Publications by authors named "Mary Pat McAndrews"

102 Publications

The psychological burden of waiting for procedures and patient-centred strategies that could support the mental health of wait-listed patients and caregivers during the COVID-19 pandemic: A scoping review.

Health Expect 2021 Mar 26. Epub 2021 Mar 26.

University Health Network Centre for Mental Health, University of Toronto, Toronto, Canada.

Background: Waiting for procedures delayed by COVID-19 may cause anxiety and related adverse consequences.

Objective: To synthesize research on the mental health impact of waiting and patient-centred mitigation strategies that could be applied in the COVID-19 context.

Methods: Using a scoping review approach, we searched 9 databases for studies on waiting lists and mental health and reported study characteristics, impacts and intervention attributes and outcomes.

Results: We included 51 studies that focussed on organ transplant (60.8%), surgery (21.6%) or cancer management (13.7%). Most patients and caregivers reported anxiety, depression and poor quality of life, which deteriorated with increasing wait time. The impact of waiting on mental health was greater among women and new immigrants, and those of younger age, lower socio-economic status, or with less-positive coping ability. Six studies evaluated educational strategies to develop coping skills: 2 reduced depression (2 did not), 1 reduced anxiety (2 did not) and 2 improved quality of life (2 did not). In contrast, patients desired acknowledgement of concerns, peer support, and periodic communication about wait-list position, prioritization criteria and anticipated procedure date.

Conclusions: Findings revealed patient-centred strategies to alleviate the mental health impact of waiting for procedures. Ongoing research should explore how to optimize the impact of those strategies for diverse patients and caregivers, particularly in the COVID-19 context.

Patient Or Public Contribution: Six patients and four caregivers waiting for COVID-19-delayed procedures helped to establish eligibility criteria, plan data extraction and review a draft and final report.
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http://dx.doi.org/10.1111/hex.13241DOI Listing
March 2021

Response: Predicting mood decline following temporal lobe epilepsy surgery in adults.

Epilepsia 2021 May 15;62(5):1283-1284. Epub 2021 Mar 15.

Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

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http://dx.doi.org/10.1111/epi.16874DOI Listing
May 2021

An exploratory study into the influence of laterality and location of hippocampal sclerosis on seizure prognosis and global cortical thinning.

Sci Rep 2021 Feb 25;11(1):4686. Epub 2021 Feb 25.

Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada.

In mesial temporal lobe epilepsy (mTLE), the correlation between disease duration, seizure laterality, and rostro-caudal location of hippocampal sclerosis has not been examined in the context of seizure severity and global cortical thinning. In this retrospective study, we analyzed structural 3 T MRI from 35 mTLE subjects. Regions of FLAIR hyperintensity (as an indicator of sclerosis)-based on 2D coronal FLAIR sequences-in the hippocampus were manually segmented, independently and in duplicate; degree of segmentation agreement was confirmed using the DICE index. Segmented lesions were used for separate analyses. First, the correlation of cortical thickness with disease duration and seizure focus laterality was explored using linear model regression. Then, the relationship between the rostro-caudal location of the FLAIR hyperintense signal and seizure severity, based on the Cleveland Clinic seizure freedom score (ccSFS), was explored using probabilistic voxel-wise mapping and functional connectivity analysis from normative data. The mean DICE Index was 0.71 (range 0.60-0.81). A significant correlation between duration of epilepsy and decreased mean whole brain cortical thickness was identified, regardless of seizure laterality (p < 0.05). The slope of cortical volume loss over time, however, was greater in subjects with right seizure focus. Based on probabilistic voxel-wise mapping, FLAIR hyperintensity in the posterior hippocampus was significantly associated with lower ccSFS scores (greater seizure severity). Finally, the right hippocampus was found to have greater brain-wide connectivity, compared to the left side, based on normative connectomic data. We have demonstrated a significant correlation between duration of epilepsy and right-sided seizure focus with global cortical thinning, potentially due to greater brain-wide connectivity. Sclerosis along the posterior hippocampus was associated with greater seizure severity, potentially serving as an important biomarker of seizure outcome after surgery.
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http://dx.doi.org/10.1038/s41598-021-84281-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907189PMC
February 2021

Psychological distress, resilience and mental health resources in a Canadian hospital during COVID-19: Thoughts in preparing for the next wave.

Gen Hosp Psychiatry 2021 Mar-Apr;69:124-125. Epub 2020 Dec 4.

Centre for Mental Health, University Health Network, Canada; Dept. of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Canada.

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http://dx.doi.org/10.1016/j.genhosppsych.2020.11.013DOI Listing
March 2021

Lateralizing magnetic resonance imaging findings in mesial temporal sclerosis and correlation with seizure and neurocognitive outcome after temporal lobectomy.

Epilepsy Res 2021 Mar 18;171:106562. Epub 2021 Jan 18.

Krembil Research Institute, University Health Network, Toronto, ON, Canada; Division of Neurosurgery, Toronto Western Hospital, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.

Background: Mesial temporal sclerosis (MTS) is the most common cause of temporal lobe epilepsy (TLE). While MTS is associated with a high cure rate after temporal lobectomy (TL), postoperative neurocognitive deficits are common, and a subset of patients may continue to have refractory seizures.

Objective: To use magnetic resonance (MR) volumetry to identify features of the mesial temporal lobe in patients with MTS that correlate with seizure and neurocognitive outcome after temporal lobectomy.

Methods: Thirty-five patients with unilateral MTS, high-resolution MR imaging, and at least one year of postoperative assessments were retrospectively examined. Volumetric analysis of the hippocampus, parahippocampal gyrus (PHG) and FLAIR hyperintensity of the affected temporal lobe was performed. TL resections were manually segmented, and resection heat maps reflecting seizure outcome were produced. The degree of preoperative atrophy of the affected mesial structures relative to the unaffected side were related to preoperative and postoperative component scores of verbal and visuospatial memory as well as confrontation naming.

Results: Greater FLAIR hyperintense volume was associated with favorable seizure outcome at one year and last follow-up. Resections extending most medial and posteriorly were associated with favorable seizure outcome. In patients with left MTS, less atrophy of the affected PHG was predictive of higher preoperative naming scores and greater postoperative naming deficit, while less hippocampal atrophy was predictive of higher preoperative verbal memory component scores.

Conclusion: Greater hippocampal FLAIR volume is associated with favorable surgical outcome. Hippocampal volume correlates with preoperative verbal memory, while PHG volume is implicated in confrontation naming ability.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106562DOI Listing
March 2021

Predicting mood decline following temporal lobe epilepsy surgery in adults.

Epilepsia 2021 02 19;62(2):450-459. Epub 2021 Jan 19.

Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Objective: To develop a model to predict the probability of mood decline in adults following temporal lobe resection for the treatment of pharmacoresistant epilepsy.

Methods: Variable selection was performed on 492 patients from the Cleveland Clinic using best subsets regression. After completing variable selection, a subset of variables was requested from four epilepsy surgery centers across North America (n = 100). All data were combined to develop a final model to predict postoperative mood decline (N = 592). Internal validation with bootstrap resampling was performed. A clinically significant increase in depressive symptoms was defined as a 15% increase in Beck Depression Inventory-Second Edition score and a postoperative raw score > 11.

Results: Fourteen percent of patients in the Cleveland Clinic cohort and 22% of patients in the external cohort experienced clinically significant increases in depressive symptoms following surgery. The final prediction model included six predictor variables: psychiatric history, resection side, relationship status, verbal fluency score, age at preoperative testing, and presence/absence of malformation of cortical development on magnetic resonance imaging. The model had an optimism-adjusted c-statistic of .70 and good calibration, with slight probability overestimation in higher risk patients.

Significance: Clinicians can utilize our nomogram via a paper tool or online calculator to estimate the risk of postoperative mood decline for individual patients prior to temporal lobe epilepsy surgery.
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http://dx.doi.org/10.1111/epi.16800DOI Listing
February 2021

Theta burst transcranial magnetic stimulation to induce seizures in an epilepsy monitoring unit.

Brain Stimul 2020 Nov - Dec;13(6):1800-1802. Epub 2020 Oct 22.

Division of Neurology, Department of Medicine, Ontario, Canada.

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http://dx.doi.org/10.1016/j.brs.2020.10.009DOI Listing
October 2020

Sleep Fragmentation and Cognitive Trajectories After Critical Illness.

Chest 2021 Jan 24;159(1):366-381. Epub 2020 Jul 24.

Interdepartment Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada; Department of Medicine (Critical Care Medicine), Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background: ICU survivors can experience both cognitive dysfunction and persistent sleep disturbances after hospitalization. Sleep disturbances have been linked with cognitive impairment in various patient populations, and the apolipoprotein E (APOE) genotype has been linked to sleep-related impairments in cognition.

Research Question: Is there an association between sleep, long-term cognition, and APOE status in ICU survivors?

Study Design And Methods: We enrolled 150 patients from five centers who had been mechanically ventilated for at least 3 days; 102 patients survived to ICU discharge. Actigraphy and cognitive testing were undertaken at 7 days, 6 months, and 12 months after ICU discharge, and sleep duration, quality, and timing were estimated by actigraphy. APOE single nucleotide polymorphisms were assessed for each patient.

Results: Actigraphy-estimated sleep fragmentation, but not total sleep time or interdaily stability (estimate of circadian rhythmicity), was associated with worse cognitive impairment at 7 days of ICU discharge. No actigraphy-estimated variable of sleep estimation at 7 days post-ICU discharge predicted cognitive impairment or persistent sleep abnormalities at 6 and 12 months of follow-up in subsequently assessed survivors. Possessing the APOE ε4 allele was not significantly associated with sleep disturbances and its presence did not modify the risk of sleep-related cognitive impairment at follow-up.

Interpretation: Sleep fragmentation estimated by actigraphy was associated with worse cognitive performance in hospital, but not at later time intervals. Further research is needed to better delineate the relationship between persistent sleep disturbances and cognition in larger numbers of ICU survivors.

Trial Registry: ClinicalTrials.gov; No.: NCT02086877; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2020.07.036DOI Listing
January 2021

Identification of neural networks preferentially engaged by epileptogenic mass lesions through lesion network mapping analysis.

Sci Rep 2020 07 3;10(1):10989. Epub 2020 Jul 3.

Division of Neurosurgery, University Health Network, Toronto, ON, USA.

Lesion network mapping (LNM) has been applied to true lesions (e.g., cerebrovascular lesions in stroke) to identify functionally connected brain networks. No previous studies have utilized LNM for analysis of intra-axial mass lesions. Here, we implemented LNM for identification of potentially vulnerable epileptogenic networks in mass lesions causing medically-refractory epilepsy (MRE). Intra-axial brain lesions were manually segmented in patients with MRE seen at our institution (EL_INST). These lesions were then normalized to standard space and used as seeds in a high-resolution normative resting state functional magnetic resonance imaging template. The resulting connectivity maps were first thresholded (p < 0.05) and binarized; the thresholded binarized connectivity maps were subsequently summed to produce overall group connectivity maps, which were compared with established resting-state networks to identify potential networks prone to epileptogenicity. To validate our data, this approach was also applied to an external dataset of epileptogenic lesions identified from the literature (EL_LIT). As an additional exploratory analysis, we also segmented and computed the connectivity of institutional non-epileptogenic lesions (NEL_INST), calculating voxel-wise odds ratios (VORs) to identify voxels more likely to be functionally-connected with EL_INST versus NEL_INST. To ensure connectivity results were not driven by anatomical overlap, the extent of lesion overlap between EL_INST, and EL_LIT and NEL_INST was assessed using the Dice Similarity Coefficient (DSC, lower index ~ less overlap). Twenty-eight patients from our institution were included (EL_INST: 17 patients, 17 lesions, 10 low-grade glioma, 3 cavernoma, 4 focal cortical dysplasia; NEL_INST: 11 patients, 33 lesions, all brain metastases). An additional 23 cases (25 lesions) with similar characteristics to the EL_INST data were identified from the literature (EL_LIT). Despite minimal anatomical overlap of lesions, both EL_INST and EL_LIT showed greatest functional connectivity overlap with structures in the Default Mode Network, Frontoparietal Network, Ventral Attention Network, and the Limbic Network-with percentage volume overlap of 19.5%, 19.1%, 19.1%, and 12.5%, respectively-suggesting them as networks consistently engaged by epileptogenic mass lesions. Our exploratory analysis moreover showed that the mesial frontal lobes, parahippocampal gyrus, and lateral temporal neocortex were at least twice as likely to be functionally connected with the EL_INST compared to the NEL_INST group (i.e. Peak VOR > 2.0); canonical resting-state networks preferentially engaged by EL_INSTs were the Limbic and the Frontoparietal Networks (Mean VOR > 1.5). In this proof of concept study, we demonstrate the feasibility of LNM for intra-axial mass lesions by showing that ELs have discrete functional connections and may preferentially engage in discrete resting-state networks. Thus, the underlying normative neural circuitry may, in part, explain the propensity of particular lesions toward the development of MRE. If prospectively validated, this has ramifications for patient counseling along with both approach and timing of surgery for lesions in locations prone to development of MRE.
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http://dx.doi.org/10.1038/s41598-020-67626-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335039PMC
July 2020

Use of Machine Learning for Predicting Escitalopram Treatment Outcome From Electroencephalography Recordings in Adult Patients With Depression.

JAMA Netw Open 2020 01 3;3(1):e1918377. Epub 2020 Jan 3.

School of Mechatronic Systems Engineering, Simon Fraser University, Surrey, British Columbia, Canada.

Importance: Social and economic costs of depression are exacerbated by prolonged periods spent identifying treatments that would be effective for a particular patient. Thus, a tool that reliably predicts an individual patient's response to treatment could significantly reduce the burden of depression.

Objective: To estimate how accurately an outcome of escitalopram treatment can be predicted from electroencephalographic (EEG) data on patients with depression.

Design, Setting, And Participants: This prognostic study used a support vector machine classifier to predict treatment outcome using data from the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) study. The CAN-BIND-1 study comprised 180 patients (aged 18-60 years) diagnosed with major depressive disorder who had completed 8 weeks of treatment. Of this group, 122 patients had EEG data recorded before the treatment; 115 also had EEG data recorded after the first 2 weeks of treatment.

Interventions: All participants completed 8 weeks of open-label escitalopram (10-20 mg) treatment.

Main Outcomes And Measures: The ability of EEG data to predict treatment outcome, measured as accuracy, specificity, and sensitivity of the classifier at baseline and after the first 2 weeks of treatment. The treatment outcome was defined in terms of change in symptom severity, measured by the Montgomery-Åsberg Depression Rating Scale, before and after 8 weeks of treatment. A patient was designated as a responder if the Montgomery-Åsberg Depression Rating Scale score decreased by at least 50% during the 8 weeks and as a nonresponder if the score decrease was less than 50%.

Results: Of the 122 participants who completed a baseline EEG recording (mean [SD] age, 36.3 [12.7] years; 76 [62.3%] female), the classifier was able to identify responders with an estimated accuracy of 79.2% (sensitivity, 67.3%; specificity, 91.0%) when using only the baseline EEG data. For a subset of 115 participants who had additional EEG data recorded after the first 2 weeks of treatment, use of these data increased the accuracy to 82.4% (sensitivity, 79.2%; specificity, 85.5%).

Conclusions And Relevance: These findings demonstrate the potential utility of EEG as a treatment planning tool for escitalopram therapy. Further development of the classification tools presented in this study holds the promise of expediting the search for optimal treatment for each patient.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.18377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991244PMC
January 2020

Episodic simulation and empathy in older adults and patients with unilateral medial temporal lobe excisions.

Neuropsychologia 2019 12 4;135:107243. Epub 2019 Nov 4.

Department of Psychology, University of Toronto, Canada; Rotman Research Institute at Baycrest Hospital, Canada.

Recent work shows that vividly imagining oneself helping others in situations of need (episodic simulation) increases one's willingness to help. The mechanisms underlying this effect are unclear, though it is known that the medial temporal lobe (MTL) is critical for supporting episodic simulation in general. Therefore, individuals who have compromised MTL functioning, such as older adults and those who have undergone resection of medial temporal lobe tissue as treatment for epilepsy (mTLE patients), may not show the prosocial effects of episodic simulation. Our lab previously found that older adults and mTLE patients are impaired on a problem-solving task that requires the simulation of hypothetical scenarios. Using similar logic in the present study, we predicted that older adults and mTLE patients would show reduced effects of episodic simulation on their empathic concern for, and willingness to help, people in hypothetical situations of need, compared to young adults and age-matched healthy controls, respectively. We also predicted that the subjective vividness and the amount of context-specific detail in imagined helping events would correlate with willingness to help and empathic concern. Participants read brief stories describing individuals in situations of need, and after each story either imagined themselves helping the person or performed a filler task. We analyzed the details in participants' oral descriptions of their imagined helping events and also collected subjective ratings of vividness, willingness to help, and empathic concern. Episodic simulation significantly boosted willingness to help in all groups except for mTLE patients, and it increased empathic concern in young adults and healthy controls but not in older adults or mTLE patients. While the level of context-specific detail in participants' oral descriptions of imaged events was unrelated to willingness to help and empathic concern, the effects of episodic simulation on these measures was completely mediated by subjective vividness, though to a significantly lesser degree among mTLE patients. These results increase our understanding not only of how episodic simulation works in healthy people, but also of the social and emotional consequences of compromised MTL functioning.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107243DOI Listing
December 2019

Parcellation of the Hippocampus Using Resting Functional Connectivity in Temporal Lobe Epilepsy.

Front Neurol 2019 22;10:920. Epub 2019 Aug 22.

Krembil Research Institute, University Health Network, Toronto, ON, Canada.

We have previously shown that the connectivity of the hippocampus to other regions of the default mode network (DMN) is a strong indicator of memory ability in people with temporal lobe epilepsy (TLE). Recent work in the cognitive neuroscience literature has suggested that the anterior and posterior aspects of the hippocampus have distinct connections to the rest of the DMN and may support different memory operations. Further, structural analysis of epileptogenic hippocampi has found greater atrophy, characterized by mesial temporal sclerosis, in the anterior region of the hippocampus. Here, we used resting state FMRI data to parcellate the hippocampus according to its functional connectivity to the rest of the brain in people with left lateralized TLE (LTLE) and right lateralized TLE (RTLE), and in a group of neurologically healthy controls. We found similar anterior and posterior compartments in all groups. However, there was weaker connectivity of the epileptogenic hippocampus to multiple regions of the DMN. Both TLE groups showed reduced connectivity of the posterior hippocampus to key hubs of the DMN, the posterior cingulate cortex (PCC) and the medial pre-frontal cortex (mPFC). In the LTLE group, the anterior hippocampus also showed reduced connectivity to the DMN, and this effect was influenced by the presence of mesial temporal sclerosis. When we explored brain-behavior relationships, we found that reduced connectivity of the left anterior hippocampus to the DMN hubs related to poorer verbal memory ability in people with LTLE, and reduced connectivity of the right posterior hippocampus to the PCC related to poorer visual memory ability in those with RTLE. These findings may inform models regarding functional distinctions of the hippocampal anteroposterior axis.
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http://dx.doi.org/10.3389/fneur.2019.00920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714062PMC
August 2019

Actigraphic measures of sleep on the wards after ICU discharge.

J Crit Care 2019 12 16;54:163-169. Epub 2019 Aug 16.

Department of Medicine (Neurology), Sunnybrook Health Sciences Centre and University of Toronto, Toronto, Canada. Electronic address:

Background: The purpose of this study was to use an objective measure to evaluate sleep quality on the ward after ICU discharge in survivors of critical illness.

Materials And Methods: This was a prospective cohort study of 94 patients admitted to a multidisciplinary intensive care unit (ICU) between December 2013 and June 2017. Adult patients received ≥3 days of mechanical ventilation. Sleep quality was measured using multi-night sleep actigraphy. Baseline sleep quality (i.e. sleep prior to hospitalization) was evaluated using the Pittsburgh Sleep Quality Index.

Results: A total of 65% of patients had poor sleep quality measured with the PSQI. The average (SD) sleep time and sleep efficiency was 6.03 h (3.70 h) and 44% (27%), respectively. An admission diagnosis of sepsis was associated with shorter total sleep time (TST; p = .03) and reduced sleep efficiency (SE; p = .04) as were severity of illness and duration of sedative exposure (p = .12 and 0.03; p = .09 and < 0.01; respectively for TST and SE). Weak correlations were seen between pro-inflammatory biomarkers and sleep quality.

Conclusions: This study highlights the important role that future interventions might have in patients at high-risk of sleep disorders after critical illness.
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http://dx.doi.org/10.1016/j.jcrc.2019.08.006DOI Listing
December 2019

Do distance-delivery group interventions improve depression in people with epilepsy?

Epilepsy Behav 2019 09 30;98(Pt A):153-160. Epub 2019 Jul 30.

University of Toronto, Toronto, Ontario, Canada; Hospital for Sick Children, Toronto, Ontario, Canada.

About one-third of people with epilepsy experience comorbid depression. The present study examined outcomes of a distance-delivery group intervention program designed to improve emotional well-being. Participants were 55 adults with epilepsy and self-reported depressive symptoms who were randomly assigned to take part in either a mindfulness-based cognitive behavioral therapy (CBT) program (UPLIFT, n = 20), an epilepsy information and self-management program (EpINFO, n = 24) that served as an active control group, or a wait-list control (WLC) group (n = 11). The Quick Inventory of Depressive Symptomatology (QIDS), Neurological Disorders Depression Inventory for Epilepsy (NDDIE), and the psychological health subscale of the World Health Organization Quality of Life (WHOQOL-BREF) scale were used to assess depression and psychological quality of life before and after treatment, and at short-term (six months) and long-term follow-up (one year) upon program completion. From pre- to posttreatment, a main effect of time was found, with participants in both the UPLIFT and EpINFO groups having reported to a similar degree a significant decrease in depressive symptoms and improved psychological health, improvements that were not seen in the WLC group. The time by group interaction effect was not significant. The effects seen at posttreatment in the UPLIFT and EpINFO groups remained at six months and one year after treatment. These data suggest that distance-delivery group intervention programs are effective at improving depression and psychological quality of life, with the EpINFO program offering benefits similar to the UPLIFT program.
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http://dx.doi.org/10.1016/j.yebeh.2019.06.037DOI Listing
September 2019

The medial temporal lobe in nociception: a meta-analytic and functional connectivity study.

Pain 2019 06;160(6):1245-1260

Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.

Recent neuroimaging studies implicate the medial temporal lobe (MTL) in nociception and pain modulation. Here, we aim to identify which subregions of the MTL are involved in human pain and to test its connectivity in a cohort of chronic low-back pain patients (CBP). We conducted 2 coordinate-based meta-analyses to determine which regions within the MTL showed consistent spatial patterns of functional activation (1) in response to experimental pain in healthy participants and (2) in chronic pain compared with healthy participants. We followed PRISMA guidelines and performed activation likelihood estimate (ALE) meta-analyses. The first meta-analysis revealed consistent activation in the right anterior hippocampus (right antHC), parahippocampal gyrus, and amygdala. The second meta-analysis revealed consistently less activation in patients' right antHC, compared with healthy participants. We then conducted a seed-to-voxel resting state functional connectivity of the right antHC seed with the rest of the brain in 77 CBP and 79 age-matched healthy participants. We found that CBP had significantly weaker antHC functional connectivity to the medial prefrontal cortex compared with healthy participants. Taken together, these data indicate that the antHC has abnormally lower activity in chronic pain and reduced connectivity to the medial prefrontal cortex in CBP. Future studies should investigate the specific role of the antHC in the development and management of chronic pain.
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http://dx.doi.org/10.1097/j.pain.0000000000001519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527473PMC
June 2019

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Alzheimers Res Ther 2018 07 18;10(1):65. Epub 2018 Jul 18.

Baycrest Health Sciences, 3560 Bathurst Street, Toronto, ON, M6A 2E1, Canada.

Background: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals.

Methods: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community.

Results: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent.

Conclusions: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.
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http://dx.doi.org/10.1186/s13195-018-0382-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052695PMC
July 2018

Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans.

Hippocampus 2018 10;28(10):745-764

Rotman Research Institute, Toronto, Ontario, Canada.

The dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation.
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http://dx.doi.org/10.1002/hipo.23009DOI Listing
October 2018

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

J Alzheimers Dis 2018 ;64(2):597-606

Department of Psychiatry and Behavioral Sciences, Memory and Alzheimer's Treatment Center andAlzheimer's Disease Research Center, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years.

Objective: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years.

Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial.

Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants.

Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.
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http://dx.doi.org/10.3233/JAD-180121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518401PMC
July 2019

Sleep on the ward in intensive care unit survivors: a case series of polysomnography.

Intern Med J 2018 07;48(7):795-802

Interdepartment Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Few studies have investigated sleep in patients after intensive care despite the possibility that inadequate sleep might further complicate an acute illness impeding recovery.

Aims: To assess the quality and quantity of a patient's sleep on the ward by polysomnography (PSG) within a week of intensive care unit (ICU) discharge and to explore the prevalence of key in-ICU risk factors for persistent sleep fragmentation.

Methods: We enrolled 20 patients after they have been mechanically ventilated for at least 3 days and survived to ICU discharge. We included all patients over the age of 16 years and excluded patients with advanced cognitive impairment or who were unable to follow simple commands before their acute illness, primary admission diagnosis of neurological injury, uncontrolled psychiatric illness or not fluent in English.

Results: Twenty patients underwent an overnight PSG recording on day 7 after ICU discharge (SD, 1 day). ICU survivors provided 292.8 h of PSG recording time with median recording times of 16.8 h (Interquartile range (IQR), 15.0-17.2 h). The median total sleep time per patient was 5.3 h (IQR, 2.6-6.3 h). In a multivariable regression model, postoperative admission diagnosis (P = 0.04) and patient report of poor ICU sleep (P = 0.001) were associated with less slow-wave (restorative) sleep on the wards after ICU discharge.

Conclusions: Patients reported poor sleep while in the ICU, and a postoperative admission diagnosis may identify a high-risk subgroup of patients who may derive greater benefit from interventions to improve sleep hygiene.
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http://dx.doi.org/10.1111/imj.13791DOI Listing
July 2018

The comparative effectiveness of electroencephalographic indices in predicting response to escitalopram therapy in depression: A pilot study.

J Affect Disord 2018 02 3;227:542-549. Epub 2017 Nov 3.

Department of Psychiatry, University of Toronto, Toronto, Canada; Department of Psychiatry, University Health Network, Toronto, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.

Background: This study aims to compare the effectiveness of EEG frequency band activity including interhemispheric asymmetry and prefrontal theta cordance in predicting response to escitalopram therapy at 8-weeks post-treatment, in a multi-site initiative.

Methods: Resting state 64-channel EEG data were recorded from 44 patients with a diagnosis of major depressive disorder (MDD) as part of a larger, multisite discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). Clinical response was measured at 8-weeks post-treatment as change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score of 50% or more. EEG measures were analyzed at (1) pre-treatment baseline (2) 2 weeks post-treatment and (3) as an ''early change" variable defined as change in EEG from baseline to 2 weeks post-treatment.

Results: At baseline, treatment responders showed elevated absolute alpha power in the left hemisphere while non-responders showed the opposite. Responders further exhibited a cortical asymmetry in the parietal region. Groups also differed in pre-treatment relative delta power with responders showing greater power in the right hemisphere over the left while non-responders showed the opposite. At 2 weeks post-treatment, responders exhibited greater absolute beta power in the left hemisphere relative to the right and the opposite was noted for non-responders. A reverse pattern was noted for absolute and relative delta power at 2 weeks post-treatment. Responders exhibited early reductions in relative alpha power and early increments in relative theta power. Non-responders showed a significant early increase in prefrontal theta cordance.

Conclusions: Hemispheric asymmetries in the alpha and delta bands at baseline and at 2 weeks post-treatment have moderately strong predictive utility in predicting response to antidepressant treatment.
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http://dx.doi.org/10.1016/j.jad.2017.10.028DOI Listing
February 2018

Applications of Resting-State Functional MR Imaging to Epilepsy.

Neuroimaging Clin N Am 2017 Nov;27(4):697-708

Krembil Research Institute, University Health Network, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada; Department of Psychology, University of Toronto, 100 St George Street, Toronto, ON M5S 3G3, Canada. Electronic address:

We discuss the value of resting-state functional MR imaging (rsfMR imaging) as an emerging technique to address questions about memory and language that are central in surgery for temporal-lobe epilepsy, namely the identification and characterization of eloquent cortex to avoid surgical morbidity. The emergence of a robust set of data using rsfMR imaging has opened new avenues for exploring more direct relationships between neural networks and current cognitive function and prediction of postoperative change. These techniques are also being explored for their potential to characterize epilepsy subtypes, identify epileptic foci, and monitor treatment effects.
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http://dx.doi.org/10.1016/j.nic.2017.06.002DOI Listing
November 2017

Different neural routes to autobiographical memory recall in healthy people and individuals with left medial temporal lobe epilepsy.

Neuropsychologia 2018 02 10;110:26-36. Epub 2017 Aug 10.

Krembil Research Institute, University Health Network, Toronto, ON, Canada M5T 2S8; Psychology Department, University of Toronto, Toronto, ON, Canada M5S 3G3. Electronic address:

Individuals with medial temporal lobe epilepsy (mTLE) are poor at recalling vivid details from autobiographical memories (AM), instead retrieving gist-like schematic memories. Recent research has suggested that this impoverished recall in comparison to controls may reflect (1) differential engagement of anterior vs posterior regions of the hippocampus (HC) and/or (2) differences between the engagement of the HC vs the ventromedial prefrontal cortex (vmPFC). Here we examined these hypotheses by comparing connectivity amongst hippocampal regions and between vmPFC and other brain regions during construction (retrieval of a particular event) vs elaboration (retrieval of perceptual detail) phases of AM recall in 12 individuals with left mTLE and 12 matched controls. Whereas functional connectivity amongst hippocampal regions changed from AM construction to elaboration in controls, the pattern of intra-hippocampal connectivity was unvarying in patients. Furthermore, patterns of connectivity from the vmPFC differed between phases in distinct ways in the two groups of participants. In patients, vmPFC activation was correlated with other prefrontal and lateral temporal cortices during construction and with visual-perceptual cortices during elaboration. While controls did not show a difference in whole-brain connectivity, they did uniquely show a dynamic shift from vmPFC connectivity to anterior HC during construction and to posterior HC during elaboration. Together, these findings suggest that impoverished AM recall in mTLE is a consequence of reduced activation and flexibility of bilateral hippocampal networks and greater reliance on neocortical contributions to memory retrieval.
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http://dx.doi.org/10.1016/j.neuropsychologia.2017.08.014DOI Listing
February 2018

Standardization of electroencephalography for multi-site, multi-platform and multi-investigator studies: insights from the canadian biomarker integration network in depression.

Sci Rep 2017 08 7;7(1):7473. Epub 2017 Aug 7.

Department of Psychiatry, University of Toronto, 250 College Street, 8th floor, Toronto, ON, M5T 1R8, Canada.

Subsequent to global initiatives in mapping the human brain and investigations of neurobiological markers for brain disorders, the number of multi-site studies involving the collection and sharing of large volumes of brain data, including electroencephalography (EEG), has been increasing. Among the complexities of conducting multi-site studies and increasing the shelf life of biological data beyond the original study are timely standardization and documentation of relevant study parameters. We present the insights gained and guidelines established within the EEG working group of the Canadian Biomarker Integration Network in Depression (CAN-BIND). CAN-BIND is a multi-site, multi-investigator, and multi-project network supported by the Ontario Brain Institute with access to Brain-CODE, an informatics platform that hosts a multitude of biological data across a growing list of brain pathologies. We describe our approaches and insights on documenting and standardizing parameters across the study design, data collection, monitoring, analysis, integration, knowledge-translation, and data archiving phases of CAN-BIND projects. We introduce a custom-built EEG toolbox to track data preprocessing with open-access for the scientific community. We also evaluate the impact of variation in equipment setup on the accuracy of acquired data. Collectively, this work is intended to inspire establishing comprehensive and standardized guidelines for multi-site studies.
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http://dx.doi.org/10.1038/s41598-017-07613-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547036PMC
August 2017

Epilepsy: Transition from pediatric to adult care. Recommendations of the Ontario epilepsy implementation task force.

Epilepsia 2017 09 6;58(9):1502-1517. Epub 2017 Jul 6.

Neurologist, Toronto, Ontario, Canada.

The transition from a pediatric to adult health care system is challenging for many youths with epilepsy and their families. Recently, the Ministry of Health and Long-Term Care of the Province of Ontario, Canada, created a transition working group (TWG) to develop recommendations for the transition process for patients with epilepsy in the Province of Ontario. Herein we present an executive summary of this work. The TWG was composed of a multidisciplinary group of pediatric and adult epileptologists, psychiatrists, and family doctors from academia and from the community; neurologists from the community; nurses and social workers from pediatric and adult epilepsy programs; adolescent medicine physician specialists; a team of physicians, nurses, and social workers dedicated to patients with complex care needs; a lawyer; an occupational therapist; representatives from community epilepsy agencies; patients with epilepsy; parents of patients with epilepsy and severe intellectual disability; and project managers. Three main areas were addressed: (1) Diagnosis and Management of Seizures; 2) Mental Health and Psychosocial Needs; and 3) Financial, Community, and Legal Supports. Although there are no systematic studies on the outcomes of transition programs, the impressions of the TWG are as follows. Teenagers at risk of poor transition should be identified early. The care coordination between pediatric and adult neurologists and other specialists should begin before the actual transfer. The transition period is the ideal time to rethink the diagnosis and repeat diagnostic testing where indicated (particularly genetic testing, which now can uncover more etiologies than when patients were initially evaluated many years ago). Some screening tests should be repeated after the move to the adult system. The seven steps proposed herein may facilitate transition, thereby promoting uninterrupted and adequate care for youth with epilepsy leaving the pediatric system.
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http://dx.doi.org/10.1111/epi.13832DOI Listing
September 2017

A pilot, open-label, 8-week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression.

Bipolar Disord 2017 05;19(3):198-213

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Objectives: The objectives of the study were to determine if adjunctive minocycline mitigates depressive symptom severity and improves cognitive function in individuals with bipolar I/II disorder (BD). The study also aimed to determine if changes in depressive and/or cognitive symptoms over the course of treatment were associated with changes in circulating inflammatory cytokine levels.

Methods: A total of 29 (intention-to-treat: n=27) adults meeting DSM-IV-TR criteria for a major depressive episode as part of bipolar I or II disorder (i.e. Hamilton Depression Rating Scale 17-item [HAMD-17] ≥20) were enrolled in an 8-week, open-label study with adjunctive minocycline (100 mg bid). The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS). The HAMD-17, Clinical Global Impression-Severity (CGI-S), cognitive test composite scores and plasma cytokines were secondary outcome measures. Plasma cytokines were measured with the 30 V-Plex Immunoassay from Meso Scale Discovery.

Results: Adjunctive minocycline was associated with a reduction in depressive symptom severity from baseline to week 8 on the MADRS (P<.001, d=0.835), HAMD-17 (P<.001, d=0.949) and CGI-S (P<.001, d=1.09). Improvement in psychomotor speed, but not verbal memory or executive function, was observed only amongst individuals exhibiting a reduction in depression severity (P=.007, d=0.826). Levels of interleukin (IL)-12/23p40 (P=.002) were increased, while levels of IL-12p70 (P=.001) and C-C motif chemokine ligand 26 (CCL26) (P<.001) were reduced from baseline to week 8. A reduction in CCL26 levels was associated with a less favourable treatment response (P<.001).

Conclusions: Results from the pilot study suggest that adjunctive minocycline may exert antidepressant effects in individuals with bipolar depression, possibly by targeting inflammatory cytokines.
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http://dx.doi.org/10.1111/bdi.12496DOI Listing
May 2017

Language Representation Following Left MCA Stroke in Children and Adults: An fMRI Study.

Can J Neurol Sci 2017 Sep 4;44(5):483-497. Epub 2017 May 4.

1Children's Stroke Program,University of Toronto,Toronto,Ontario,Canada.

Background: In this case series, functional magnetic resonance imaging was used to examine brain networks that mediate different aspects of language function in 4 young adults (17-22 years) with a history of left middle cerebral artery (MCA) stroke in childhood (40 years of age). Although it is widely believed that altered lateralization patterns are more likely to occur following early brain injuries compared with later brain injuries, the presumed plasticity of the young brain has been challenged in recent years, particularly in the domain of language.

Methods: We explored this issue by contrasting the brain activation patterns of individuals with childhood left MCA stroke and adult left MCA stroke while performing two language tasks: verb generation and picture-word matching. Importantly, both groups showed significant recovery of language function, based on standard clinical indicators.

Results: Controls showed left lateralized activation for both tasks, although much more pronounced for verb generation. Adult stroke patients also showed left lateralization for both tasks, though somewhat weaker than controls. Childhood stroke patients exhibited significantly weaker lateralization than the adult group for verb generation, but there was no significant group difference for picture-word matching.

Conclusions: These preliminary findings suggest that successful reorganization of language function is more likely to involve bilateral recruitment following left MCA stroke in childhood than in adulthood. Of importance, although childhood stroke patients had primarily subcortical lesions, there were substantial alterations in cortical activation patterns.
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http://dx.doi.org/10.1017/cjn.2017.44DOI Listing
September 2017

The retrieval of perceptual memory details depends on right hippocampal integrity and activation.

Cortex 2016 11 27;84:15-33. Epub 2016 Aug 27.

Krembil Neuroscience Centre, Toronto Western Hospital, UHN, Toronto, Ontario, Canada; Department of Psychology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

We assessed whether perceptual richness, a defining feature of episodic memory, depends on the engagement and integrity of the hippocampus during episodic memory retrieval. We tested participants' memory for complex laboratory events (LEs) that differed in perceptual content: short stories were either presented as perceptually rich film clips or as perceptually impoverished narratives. Participants underwent functional magnetic resonance imaging (fMRI) while retrieving these LEs (narratives and clips), as well as events from their personal life (autobiographical memories). In a group of healthy adults, a conjunction analysis showed that both real-life and laboratory memories engaged overlapping regions from an autobiographical memory (AM) retrieval network, indicating that laboratory memories mimicked autobiographical events successfully. A direct contrast between the film clip and the narrative laboratory conditions identified regions activated by the retrieval of perceptual memory content, which included the right hippocampus, parahippocampal gyrus, middle occipital gyrus and precuneus. In individuals with medial temporal lobe epilepsy (mTLE) originating from the right hippocampus, the magnitude of this "perceptually rich" signal was reduced significantly, which is consistent with evidence of reduced perceptual memory content in this clinical population. In healthy controls, right hippocampal activation also correlated positively with a behavioral measure of perceptual content in the clip condition. Thus, right hippocampal activity contributed to the retrieval of perceptual episodic memory content in the healthy brain, while right hippocampal damage disrupted activation in regions that process perceptual memory content. Our results suggest that the hippocampus contributes to recollection by retrieving and integrating perceptual details into vivid memory constructs.
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http://dx.doi.org/10.1016/j.cortex.2016.08.010DOI Listing
November 2016

Pupillary responses and memory-guided visual search reveal age-related and Alzheimer's-related memory decline.

Behav Brain Res 2017 03 9;322(Pt B):351-361. Epub 2016 Sep 9.

Department of Psychology, Department of Biology, Centre for Vision Research, Toronto, ON, M3J 1P3, Canada. Electronic address:

Episodic memory - composed of memory for unique spatiotemporal experiences - is known to decline with aging, and even more severely in Alzheimer 's disease (AD). Memory for trial-unique objects in spatial scenes depends on the integrity of the hippocampus and interconnected structures that are among the first areas affected in AD. We reasoned that memory for objects-in-scenes would be impaired with aging, and that further impairments would be observed in AD. We asked younger adults, healthy older adults, older adults at-risk for developing cognitive impairments, and older adults with probable early AD to find changing items ('targets') within images of natural scenes, measuring repeated-trial changes in search efficiency and pupil diameter. Compared to younger adults, older adults took longer to detect target objects in repeated scenes, they required more fixations and those fixations were more dispersed. Whereas individuals with AD showed some benefit of memory in this task, they had substantially longer detection times, and more numerous, dispersed fixations on repeated scenes compared to age-matched older adults. Correspondingly, pupillary responses to novel and repeated scenes were diminished with aging and further in AD, and the memory-related changes were weaker with aging and absent in AD. Our results suggest that several nonverbal measures from memory-guided visual search tasks can index aging and Alzheimer's disease status, including pupillary dynamics. The task measurements are sensitive to the integrity of brain structures that are associated with Alzheimer's-related neurodegeneration, the task is well tolerated across a range of abilities, and thus, it may prove useful in early diagnostics and longitudinal tracking of memory decline.
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http://dx.doi.org/10.1016/j.bbr.2016.09.014DOI Listing
March 2017

A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer's Disease.

J Alzheimers Dis 2016 09;54(2):777-87

Memory and Alzheimer's Treatment Center & Alzheimer's Disease Research Center, Division of Geriatric Psychiatry and Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown.

Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD).

Methods: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation.

Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism.

Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.
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http://dx.doi.org/10.3233/JAD-160017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026133PMC
September 2016