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Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh-null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation.

The roof plate is a specialized embryonic midline tissue of the central nervous system that functions as a signaling center regulating dorsal neural patterning. In the developing hindbrain, roof plate cells express Gdf7 and previous genetic fate mapping studies showed that these cells contribute mostly to non-neural choroid plexus epithelium. We demonstrate here that constitutive activation of the Sonic hedgehog signaling pathway in the Gdf7 lineage invariably leads to medulloblastoma. Lineage tracing analysis reveals that Gdf7-lineage cells not only are a source of choroid plexus epithelial cells, but are also present in the cerebellar rhombic lip and contribute to a subset of cerebellar granule neuron precursors, the presumed cell-of-origin for Sonic hedgehog-driven medulloblastoma. We further show that Gdf7-lineage cells also contribute to multiple neuronal and glial cell types in the cerebellum, including glutamatergic granule neurons, unipolar brush cells, Purkinje neurons, GABAergic interneurons, Bergmann glial cells, and white matter astrocytes. These findings establish hindbrain roof plate as a novel source of diverse neural cell types in the cerebellum that is also susceptible to oncogenic transformation by deregulated Sonic hedgehog signaling.

Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.

Sonic hedgehog (Shh) signaling regulates cell growth during embryonic development, tissue homeostasis and tumorigenesis. Concentration-dependent cellular responses to secreted Shh protein are essential for tissue patterning. Shh ligand is covalently modified by two lipid moieties, cholesterol and palmitate, and their hydrophobic properties are known to govern the cellular release and formation of soluble multimeric Shh complexes. However, the influences of the lipid moieties on cellular reception and signal response are not well understood.We analyzed fully lipidated Shh and mutant forms to eliminate one or both adducts in NIH3T3 mouse embryonic fibroblasts. Quantitative measurements of recombinant Shh protein concentration, cellular localization, and signaling potency were integrated to determine the contributions of each lipid adduct on ligand cellular localization and signaling potency. We demonstrate that lipid modification is required for cell reception, that either adduct is sufficient to confer cellular association, that the cholesterol adduct anchors ligand to the plasma membrane and that the palmitate adduct augments ligand internalization. We further show that signaling potency correlates directly with cellular concentration of Shh ligand.The findings of this study demonstrate that lipid modification of Shh determines cell concentration and potency, revealing complementary functions of hydrophobic modification in morphogen signaling by attenuating cellular release and augmenting reception of Shh protein in target tissues.

There is a clear need for experts with the requisite knowledge and experience to offer medicolegal opinions pertaining to various neuropsychiatric conditions. There is also an important distinction between clinical and medicolegal roles, and the need for training and expertise applicable to forensic assessment. But there remain few available experts with credentials spanning neuropsychiatry and forensic assessment. This creates a dilemma whereby parties involved in litigation featuring neuropsychiatric illness or injury are frequently forced to choose between experts with either knowledge and skills applicable to neuropsychiatric conditions or experts with skills and experience applicable to forensic assessment. Either choice introduces risk. Whether flawed medicolegal opinions are a consequence of deficient medical knowledge or an inadequate forensic evaluation process, the result remains the same, with triers of fact potentially being exposed to problematic testimony. There is, however, a more fundamental problem that implicates patient care more broadly: spurious dichotomies created by the historical segregation of psychiatry and neurology. Optimizing clinical care for patients with neuropsychiatric conditions, improving medical education in support of such care, and enabling forensic neuropsychiatric assessment must then start with more proactive efforts to reintegrate psychiatry and neurology., (© 2024 American Academy of Psychiatry and the Law.)

The clinical and scientific challenges inherent in treating and investigating suicide warrant novel approaches to this public health issue of paramount importance. The implementation of suicide-specific diagnoses has been proposed as one possible way to address this problem and was described in the first column of this special 2-part series. This second column explores potential unintended consequences related to such proposed diagnoses and alternative solutions that might afford greater benefits. The idea of suicide-specific diagnoses represents a novel approach, and one worthy of further discussion and consideration; the debate featured in this series represents a joint effort to advance the dialogue about suicide and to promote innovation.

Both public awareness of suicide and professional efforts directed at suicide prevention have increased considerably in recent years. Unfortunately, rates of death by suicide have remained relatively stable over the past decade despite these enhanced efforts. Some have argued that "suicide risk assessment doesn't work" and have called into question the utility of devoting clinical time and energy to risk assessment. In this column, the authors first present an overview of the argument against suicide risk assessment and the data supporting that argument, followed by an alternate argument as to why suicide risk assessment still matters. When properly performed in concert with patient-centered mental health care, suicide risk assessment and management may add to the therapeutic and recovery-oriented benefits of care, independent of the ability to predict death by suicide.

The American Academy of Psychiatry and the Law (AAPL) recently published guidelines for forensic assessment intended for psychiatrists and other clinicians working in medicolegal roles, or performing evaluations and offering opinions in relation to legal or regulatory matters. Although these guidelines do not establish a singular standard for forensic evaluation, they are intended to inform practice. Although nuances pertaining to any given case and the pertinent medicolegal issues involved will require professional judgment as to how best to conduct any particular evaluation, the guidelines do offer many helpful tenets and guiding principles that are broadly applicable. Psychiatrists and other clinicians performing forensic evaluations need to be aware of these guidelines and should strive to incorporate them as appropriate. In this column we offer a brief synopsis of the approach to the forensic psychiatric assessment based upon the AAPL Practice Guideline for the Forensic Assessment.

Traumatic brain injury (TBI) involves a wide range of potential neuropsychiatric outcomes, from death or profound impairment to full and fast recovery. This circumstance has contributed to an atmosphere with considerable potential for both clinical confusion and unjustified medicolegal outcomes. Given that mild (m)TBI accounts for most (∼80%) TBI events and is generally associated with an excellent prognosis, the risk for erroneous clinical formulations and unmerited legal outcomes seems particularly high in cases involving mTBI. In this article, we summarize the recent results published by the International Collaboration on Mild Traumatic Brain Injury Prognosis (ICMTBIP) and the new approach of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, to TBI, and we explore the clinical and medicolegal implications. Symptoms that emerge after mTBI remain nonspecific, and potential etiologies are diverse. Clinicians and medicolegal experts should be familiar with the natural history of mTBI, able to recognize atypical outcomes, and willing to search for alternative explanations when confronted with persistent or severe impairment., (© 2015 American Academy of Psychiatry and the Law.)

Mental health professionals who provide medicolegal services need to be aware of the very important differences between clinical and retained expert/forensic roles. This column offers a distinction between clinical and forensic roles in terms of responsibilities, objectives, and guiding ethical principles. Existing professional guidelines and other views from the medical literature that discourage the mixing of such roles are reviewed. The conflation of clinical and forensic roles and the attendant risks are considered, in terms of both competing interests and the possible ethical threat associated with assuming a dual role. Knowingly or unwittingly assuming a dual role is potentially harmful to the therapeutic alliance, threatens the expert's objectivity, and may jeopardize a patient's legal case. Guidance is offered as to how to avoid conflating clinical and forensic roles when compelled to provide medicolegal services.

Collateral information facilitates comprehensive mental health care and is consistent with recovery-oriented models of care. But providers are often faced with complex decisions about obtaining collateral information, particularly when patients do not consent to communication with third parties for information gathering. Such situations require a thoughtful balance of best clinical practices, legal and ethical responsibilities, and patient safety concerns. This column offers an overview of the clinical utility of collateral information as well as the ethical and legal regulations concerning confidentiality that guide the process of obtaining collateral information. The risk-benefit analysis process related to obtaining collateral information without patient permission is illustrated. Recommendations about clinical consultation and documentation that facilitate optimal and ethical patient care are offered.

This column is the fourth in a series describing a model for therapeutic risk management of the suicidal patient. Previous columns presented an overview of the therapeutic risk management model, provided recommendations for how to augment risk assessment using structured assessments, and discussed the importance of risk stratification in terms of both severity and temporality. This final column in the series discusses the safety planning intervention as a critical component of therapeutic risk management of suicide risk. We first present concerns related to the relatively common practice of using no-suicide contracts to manage risk. We then present the safety planning intervention as an alternative approach and provide recommendations for how to use this innovative strategy to therapeutically mitigate risk in the suicidal patient.

This column is the third in a series describing a model for therapeutic risk management of the suicidal patient. In the preceding column, we described augmenting clinical suicide risk assessment with structured instruments. In this column, we describe how clinicians can use the totality of available clinical data to offer a two-dimensional risk stratification that qualifies risk in terms of both severity and temporality. By offering two separate designations that reflect severity for both acute and chronic risk, conceptualizing and communicating a patient's risk for suicide is accomplished in a more nuanced way, providing the level of detail necessary when working with high risk individuals, especially those struggling with chronic suicidal ideation. Formulations reflecting suicide risk need to be accurate and facilitate good clinical decision-making in order to optimally balance the principles of autonomy, non-maleficence, and beneficence. Stratifying risk in terms of both severity and temporality helps identify situations in which involuntary hospitalization is warranted, while also helping to minimize unnecessary admissions. Hence, two-dimensional risk stratification that addresses both acute and chronic risk for suicide is an essential component of therapeutic risk management of the suicidal patient.

While the practice of psychiatry involves many challenges, few scenarios are as clinically and emotionally demanding as managing the patient who is at high risk for suicide. Risk management is a reality of psychiatric practice, and this necessitates practicing and documenting thoughtful suicide risk assessment and management. Therapeutic risk management is based on clinical risk management that is patient-centered, supportive of the treatment process, and maintains the therapeutic alliance. In this article, the authors present a broad overview of a model for achieving therapeutic risk management of the suicidal patient that involves augmenting clinical risk assessment with structured instruments, stratifying risk in terms of both severity and temporality, and developing and documenting a safety plan. These elements are readily accessible to and deployable by mental health clinicians in most disciplines and treatment settings, and they collectively yield a suicide risk assessment and management process (and attendant documentation) that should withstand the scrutiny that often occurs in the wake of a patient suicide or suicide attempt.