain perfusion single photon emission computed tomography (SPECT) neuroimaging reveals visual correlates of brain function. Herein, a family cohort all with bipolar disorder is described and their symptoms correlated with findings on the individual SPECT brain scans. The family consisted of two parents and three children (one female). The scans were interpreted by a panel of experts. Then a post hoc region-of-interest (ROI) analysis was conducted on SPECT data normalized to the cerebellum maximum with comparison to similarly normalized data from a normative sample. These findings support two distinct patterns of SPECT perfusion scan changes that can be found in individuals with bipolar disorder. In addition, these findings indicate that SPECT scan findings may be predictive of individual risk for progressing to symptomatic bipolar disorder. While preliminary, the findings in this cohort support the need for larger, diverse cohort studies of bipolar and control subjects to assess the predictive value of these particular SPECT perfusion findings in bipolar disorder.

The Legacy of the TTASAAN Report - Premature Conclusions and Forgotten Promises About SPECT Neuroimaging: A Review of Policy and Practice Part II.

Brain perfusion single photon emission computed tomography (SPECT) scans were initially developed in 1970s. A key radiopharmaceutical, hexamethylpropyleneamine oxime (HMPAO), was not stabilized until 1993 and most early SPECT scans were performed on single-head gamma cameras. These early scans were of inferior quality. In 1996, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (TTASAAN) issued a report regarding the use of SPECT in the evaluation of neurological disorders. This two-part series explores the policies and procedures related to perfusion SPECT functional neuroimaging. In Part I, the comparison between the quality of the SPECT scans and the depth of the data for key neurological and psychiatric indications at the time of the TTASAAN report vs. the intervening 25 years were presented. In Part II, the technical aspects of perfusion SPECT neuroimaging and image processing will be explored. The role of color scales will be reviewed and the process of interpreting a SPECT scan will be presented. Interpretation of a functional brain scans requires not only anatomical knowledge, but also technical understanding on correctly performing a scan, regardless of the scanning modality. Awareness of technical limitations allows the clinician to properly interpret a functional brain scan. With this foundation, four scenarios in which perfusion SPECT neuroimaging, together with other imaging modalities and testing, lead to a narrowing of the differential diagnoses and better treatment. Lastly, recommendations for the revision of current policies and practices are made.

Longitudinal Single Photon Emission Computed Tomography Neuroimaging as an Indication of Improvement in Psychiatric Disorders in a Community Psychiatric Practice.

In the community, there is a need to more objectively evaluate the response of common chronic psychiatric disorders to treatment. Brain single photon emission computed tomography (SPECT) indirectly measures cerebral functional activity by uptake of a radiotracer, which follows regional cerebral blood flow. Brain 3D Thresholded SPECT scans are thresholded three dimensional images derived from brain SPECT data. A retrospective community study of longitudinal (before and after treatment) brain 3D Thresholded SPECT scans of 73 patients with all-cause psychiatric disorders (most frequent diagnostic clusters: attention-deficit hyperactivity disorder, post-mild traumatic brain injury, affective disorders, psychotic disorders, post-viral chronic syndromes), shows these baseline SPECT scans predict improvement (non-worsening to large improvement) in clinical functioning with a sensitivity of 94% (95% confidence interval 86-98%) and a specificity of 67% (95% confidence interval 21-94%). In contrast, contemporaneous analysis by the same radiologist of conventional 2D reading of the same before and after treatment brain SPECT scan data of the same 73 patients, predicted improvement (non-worsening to large improvement) in clinical functioning with a sensitivity of only 26% (95% confidence interval 17-37%) although with a specificity of 100% (95% confidence interval 44-100%). These data suggest 3D Thresholded SPECT scans can provide the clinician with a more objective measure for verifying improvement in psychiatric disorders seen in the community, consistent with prior studies of SPECT as a measure of neurobiological change. Furthermore, these data suggest 3D Thresholded SPECT scans may have clinical application in guiding treatment and potentially improving outcomes.

SPECT Functional Neuroimaging Distinguishes Adult Attention Deficit Hyperactivity Disorder From Healthy Controls in Big Data Imaging Cohorts.

Background: The diagnosis of attention deficit hyperactivity disorder (ADHD) relies on history and observation, as no reliable biomarkers have been identified. In this study, we compared a large single diagnosis group of patients with ADHD (combined, inattentive, and hyperactive) to healthy controls using brain perfusion single-photon emission computed tomography (SPECT) imaging to determine specific brain regions which could serve as potential biomarkers to reliably distinguish ADHD. Methods: In a retrospective analysis, subjects (n = 1,135) were obtained from a large multisite psychiatric database, where resting state (baseline) and on-task SPECT scans were obtained. Only baseline scans were analyzed in the present study. Subjects were separated into two groups - Group 1 (n = 1,006) was composed of patients who only met criteria for ADHD with no comorbid diagnoses, while a control group (n = 129) composed of individuals who did not meet criteria for any psychiatric diagnosis, brain injury, or substance use served as a non-matched control. SPECT regions of interests (ROIs) and visual readings were analyzed using binary logistic regression. Predicted probabilities from this analysis were inputted into a Receiver Operating Characteristic analysis to identify sensitivity, specificity, and accuracy. Results: The baseline ROIs and visual readings show significant separations from healthy controls. Sensitivity of the visual reads was 100% while specificity was >97%. The sensitivity and specificity of the post-hoc ROI analysis were both 100%. Decreased perfusion was primarily seen in the orbitofrontal cortices, anterior cingulate gyri, areas of the prefrontal cortices, basal ganglia, and temporal lobes. In addition, ROI analysis revealed some unexpected areas with predictive value in distinguishing ADHD, such as cerebellar subregions and portions of the temporal lobes. Conclusions: Brain perfusion SPECT distinguishes adult ADHD patients without comorbidities from healthy controls. Areas which were highly significantly different from control and thus may serve as biomarkers in baseline SPECT scans included: medial anterior prefrontal cortex, left anterior temporal lobe, and right insular cortex. Future studies of these potential biomarkers in ADHD patients with comorbidities are warranted.

The Legacy of the TTASAAN Report-Premature Conclusions and Forgotten Promises: A Review of Policy and Practice Part I.

Brain perfusion single photon emission computed tomography (SPECT) scans were initially developed in 1970's. A key radiopharmaceutical, hexamethylpropyleneamine oxime (HMPAO), was originally approved in 1988, but was unstable. As a result, the quality of SPECT images varied greatly based on technique until 1993, when a method of stabilizing HMPAO was developed. In addition, most SPECT perfusion studies pre-1996 were performed on single-head gamma cameras. In 1996, the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (TTASAAN) issued a report regarding the use of SPECT in the evaluation of neurological disorders. Although the TTASAAN report was published in January 1996, it was approved for publication in October 1994. Consequently, the reported brain SPECT studies relied upon to derive the conclusions of the TTASAAN report largely pre-date the introduction of stabilized HMPAO. While only 12% of the studies on traumatic brain injury (TBI) in the TTASAAN report utilized stable tracers and multi-head cameras, 69 subsequent studies with more than 23,000 subjects describe the utility of perfusion SPECT scans in the evaluation of TBI. Similarly, dementia SPECT imaging has improved. Modern SPECT utilizing multi-headed gamma cameras and quantitative analysis has a sensitivity of 86% and a specificity of 89% for the diagnosis of mild to moderate Alzheimer's disease-comparable to fluorodeoxyglucose positron emission tomography. Advances also have occurred in seizure neuroimaging. Lastly, developments in SPECT imaging of neurotoxicity and neuropsychiatric disorders have been striking. At the 25-year anniversary of the publication of the TTASAAN report, it is time to re-examine the utility of perfusion SPECT brain imaging. Herein, we review studies cited by the TTASAAN report vs. current brain SPECT imaging research literature for the major indications addressed in the report, as well as for emerging indications. In Part II, we elaborate technical aspects of SPECT neuroimaging and discuss scan interpretation for the clinician.

Functional Neuroimaging in Psychiatry-Aiding in Diagnosis and Guiding Treatment. What the American Psychiatric Association Does Not Know.

While early efforts in psychiatry were focused on uncovering the neurobiological basis of psychiatric symptoms, they made little progress due to limited ability to observe the living brain. Today, we know a great deal about the workings of the brain; yet, none of this neurobiological awareness has translated into the practice of psychiatry. The categorical system which dominates psychiatric diagnosis and thinking fails to match up to the real world of genetics, sophisticated psychological testing, and neuroimaging. Nevertheless, the American Psychiatric Association (APA) recently published a position paper stating that neuroimaging provided no benefit to the diagnosis and treatment of psychiatric disorders. Using the diagnosis of depression as a model, we illustrate how setting aside the unrealistic expectation of a pathognomonic "fingerprint" for categorical diagnoses, we can avoid missing the biological and, therefore, treatable contributors to psychopathology which can and are visualized using functional neuroimaging. Infection, toxicity, inflammation, gut-brain dysregulation, and traumatic brain injury can all induce psychiatric manifestations which masquerade as depression and other psychiatric disorders. We review these and provide illustrative clinical examples. We further describe situations for which single photon emission computed tomography (SPECT) and positron emission tomography (PET) functional neuroimaging already meet or exceed the criteria set forth by the APA to define a neuroimaging biomarker, including the differential diagnosis of Alzheimer's disease and other dementias, the differential diagnosis of ADHD, and the evaluation of traumatic brain injury. The limitations, both real and perceived, of SPECT and PET functional neuroimaging in the field of psychiatry are also elaborated. An important overarching concept for diagnostic imaging in all its forms, including functional neuroimaging, is that imaging allows a clinician to eliminate possibilities, narrow the differential diagnosis, and tailor the treatment plan. This progression is central to any medical diagnostic process.

PET and Single-Photon Emission Computed Tomography in Brain Concussion.

This article offers an overview of the application of PET and single photon emission computed tomography brain imaging to concussion, a type of mild traumatic brain injury and traumatic brain injury, in general. The article reviews the application of these neuronuclear imaging modalities in cross-sectional and longitudinal studies. Additionally, this article frames the current literature with an overview of the basic physics and radiation exposure risks of each modality.

Multi-Watt Near-Infrared Phototherapy for the Treatment of Comorbid Depression: An Open-Label Single-Arm Study.

BACKGROUND: The treatment of depression has been hampered by low efficacy of antidepressant medications and safety concerns with alternative modalities. Recent work demonstrated that multi-Watt transcranial near-infrared light therapy (NILT) can effectively treat traumatic brain injury (TBI). The current objective is to explore multi-Watt NILT efficacy in a proof-of-concept study as a treatment for depression. METHODS: Thirty-nine sequential patients treated for TBI between March 2013 and May 2017 provided depression self-assessment data and/or were administered the Hamilton depression rating scale. Each completed the Quick Inventory of Depression Symptomatology-Self Report (QIDS) before and after treatment. Patients received multi-Watt NILT using near-infrared lasers (810/980 nm at 8-15 W) applied to forehead and temporal regions bilaterally for 9-12 min to each area. Pre- and posttreatment scores were analyzed by paired t-tests. RESULTS: All met QIDS criteria for mild to severe depression and 69% had prior antidepressant trials. For 36 of the 39 patients, after 16.82 ± 6.26 treatments, QIDS scores indicated a robust response (decrease of QIDS total score by ≥50%). For 32 of 39 patients, posttreatment QIDS scores indicated a remission from depression (decrease of QIDS total score ≤5). Overall, the QIDS score fell from 14.10 ± 3.39 to 3.41 ± 3.30 SD (p = 6.29 × 10-19). With 12 or fewer treatments, QIDS score dropped from 14.83 ± 2.55 to 4.17 ± 3.93. Patients receiving ≥13 treatments showed a change in QIDS score from 13.67 ± 3.64 to 3.11 ± 3.14. Those (N = 15) who received the entire treatment course within ≤8 weeks (5.33 ± 1.72 weeks) showed a change in QIDS score from 13.86 ± 3.14 to 4.5 ± 3.94. Suicidal ideation resolved in all, but two patients. Patients remained in remission for up to 55 months after a single course of treatment. CONCLUSION: This is the first report of high-powered NILT showing efficacy for depression. Multi-Watt NILT showed far greater efficacy and persistent benefit compared to low-power (<1 Watt) infrared light treatments. Patients saw benefit often within four treatments and resolution of depressive symptoms occurred within 4 weeks for some. These data raise an intriguing possibility-that multi-Watt NILT may be a safe, effective, and rapid treatment for depression comorbid with TBI and possibly primary major depression disorder. A double-blind, placebo controlled trial is warranted to verify these proof-of-concept data.

Practical application of the neuroregenerative properties of ketamine: real world treatment experience.

While controversial, ketamine has emerged as an effective treatment for refractory depression. Serial infusions have been performed 3 times per week, but our practical experience has challenged this precept concerning infusion frequency. Depression is associated with neuron loss, reduced synapse numbers, and dearborization of dendrites. Ketamine appears to potently induce mechanisms which reverse these neurodegenerative processes. Ketamine not only blocks the glutamate receptor, it activates eukaroyotic elongation factor 2 (eEF2). This, in turn, activates brain-derived neurotrophic factor (BDNF) protein synthesis. This is thought to underlie ketamine's enduring benefits. In addition, ketamine alters glycogen synthase kinase-3 (GSK-3) phosphorylation, probably responsible for its rapid antidepressant effect. Notably, inhibition of the BDNF receptor does not block the immediate benefits of ketamine, but does prevent the enduring effects. Neuro-Luminance Ketamine Infusion Centers have been treating patients with serial ketamine infusions for over three years. Our methods differ from what is often reported, as we perform infusions only once per week and generally do not perform more than five infusions. Data from 100 patients showed that 80% of the patients responded. The baseline Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score was 17.8 ± 2.8. Responders to ketamine showed a drop in QIDS-SR score of 10.8 ± 3.5, while non-responders showed a 0.8 ± 1.8 change. Moreover, they often had persistent benefits over several months. Recently, it was proposed that psychotomimetic effects are necessary during a ketamine infusion to yield effective antidepressant benefits. Yet, only one patient in our clinic has experienced hallucinations in three years. Nevertheless, 80% of our patients show clinical improvement. Further studies of clinical methods for ketamine infusion therapy are encouraged.

Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis.

We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: "near-infrared radiation," "NIR," "low-level light therapy," "low-level laser therapy," or "LLLT" plus "depression." We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD.

SPECT Perfusion Imaging Demonstrates Improvement of Traumatic Brain Injury With Transcranial Near-infrared Laser Phototherapy.

Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. Near-infrared (NIR) light has shown benefits in animal models and human trials for stroke and in animal models for TBI. Diodes emitting low-level NIR often have lacked therapeutic efficacy, perhaps failing to deliver sufficient radiant energy to the necessary depth. In this case report, a patient with moderate TBI documented in anatomical magnetic resonance imaging (MRI) and perfusion single-photon emission computed tomography (SPECT) received 20 NIR treatments in the course of 2 mo using a high-power NIR laser. Symptoms were monitored by clinical examination and a novel patient diary system specifically designed for this patient population. Clinical application of these levels of infrared energy for this patient with TBI yielded highly favorable outcomes with decreased depression, anxiety, headache, and insomnia, whereas cognition and quality of life improved. Neurological function appeared to improve based on changes in the SPECT by quantitative analysis. NIR in the power range of 10-15 W at 810 and 980 nm can safely and effectively treat chronic symptoms of TBI.

Near-infrared photonic energy penetration: can infrared phototherapy effectively reach the human brain?

Traumatic brain injury (TBI) is a growing health concern effecting civilians and military personnel. Research has yielded a better understanding of the pathophysiology of TBI, but effective treatments have not been forthcoming. Near-infrared light (NIR) has shown promise in animal models of both TBI and stroke. Yet, it remains unclear if sufficient photonic energy can be delivered to the human brain to yield a beneficial effect. This paper reviews the pathophysiology of TBI and elaborates the physiological effects of NIR in the context of this pathophysiology. Pertinent aspects of the physical properties of NIR, particularly in regards to its interactions with tissue, provide the background for understanding this critical issue of light penetration through tissue. Our recent tissue studies demonstrate no penetration of low level NIR energy through 2 mm of skin or 3 cm of skull and brain. However, at 10-15 W, 0.45%-2.90% of 810 nm light penetrated 3 cm of tissue. A 15 W 810 nm device (continuous or non-pulsed) NIR delivered 2.9% of the surface power density. Pulsing at 10 Hz reduced the dose of light delivered to the surface by 50%, but 2.4% of the surface energy reached the depth of 3 cm. Approximately 1.22% of the energy of 980 nm light at 10-15 W penetrated to 3 cm. These data are reviewed in the context of the literature on low-power NIR penetration, wherein less than half of 1% of the surface energy could reach a depth of 1 cm. NIR in the power range of 10-15 W at 810 and 980 nm can provide fluence within the range shown to be biologically beneficial at 3 cm depth. A companion paper reviews the clinical data on the treatment of patients with chronic TBI in the context of the current literature.

Treatments for traumatic brain injury with emphasis on transcranial near-infrared laser phototherapy.

Traumatic brain injury (TBI) is a growing health concern affecting civilians and military personnel. In this review, treatments for the chronic TBI patient are discussed, including pharmaceuticals, nutraceuticals, cognitive therapy, and hyperbaric oxygen therapy. All available literature suggests a marginal benefit with prolonged treatment courses. An emerging modality of treatment is near-infrared (NIR) light, which has benefit in animal models of stroke, spinal cord injury, optic nerve injury, and TBI, and in human trials for stroke and TBI. The extant literature is confounded by variable degrees of efficacy and a bewildering array of treatment parameters. Some data indicate that diodes emitting low-level NIR energy often have failed to demonstrate therapeutic efficacy, perhaps due to failing to deliver sufficient radiant energy to the necessary depth. As part of this review, we present a retrospective case series using high-power NIR laser phototherapy with a Class IV laser to treat TBI. We demonstrate greater clinical efficacy with higher fluence, in contrast to the bimodal model of efficacy previously proposed. In ten patients with chronic TBI (average time since injury 9.3 years) given ten treatments over the course of 2 months using a high-power NIR laser (13.2 W/0.89 cm(2) at 810 nm or 9 W/0.89 cm(2) at 810 nm and 980 nm), symptoms of headache, sleep disturbance, cognition, mood dysregulation, anxiety, and irritability improved. Symptoms were monitored by depression scales and a novel patient diary system specifically designed for this study. NIR light in the power range of 10-15 W at 810 nm and 980 nm can safely and effectively treat chronic symptoms of TBI. The clinical benefit and effects of infrared phototherapy on mitochondrial function and secondary molecular events are discussed in the context of adequate radiant energy penetration.

Functional neuroimaging with default mode network regions distinguishes PTSD from TBI in a military veteran population.

PTSD and TBI are two common conditions in veteran populations that can be difficult to distinguish clinically. The default mode network (DMN) is abnormal in a multitude of neurological and psychiatric disorders. We hypothesize that brain perfusion SPECT can be applied to diagnostically separate PTSD from TBI reliably in a veteran cohort using DMN regions. A group of 196 veterans (36 with PTSD, 115 with TBI, 45 with PTSD/TBI) were selected from a large multi-site population cohort of individuals with psychiatric disease. Inclusion criteria were peacetime or wartime veterans regardless of branch of service and included those for whom the traumatic brain injury was not service related. SPECT imaging was performed on this group both at rest and during a concentration task. These measures, as well as the baseline-concentration difference, were then inputted from DMN regions into separate binary logistic regression models controlling for age, gender, race, clinic site, co-morbid psychiatric diseases, TBI severity, whether or not the TBI was service related, and branch of armed service. Predicted probabilities were then inputted into a receiver operating characteristic analysis to compute sensitivity, specificity, and accuracy. Compared to PSTD, persons with TBI were older, male, and had higher rates of bipolar and major depressive disorder (p < 0.05). Baseline quantitative regions with SPECT separated PTSD from TBI in the veterans with 92 % sensitivity, 85 % specificity, and 94 % accuracy. With concentration scans, there was 85 % sensitivity, 83 % specificity and 89 % accuracy. Baseline-concentration (the difference metric between the two scans) scans were 85 % sensitivity, 80 % specificity, and 87 % accuracy. In separating TBI from PTSD/TBI visual readings of baseline scans had 85 % sensitivity, 81 % specificity, and 83 % accuracy. Concentration scans had 80 % sensitivity, 65 % specificity, and 79 % accuracy. Baseline-concentration scans had 82 % sensitivity, 69 % specificity, and 81 % accuracy. For separating PTSD from PTSD/TBI baseline scans had 87 % sensitivity, 83 % specificity, and 92 % accuracy. Concentration scans had 91 % sensitivity, 76 % specificity, and 88 % accuracy. Baseline-concentration scans had 84 % sensitivity, 64 % specificity, and 85 % accuracy. This study demonstrates the ability to separate PTSD and TBI from each other in a veteran population using functional neuroimaging.

Functional Neuroimaging Distinguishes Posttraumatic Stress Disorder from Traumatic Brain Injury in Focused and Large Community Datasets.

BACKGROUND: Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are highly heterogeneous and often present with overlapping symptomology, providing challenges in reliable classification and treatment. Single photon emission computed tomography (SPECT) may be advantageous in the diagnostic separation of these disorders when comorbid or clinically indistinct. METHODS: Subjects were selected from a multisite database, where rest and on-task SPECT scans were obtained on a large group of neuropsychiatric patients. Two groups were analyzed: Group 1 with TBI (n=104), PTSD (n=104) or both (n=73) closely matched for demographics and comorbidity, compared to each other and healthy controls (N=116); Group 2 with TBI (n=7,505), PTSD (n=1,077) or both (n=1,017) compared to n=11,147 without either. ROIs and visual readings (VRs) were analyzed using a binary logistic regression model with predicted probabilities inputted into a Receiver Operating Characteristic analysis to identify sensitivity, specificity, and accuracy. One-way ANOVA identified the most diagnostically significant regions of increased perfusion in PTSD compared to TBI. Analysis included a 10-fold cross validation of the protocol in the larger community sample (Group 2). RESULTS: For Group 1, baseline and on-task ROIs and VRs showed a high level of accuracy in differentiating PTSD, TBI and PTSD+TBI conditions. This carefully matched group separated with 100% sensitivity, specificity and accuracy for the ROI analysis and at 89% or above for VRs. Group 2 had lower sensitivity, specificity and accuracy, but still in a clinically relevant range. Compared to subjects with TBI, PTSD showed increases in the limbic regions, cingulum, basal ganglia, insula, thalamus, prefrontal cortex and temporal lobes. CONCLUSIONS: This study demonstrates the ability to separate PTSD and TBI from healthy controls, from each other, and detect their co-occurrence, even in highly comorbid samples, using SPECT. This modality may offer a clinical option for aiding diagnosis and treatment of these conditions.

Development of the alpha7 nicotinic cholinergic receptor in rat hippocampal formation.

The alpha7 nicotinic receptor has been implicated in the regulation of a variety of developmental processes. The goal of the present study was to assess whether the alpha7 receptor might participate in the regulation of hippocampal ontogeny by describing the spatiotemporal development of alpha7 mRNA and alpha-bungarotoxin binding in rat hippocampal formation. Message for the alpha7 receptor was initially observed in the hippocampal neuroepithelium at embryonic day 13 and in the anlage of the hippocampal formation on embryonic day 14. Binding of alpha-bungarotoxin was initially seen on embryonic day 15 in the dorsal portion of the anlage of stratum oriens and stratum radiatum-lacunosum moleculare, but was never observed in the neuroepithelium. Dramatic elevations in both alpha7 mRNA and alpha-bungarotoxin binding were observed in most regions of the hippocampal formation neonatally. The levels of both alpha7 message and protein gradually decreased during the first three postnatal weeks to adult levels in most regions. The lack of alpha-bungarotoxin binding in the neuroepithelium suggests that the alpha7 receptor does not influence neurogenesis. The early appearance and complex, prolonged pattern of development of the alpha7 receptor suggest that it may influence processes as diverse as cell migration, dendritic elaboration and apoptosis during hippocampal maturation.