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Near infrared (NIR) light has been shown to provide beneficial treatment of traumatic brain injury (TBI) and other neurological problems. This concept has spawned a plethora of commercial entities and practitioners utilizing panels of light emitting diodes (LEDs) and promising to treat patients with TBI and other disorders, who are desperate for some treatment for their untreatable conditions. Unfortunately, an LED intended to deliver photonic energy to the human brain does not necessarily do what an LED pointed at a mouse brain does. There is a problem of scale. Extensive prior research has shown that infrared light from a 0.5-watt LED will not penetrate the scalp and skull of a human. Both the properties of NIR light and the manner in which it interacts with tissue are examined. Based on these principles, the shortcomings of current approaches to treating neurological disorders with NIR light are explored. Claims of clinical benefit from low-level LED-based devices are explored and the proof of concept challenged. To date, that proof is thin with marginal benefits which are largely transient. Extensive research has shown fluence at the level of the target tissue which falls within the range of 0.9 J/cm2 to 15 J/cm2 is most effective in activating the biological processes at the cellular level which underlie direct photobiomodulation. If low-level infrared light from LED devices is not penetrating the scalp and skull, then these devices certainly are not delivering that level of fluence to the neurons of the subjacent brain. Alternative mechanisms, such as remote photobiomodulation, which may underlie the small and transient benefits for TBI symptoms reported for low-power LED-based NIR studies are presented. Actionable recommendations for the field are offered.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.