Clinical and Family Implications of Cannabidiol (CBD)-Dominant Full-Spectrum Phytocannabinoid Extract in Children and Adolescents with Moderate to Severe Non-Syndromic Autism Spectrum Disorder (ASD): An Observational Study on Neurobehavioral Management.

Autism Spectrum Disorder (ASD) encompasses a wide range of neurodevelopmental conditions characterized by deficits in social interaction, communication and behavior. Current pharmacological options are limited and feature significant side effects. In this study, we conducted a retrospective, observational, and cross-sectional cohort study to evaluate the effects of Cannabidiol (CBD)-dominant, full-spectrum cannabis extract, containing Tetrahydrocannabinol (THC) in a ratio of 33:1 (CBD:THC), on non-syndromic children and adolescents (5-18 years old) with moderate to severe ASD. Thirty volunteers were recruited, underwent neuropsychological evaluations and were treated with individualized doses of CBD-dominant extract. Clinical assessments were conducted by the designated clinician. Additionally, parents or caregivers were independently interviewed to assess perceived treatment effects. We found significant improvements in various symptomatic and non-symptomatic aspects of ASD, with minimal untoward effects, as reported by both clinical assessments and parental perceptions. The observed improvements included increased communicative skills, attention, learning, eye contact, diminished aggression and irritability, and an overall increase in both the patient's and family's quality of life. Despite its limitations, our findings suggest that treatment with full-spectrum CBD-dominant extract may be a safe and effective option for core and comorbid symptoms of ASD, and it may also increase overall quality of life for individuals with ASD and their families.

Individually tailored dosage regimen of full-spectrum Cannabis extracts for autistic core and comorbid symptoms: a real-life report of multi-symptomatic benefits.

Autism Spectrum Disorders (ASD) may significantly impact the well-being of patients and their families. The therapeutic use of cannabis for ASD has gained interest due to its promising results and low side effects, but a consensus on treatment guidelines is lacking. In this study, we conducted a retrospective analysis of 20 patients with autistic symptoms who were treated with full-spectrum cannabis extracts (FCEs) in a response-based, individually-tailored dosage regimen. The daily dosage and relative proportions of cannabidiol (CBD) and tetrahydrocannabinol (THC) were adjusted based on treatment results following periodic clinical evaluation. Most patients (80%) were treated for a minimum of 6 months. We have used a novel, detailed online patient- or caregiver-reported outcome survey that inquired about core and comorbid symptoms, and quality of life. We also reviewed patients' clinical files, and no individual condition within the autistic spectrum was excluded. This real-life approach enabled us to gain a clearer appraisal of the ample scope of benefits that FCEs can provide for ASD patients and their families. Eighteen patients started with a CBD-rich FCE titrating protocol, and in three of them, the CBD-rich (CBD-dominant) FCE was gradually complemented with low doses of a THC-rich (THC-dominant) FCE based on observed effects. Two other patients have used throughout treatment a blend of two FCEs, one CBD-rich and the other THC-rich. The outcomes were mainly positive for most symptoms, and only one patient from each of the two above-mentioned situations displayed important side effects one who has used only CBD-rich FCE throughout the treatment, and another who has used a blend of CBD-Rich and THC-rich FCEs. Therefore, after FCE treatment, 18 out of 20 patients showed improvement in most core and comorbid symptoms of autism, and in quality of life for patients and their families. For them, side effects were mild and infrequent. Additionally, we show, for the first time, that allotriophagy (Pica) can be treated by FCEs. Other medications were reduced or completely discontinued in most cases. Based on our findings, we propose guidelines for individually tailored dosage regimens that may be adapted to locally available qualified FCEs and guide further clinical trials.

Bibliometric mapping of non-invasive brain stimulation techniques (NIBS) for fluent speech production.

Introduction: Language production is a finely regulated process, with many aspects which still elude comprehension. From a motor perspective, speech involves over a hundred different muscles functioning in coordination. As science and technology evolve, new approaches are used to study speech production and treat its disorders, and there is growing interest in the use of non-invasive modulation by means of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Methods: Here we analyzed data obtained from Scopus (Elsevier) using VOSViewer to provide an overview of bibliographic mapping of citation, co-occurrence of keywords, co-citation and bibliographic coupling of non-invasive brain stimulation (NIBS) use in speech research. Results: In total, 253 documents were found, being 55% from only three countries (USA, Germany and Italy), with emerging economies such as Brazil and China becoming relevant in this topic recently. Most documents were published in this last decade, with 2022 being the most productive yet, showing brain stimulation has untapped potential for the speech research field. Discussion: Keyword analysis indicates a move away from basic research on the motor control in healthy speech, toward clinical applications such as stuttering and aphasia treatment. We also observe a recent trend in cerebellar modulation for clinical treatment. Finally, we discuss how NIBS have established over the years and gained prominence as tools in speech therapy and research, and highlight potential methodological possibilities for future research.

CB1 receptor antagonism in capuchin monkeys alters social interaction and aversive memory extinction.

RATIONALE: The endocannabinoid system (eCS) is an important modulator of social anxiety and social reward, as well as memory functions. OBJECTIVES: The present study evaluated the role of eCS in social interactions and aversive memory extinction in capuchin monkeys (Sapajus spp.) by blocking the cannabinoid type 1 receptor (CB1r). METHODS: In experiment 1, spontaneous social and non-social behaviors of five capuchin males, each one living in triads with two other females, were observed after AM251 treatment (vehicle, 0.3, 1.0, and 3.0 mg/kg; i.m.). In experiment 2, seven male capuchin monkeys were trained to reach for a reward inside a wooden box. After training, they were given either vehicle or a 3.0-mg/kg i.m. dose of AM251 before a single aversive encounter with a live snake in the box. The latency to return to reach the reward inside the box in subsequent trials was measured. RESULTS: The 3.0-mg/kg dose significantly increased the time spent performing self-directed behaviors, while decreasing that of social interactions. No changes were observed in vigilance or locomotion. AM251 increased the latency to reach the reward after the aversive encounter. CONCLUSION: Taken together, these results suggest that CB1r antagonism induces social deficits without increasing anxiety levels and impairs the extinction of aversive memories. This behavioral profile in monkeys underscores the potential involvement of eCS signaling in the deficits observed in autism spectrum disorders.

Characterization of Dmrt3-Derived Neurons Suggest a Role within Locomotor Circuits.

Neuronal networks within the spinal cord, collectively known as the central pattern generator (CPG), coordinate rhythmic movements underlying locomotion. The transcription factor doublesex and mab-3-related transcription factor 3 (DMRT3) is involved in the differentiation of the dorsal interneuron 6 class of spinal cord interneurons. In horses, a non-sense mutation in the Dmrt3 gene has major effects on gaiting ability, whereas mice lacking the Dmrt3 gene display impaired locomotor activity. Although the Dmrt3 gene is necessary for normal spinal network formation and function in mice, a direct role for Dmrt3-derived neurons in locomotor-related activities has not been demonstrated. Here we present the characteristics of the Dmrt3-derived spinal cord interneurons. Using transgenic mice of both sexes, we characterized interneurons labeled by their expression of Cre driven by the endogenous Dmrt3 promoter. We used molecular, retrograde tracing and electrophysiological techniques to examine the anatomical, morphological, and electrical properties of the Dmrt3-Cre neurons. We demonstrate that inhibitory Dmrt3-Cre neurons receive extensive synaptic inputs, innervate surrounding CPG neurons, intrinsically regulate CPG neuron's electrical activity, and are rhythmically active during fictive locomotion, bursting at frequencies independent to the ventral root output. The present study provides novel insights on the character of spinal Dmrt3-derived neurons, data demonstrating that these neurons participate in locomotor coordination.SIGNIFICANCE STATEMENT In this work, we provide evidence for a role of the Dmrt3 interneurons in spinal cord locomotor circuits as well as molecular and functional insights on the cellular and microcircuit level of the Dmrt3-expressing neurons in the spinal cord. Dmrt3 neurons provide the first example of an interneuron population displaying different oscillation frequencies. This study presents novel findings on an under-reported population of spinal cord neurons, which will aid in deciphering the locomotor network and will facilitate the design and development of therapeutics for spinal cord injury and motor disorders.

Neuron-specific inactivation of Wt1 alters locomotion in mice and changes interneuron composition in the spinal cord.

Locomotion is coordinated by neuronal circuits of the spinal cord. Recently, dI6 neurons were shown to participate in the control of locomotion. A subpopulation of dI6 neurons expresses the Wilms tumor suppressor gene Wt1. However, the function of Wt1 in these cells is not understood. Here, we aimed to identify behavioral changes and cellular alterations in the spinal cord associated with Wt1 deletion. Locomotion analyses of mice with neuron-specific Wt1 deletion revealed a slower walk with a decreased stride frequency and an increased stride length. These mice showed changes in their fore-/hindlimb coordination, which were accompanied by a loss of contralateral projections in the spinal cord. Neonates with Wt1 deletion displayed an increase in uncoordinated hindlimb movements and their motor neuron output was arrhythmic with a decreased frequency. The population size of dI6, V0, and V2a neurons in the developing spinal cord of conditional Wt1 mutants was significantly altered. These results show that the development of particular dI6 neurons depends on Wt1 expression and that loss of Wt1 is associated with alterations in locomotion.

The MINDVIEW project: First results.

We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.

Ketamine alters oscillatory coupling in the hippocampus.

Recent studies show that higher order oscillatory interactions such as cross-frequency coupling are important for brain functions that are impaired in schizophrenia, including perception, attention and memory. Here we investigated the dynamics of oscillatory coupling in the hippocampus of awake rats upon NMDA receptor blockade by ketamine, a pharmacological model of schizophrenia. Ketamine (25, 50 and 75 mg/kg i.p.) increased gamma and high-frequency oscillations (HFO) in all depths of the CA1-dentate axis, while theta power changes depended on anatomical location and were independent of a transient increase of delta oscillations. Phase coherence of gamma and HFO increased across hippocampal layers. Phase-amplitude coupling between theta and fast oscillations was markedly altered in a dose-dependent manner: ketamine increased hippocampal theta-HFO coupling at all doses, while theta-gamma coupling increased at the lowest dose and was disrupted at the highest dose. Our results demonstrate that ketamine alters network interactions that underlie cognitively relevant theta-gamma coupling.

Theta phase modulates multiple layer-specific oscillations in the CA1 region.

It was recently proposed that fast gamma oscillations (60-150 Hz) convey spatial information from the medial entorhinal cortex (EC) to the CA1 region of the hippocampus. However, here we describe 2 functionally distinct oscillations within this frequency range, both coupled to the theta rhythm during active exploration and rapid eye movement sleep: an oscillation with peak activity at ∼80 Hz and a faster oscillation centered at ∼140 Hz. The 2 oscillations are differentially modulated by the phase of theta depending on the CA1 layer; theta-80 Hz coupling is strongest at stratum lacunosum-moleculare, while theta-140 Hz coupling is strongest at stratum oriens-alveus. This laminar profile suggests that the ∼80 Hz oscillation originates from EC inputs to deeper CA1 layers, while the ∼140 Hz oscillation reflects CA1 activity in superficial layers. We further show that the ∼140 Hz oscillation differs from sharp wave-associated ripple oscillations in several key characteristics. Our results demonstrate the existence of novel theta-associated high-frequency oscillations and suggest a redefinition of fast gamma oscillations.