Objective:
No universal definition for treatment-resistant depression (TRD) exists. This lack of consensus reduces the generalizability of study findings and limits the ability to study TRD. In ...addition, anecdotally, there may be a difference between the definitions of TRD within research and those applied in practice. Thus, the objective of this work was to identify current common definitions of TRD used in both research and clinical practice.
Method:
A systematic review of published literature was conducted to document TRD definitions. Extracted data were grouped based on patient cohort and method of defining TRD. Validation studies were narratively summarized. Interviews with 6 key informants were conducted to understand how definitions are applied in practice.
Results:
In total, 155 definitions for TRD were identified in the published literature, and 48.4% of all definitions specified requirement of at least 2 treatment failures. Key informant interviews indicated the concept of TRD is rarely employed in clinical practice. Instead, concepts like “complex needs,” “struggling with their disease,” and “chronic” are used. When asked directly about how they would define TRD, interview participants said an adequate trial of psychotherapy as well as an adequate trial of at least 2 to 3 antidepressant medications.
Conclusions:
There is no universally accepted definition of TRD, and substantial heterogeneity exists. This study indicates discordance between the use of the term in research and clinical practice, with several key informants emphasizing that the terminology is rarely used in their clinical experience. Development of a shared, common definition across practice and research is required.
Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain excitability and has therapeutic potential for many conditions. Several studies ...have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity, but there is little information about the underlying mechanisms. Using magnetic resonance spectroscopy (MRS), it has been shown that tDCS can affect local levels of γ-aminobutyric acid (GABA) and Glx (a measure of glutamate and glutamine combined) in adults, both of which are known to be associated with skill acquisition and plasticity; however this has yet to be studied in children and adolescents. This study examined GABA and Glx in response to conventional anodal tDCS (a-tDCS) and high definition tDCS (HD-tDCS) targeting the M1 in a pediatric population. Twenty-four typically developing, right-handed children ages 12-18 years participated in five consecutive days of tDCS intervention (sham, a-tDCS or HD-tDCS) targeting the right M1 while training in a fine motor task (Purdue Pegboard Task) with their left hand. Glx and GABA were measured before and after the protocol (at day 5 and 6 weeks) using a PRESS and GABA-edited MEGA-PRESS MRS sequence in the sensorimotor cortices. Glx measured in the left sensorimotor cortex was higher in the HD-tDCS group compared to a-tDCS and sham at 6 weeks (p = 0.001). No changes in GABA were observed in either sensorimotor cortex at any time. These results suggest that neither a-tDCS or HD-tDCS locally affect GABA and Glx in the developing brain and therefore it may demonstrate different responses in adults.
Objective To characterize white matter alterations in children with isolated or concurrent developmental coordination disorder and/or attention-deficit/hyperactivity disorder (ADHD) compared with ...typically-developing controls, and to determine whether group differences on motor and attention tasks could be explained by differences in diffusion tensor imaging (DTI) measures. Study design In a cohort of children (n = 85) with developmental coordination disorder, ADHD, or combined developmental coordination disorder+ADHD, we examined 3 major white matter tracts involved in attention and motor processes. Using DTI, the corpus callosum, superior longitudinal fasciculus, and cingulum were analyzed with respect to measures of white matter integrity. Differences in fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity were analyzed using ANOVA. Motor and attentional functioning was assessed using standardized tests, and correlated to DTI measures. Results FA reductions were noted in the frontal regions of the corpus callosum for children with ADHD ( P = .039), whereas children with developmental coordination disorder displayed similar reductions in regions of the corpus callosum underlying parietal brain regions ( P = .040), as well as the left superior longitudinal fasciculus ( P = .026). White matter integrity was impacted in both frontal and parietal regions for children with comorbid developmental coordination disorder+ADHD ( P = .029; .046). FA was positively correlated with scores on both motor and attentional assessments in a region-specific manner. Conclusion Our findings suggest that alterations in the corpus callosum underlie difficulties in motor and attention functioning. These changes are functionally and regionally distinct and could reflect a neurobiological basis for motor and attention disorders in children.
Legalization of recreational cannabis in Ontario included the legalization of flower and herbs (Phase 1, October 2018), and was followed by the deregulation of cannabis retailers and sales of edibles ...(Phase 2, February 2020). Research on the impact of cannabis legalization on acute care utilization is nascet; no research has investigated potential age, gender, and geographically vulnerable subgroup effects. Residents living in Northern Ontario not only have higher levels of substance use problems, but also have inadequate access to primary healthcare. Our study investigated the impact of Ontario’s recreational cannabis policy (including Phase 1 and 2) on cannabis-attributable emergency department (ED) visits, and estimated the impact separately for different age and gender groups, with additional analyses focused on Northern Ontarians. We created a cohort of adults (18 and over) eligible for provincial universal health insurance with continuous coverage from 2015–2021 (n = 14,900,820). An interrupted time series was used to examine the immediate impact and month-to-month changes in cannabis-related ED visits associated with Phase 1 & 2 for each subgroup. While Northern Ontario has higher rates of cannabis-related ED visits, both Northern and Southern Ontario show similar patterns of changes. Phase 1 was associated with significant increases in adults 25–64, with the strongest increases seen in women 45–64. Month-to-month trends were flattened in most groups compared to pre-legalization. Phase 2 was associated with significant immediate increases for adults aged 18–44 in both genders, but the increases were larger in women than men. No significant month-to-month changes were detected in this period. While current preventive efforts are largely focused on reducing cannabis-related harms in youths and younger adults, our results show that adults 25–64, particularly women, have been significantly impacted by cannabis policies. Further research on gender-specific cannabis dosage and targeted interventions for adult women should be investigated. Legalization did not appear to have a differential impact on Northern versus Southern Ontario, but higher rates of ED visits in the North should be addressed.
Aim
Many neurodevelopmental disorders co‐occur yet are rarely studied in terms of brain development. Developmental coordination disorder (DCD) and attention‐deficit–hyperactivity disorder (ADHD) ...co‐occur at a high frequency and are associated with functional and structural brain alterations. The objective of this study was to examine whether the effects of comorbid motor and attention problems influence cortical thickness in children and whether the pattern of changes for concurrent disorders is distinct from the alterations seen in single disorders.
Method
A total of 34 children (19 males, 15 females, mean age 9y 9mo, range 8–17y) who met the criteria for DCD (n=14), ADHD (n=10), or DCD+ADHD (n=10) were recruited into the study. Fourteen participants with typical development (eight males, six females, mean age 11y 9mo, range 8–17y) were also recruited for comparison. Participants underwent neuropsychological assessment and magnetic resonance imaging. Cortical thickness analysis was performed to determine the patterns of cortical thinning in each disorder, which was then compared across groups.
Results
Children with comorbid DCD+ADHD demonstrated more widespread decreases in cortical thickness than participants with a diagnosis of DCD or ADHD alone. Cortical thinning was found to be concentrated in the frontal, parietal, and temporal lobes, and was correlated with measures of motor and attentional functioning.
Interpretation
The co‐occurrence of DCD+ADHD was associated with a distinct global pattern of regional cortical thickness decrease, highlighting the unique neurobiology of comorbid neurodevelopmental disorders. This novel feature of concurrent DCD and ADHD may help inform diagnostic definitions and provide clues to both the shared and the isolated genetic and environmental origins of motor and attention disorders.
What this paper adds
We examined children with single and comorbid motor and attention issues for cortical thickness differences.
In participants with ADHD alone, thickness reductions were found in the left superior temporal gyrus and parahippocampal gyrus.
In participants with DCD alone, cortical thickness reductions were found in the medial orbitofrontal cortex.
In comorbid DCD+ADHD, global cortical thinning deficits were found in the frontotemporal, parietal, and occipital regions
Concurrent DCD+ADHD correlated with poorer motor and attentional performance.
This article is commented on by Brossard‐Racine on pages 211–212 of this issue.
Objectives
Agitation and aggression are common in dementia and pre‐dementia. The dementia risk syndrome mild behavioral impairment (MBI) includes these symptoms in the impulse dyscontrol domain. ...However, the neural circuitry associated with impulse dyscontrol in neurodegenerative disease is not well understood. The objective of this work was to investigate if regional micro‐ and macro‐structural brain properties were associated with impulse dyscontrol symptoms in older adults with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD).
Methods
Clinical, neuropsychiatric, and T1‐weighted and diffusion‐tensor magnetic resonance imaging (DTI) data from 80 individuals with and 123 individuals without impulse dyscontrol were obtained from the AD Neuroimaging Initiative. Linear mixed effect models were used to assess if impulse dyscontrol was related to regional DTI and volumetric parameters.
Results
Impulse dyscontrol was present in 17% of participants with NC, 43% with MCI, and 66% with AD. Impulse dyscontrol was associated with: (1) lower fractional anisotropy (FA), and greater mean, axial, and radial diffusivity in the fornix; (2) lesser FA and greater radial diffusivity in the superior fronto‐occipital fasciculus; (3) greater axial diffusivity in the cingulum; (4) greater axial and radial diffusivity in the uncinate fasciculus; (5) gray matter atrophy, specifically, lower cortical thickness in the parahippocampal gyrus.
Conclusion
Our findings provide evidence that well‐established atrophy patterns of AD are prominent in the presence of impulse dyscontrol, even when disease status is controlled for, and possibly in advance of dementia. Our findings support the growing evidence for impulse dyscontrol symptoms as an early manifestation of AD.
Key points
Impulse dyscontrol is a frequently endorsed domain of mild behavioral impairment (MBI), which is an at‐risk state for incident cognitive decline and dementia
Impulse dyscontrol is common in this sample of dementia and pre‐dementia participants at a frequency of 17% in normal cognition, 43% in mild cognitive impairment, and 66% in Alzheimer's disease
Impulse dyscontrol is associated with loss of white matter integrity in the cingulum, fornix, superior fronto‐occipital fasciculus, and uncinate fasciculus, as well as parahippocampal gyrus atrophy
This MBI domain may serve as a potential treatment target, even in advance of dementia
Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy ...of ML models but have barely been used for this purpose.
To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI.
Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer's Disease Neuroimaging Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis.
In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve ROC-AUC = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73).
Baseline NPS, categorized for MBI domain and duration, have prognostic utility in addition to brain morphology measures for predicting diagnosis change using ML. MBI total score, followed by impulse dyscontrol and affective dysregulation were most predictive of future diagnosis.
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with cognitive, motor, and emotional symptoms. The thalamus and basal ganglia form circuits with the cortex supporting all three ...of these behavioral domains. Abnormalities in the structure of subcortical regions may suggest atypical development of these networks, with implications for understanding the neural basis of ASD symptoms. Findings from previous volumetric studies have been inconsistent. Here, using advanced surface-based methodology, we investigated localized differences in shape and surface area in the basal ganglia and thalamus in ASD, using T1-weighted anatomical images from the Autism Brain Imaging Data Exchange (373 male participants aged 7-35 years with ASD and 384 typically developing). We modeled effects of diagnosis, age, and their interaction on volume, shape, and surface area. In participants with ASD, we found expanded surface area in the right posterior thalamus corresponding to the pulvinar nucleus, and a more concave shape in the left mediodorsal nucleus. The shape of both caudal putamen and pallidum showed a relatively steeper increase in concavity with age in ASD. Within ASD participants, restricted, repetitive behaviors were positively associated with surface area in bilateral globus pallidus. We found no differences in overall volume, suggesting that surface-based approaches have greater sensitivity to detect localized differences in subcortical structure. This work adds to a growing body of literature implicating corticobasal ganglia-thalamic circuits in the pathophysiology of ASD. These circuits subserve a range of cognitive, emotional, and motor functions, and may have a broad role in the complex symptom profile in ASD.
Neuromodulatory interventions are relatively novel and approaches to studying harms and tolerability have varied. Using a checklist based on guidelines from Good Clinical Practice and the Harms ...Extension of the CONSORT (Consolidated Standards of Reporting Trials) Statement, we identified how adverse events are measured, assessed, and reported in studies evaluating neuromodulation for the treatment of mental and neurodevelopmental disorders among children and adolescents. A systematic literature review identified 56 experimental and quasi-experimental studies evaluating transcranial magnetic stimulation (TMS), transcranial alternating (tACS) or direct (tDCS) current stimulation, transcranial pulse stimulation (TPS), and vagus or trigeminal nerve stimulation (VNS or TNS). For 22 studies (39%), the types of adverse events to be monitored were identified, and for 31 studies (55%), methods for collecting adverse event data were described. Methods for assessing adverse events were less commonly described with 23 studies (41%) having details on assessing event severity, and 11 studies (20%) having details on assessing event causality. Among 31 studies with reported results, headache, skin irritation, and general pain or discomfort were the most reported across studies. Seizure, untoward medical occurrences, and intracranial bleeding, edema, or other intracranial pathology were considered serious events, but these events were not reported as occurring in any results-based papers. Taken together, the findings from this review indicate that most studies of pediatric neuromodulatory interventions did not include descriptions of adverse event monitoring and evaluation. Comprehensive event monitoring and reporting across studies can significantly augment the current knowledge base.
Adolescent depression is a substantial global public health problem that contributes to academic failure, occupational impairment, deficits in social functioning, substance use disorders, teen ...pregnancy, and completed suicide. Existing treatment options often have suboptimal results and uncertain safety profiles. Transcranial magnetic stimulation may be a promising, brain-based intervention for adolescents with depression. Existing work has methodological weaknesses, and larger, neurodevelopmentally informed studies are urgently needed. Treatment with transcranial magnetic stimulation may modulate cortical GABAergic and glutamatergic imbalances. Future study will inform dosing approaches for TMS based on GABAergic and glutamatergic biomarkers.
PDF
