Brain SPECT as an Imaging Biomarker for Evaluating Effects of Novel Treatments in Psychiatry–A Case Series

The difficulties of evaluating patients with complex neuropsychiatric conditions and prescribing appropriate treatments are well known. Imaging complements clinical assessments and allows a clinician to narrow the differential diagnosis by facilitating accurate and efficient evaluation. This is particularly relevant to neuropsychiatric conditions that are often diagnosed using a trial-and error process of exclusion. Single Photon Emission Computed Tomography (SPECT) is a functional brain imaging procedure that allows practitioners to measure the functional changes of gray matter structures based on regional cerebral blood flow (rCBF). The accurate diagnosis and treatment selection in psychiatry is challenging due to complex cases and frequent comorbidities. However, such complex neuropsychiatric conditions are increasingly benefitting from new treatment approaches, in addition to established medications. Among these are combination transcranial magnetic stimulation with ketamine infusions (CTK), hyperbaric oxygen therapy (HBOT) and perispinal administration of etanercept (PSE). This article provides readers with six case study examples that demonstrate how brain SPECT imaging can be used, both as a diagnostic tool, and as a potential biomarker for monitoring and evaluating novel treatments for patients with complex neuropsychiatric conditions. Six patients were assessed in our clinic and baseline brain SPECT imagesTourettes and a long history of alcohol were visually compared with SPECT images collected after periods of treatment with CTK or HBOT followed by PSE. This retrospective review demonstrates the clinical utility of these novel treatments and describes how SPECT imaging can complement standard diagnostic assessments. A novel display technique for SPECT images is described and we argue that SPECT imaging can be used for monitoring biomarker for clinical change.

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.

Identification of ∆9-tetrahydrocannabinol (THC) impairment using functional brain imaging

The primary cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC), causes intoxication and impaired function, with implications for traffic, workplace, and other situational safety risks. There are currently no evidence-based methods to detect cannabis-impaired driving, and current field sobriety tests with gold-standard, drug recognition evaluations are resource-intensive and may be prone to bias. This study evaluated the capability of a simple, portable imaging method to accurately detect individuals with THC impairment. In this double-blind, randomized, cross-over study, 169 cannabis users, aged 18–55 years, underwent functional near-infrared spectroscopy (fNIRS) before and after receiving oral THC and placebo, at study visits one week apart. Impairment was defined by convergent classification by consensus clinical ratings and an algorithm based on post-dose tachycardia and self-rated “high.” Our primary outcome, PFC oxygenated hemoglobin concentration (HbO), was increased after THC only in participants operationalized as impaired, independent of THC dose. ML models using fNIRS time course features and connectivity matrices identified impairment with 76.4% accuracy, 69.8% positive predictive value (PPV), and 10% false-positive rate using convergent classification as ground truth, which exceeded Drug Recognition Evaluator-conducted expanded field sobriety examination (67.8% accuracy, 35.4% PPV, and 35.4% false-positive rate). These findings demonstrate that PFC response activation patterns and connectivity produce a neural signature of impairment, and that PFC signal, measured with fNIRS, can be used as a sole input to ML models to objectively determine impairment from THC intoxication at the individual level. Future work is warranted to determine the specificity of this classifier to acute THC impairment.ClinicalTrials.gov Identifier: NCT03655717

A Methodological Framework to Capture Neuromuscular Fatigue Mechanisms Under Stress

Neuromuscular fatigue is exacerbated under stress and is characterized by shorter endurance time, greater perceived effort, lower force steadiness, and higher electromyographic activity. However, the underlying mechanisms of fatigue under stress are not well-understood. This review investigated existing methods of identifying central mechanisms of neuromuscular fatigue and the potential mechanisms of the influence of stress on neuromuscular fatigue. We found that the influence of stress on the activity of the prefrontal cortex, which are also involved in exercise regulation, may contribute to exacerbated fatigue under stress. We also found that the traditional methods involve the synchronized use of transcranial magnetic stimulation, peripheral nerve stimulation, and electromyography to identify the contribution of supraspinal fatigue, through measures such as voluntary activation, motor evoked potential, and silent period. However, these popular techniques are unable to provide information about neural alterations upstream of the descending drive that may contribute to supraspinal fatigue development. To address this gap, we propose that functional brain imaging techniques, which provide insights on activation and information flow between brain regions, need to be combined with the traditional measures of measuring central fatigue to fully understand the mechanisms behind the influence of stress on fatigue.

Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation

Background: Chronic breathlessness in COPD is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness, helping to individualise therapy. Increasing evidence supports the role of expectation (i.e. placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulates any predictive model. Methods: Data from 72 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation was analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the dyspnoea-12 score. Findings: Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). Interpretation: Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain's expectation pathways (either pharmacological or non-pharmacological) merits further testing in the treatment of chronic breathlessness.

Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance

Lactate is an efficient neuronal energy source, even in presence of glucose. However, the importance of lactate shuttling between astrocytes and neurons for brain activation and function remains to be established. For this purpose, metabolic and hemodynamic responses to sensory stimulation have been measured by functional magnetic resonance spectroscopy and blood oxygen level-dependent (BOLD) fMRI after down-regulation of either neuronal MCT2 or astroglial MCT4 in the rat barrel cortex. Results show that the lactate rise in the barrel cortex upon whisker stimulation is abolished when either transporter is down-regulated. Under the same paradigm, the BOLD response is prevented in all MCT2 down-regulated rats, while about half of the MCT4 down-regulated rats exhibited a loss of the BOLD response. Interestingly, MCT4 down-regulated animals showing no BOLD response were rescued by peripheral lactate infusion, while this treatment had no effect on MCT2 down-regulated rats. When animals were tested in a novel object recognition task, MCT2 down-regulated animals were impaired in the textured but not in the visual version of the task. For MCT4 down-regulated animals, while all animal succeeded in the visual task, half of them exhibited a deficit in the textured task, a similar segregation into two groups as observed for BOLD experiments. Our data demonstrate that lactate shuttling between astrocytes and neurons is essential to give rise to both neurometabolic and neurovascular couplings, which form the basis for the detection of brain activation by functional brain imaging techniques. Moreover, our results establish that this metabolic cooperation is required to sustain behavioral performance based on cortical activation.

The Role of Chronic Physical Activity in Alleviating the Detrimental Relationship of Childhood Obesity on Brain and Cognition

Childhood obesity and its negative relation with children’s brain health has become a growing health concern. Over the last decade, literature has indicated that physical activity attenuates cognitive impairment associated with obesity and excess adiposity in children. However, there is no comprehensive review that considers the extent to which these factors affect different domains of cognition. This narrative review comprehensively summarizes behavioral, neuroimaging, and neuroelectric findings associated with chronic physical activity and fitness on brain and cognition in childhood obesity. Based on the literature reviewed, increased adiposity has a demonstrated relationship with neurocognitive health via mechanisms triggered by central inflammation and insulin resistance, with the most pronounced decrements observed for cognitive domains that are prefrontal- and hippocampal-dependent. Fortunately, physical activity, especially interventions enhancing aerobic fitness and motor coordination, have demonstrated efficacy for attenuating the negative effects of obesity across different subdomains of structural and functional brain imaging, cognition, and multiple academic outcomes in children with overweight or obesity. Such mitigating effects may be accounted for by attenuated central inflammation, improved insulin sensitivity, and increased expression of neurotrophic factors. Lastly, individual differences appear to play a role in this relationship, as the manipulation of physical activity characteristics, the employment of a wide array of cognitive and academic measures, the inclusion of different adiposity measures that are sensitive to neurocognitive function, and the utilization of an inter-disciplinary approach have been found to influence the relationship between physical activity and excess adiposity on brain and cognition.

Scalp attached tangential magnetoencephalography using tunnel magneto-resistive sensors

Non-invasive human brain functional imaging with millisecond resolution can be achieved only with magnetoencephalography (MEG) and electroencephalography (EEG). MEG has better spatial resolution than EEG because signal distortion due to inhomogeneous head conductivity is negligible in MEG but serious in EEG. However, this advantage has been practically limited by the necessary setback distances between the sensors and scalp, because the Dewar vessel containing liquid helium for superconducting sensors requires a thick vacuum wall. Latest developments of high critical temperature (high-Tc) superconducting or optically pumped magnetometers have not allowed scalp-attached MEG due to cold or hot temperatures at the sensing point, respectively. Here we applied tunnel magneto-resistive (TMR) sensors that operate at room temperature. Improvement of TMR sensitivity with magnetic flux concentrators enabled scalp-attached and scalp-tangential MEG to target the largest signal component produced by the neural current below. In a healthy subject, our single-channel TMR-MEG system clearly demonstrated the N20m, the initial cortical component of the somatosensory evoked response after median nerve stimulation. Multisite measurement confirmed a spatially and temporally steep peak of N20m, immediately above the source at a latency around 20 ms, indicating a new approach to non-invasive functional brain imaging with millimeter and millisecond resolutions.

Characterization of red fluorescent reporters for dual-color in vivo three-photon microscopy

Three-photon (3P) microscopy significantly increases the depth and resolution of in vivo imaging due to decreased scattering and nonlinear optical sectioning. Past studies used separate 1300 and 1700 nm excitation sources to excite green and red fluorescent proteins. Recently work shows that a single 1300 nm excitation source allows for dual color 3P imaging with increased signal-to-background and decreased average power. Future use of single excitation 3P microscopes would reduce the need for additional custom optical elements and decrease cost. However, there is a lack of experimental data characterizing the excitation properties of specific fluorophore combinations in the near-infrared range. Here, we assess the dual-color imaging potential of tdTomato or mScarlet in combination with EGFP when excited by a single excitation source tuned from 1225-1360 nm in the living mouse brain. We find that tdTomato and mScarlet, expressed in oligodendrocytes and neurons respectively, have exceptional signal-to-background in the 1300-1360 nm range in deep cortex, consistent with enhanced 3P cross sections. These results suggest that a single excitation source is advantageous for multiple applications of dual-color structural and functional brain imaging highlighting the importance of empirical characterization of individual fluorophores in the near-infrared region.