Tarique Perera - Academia.edu (original) (raw)

Papers by Tarique Perera

The primary care companion for CNS disorders, Feb 2, 2017

Biological Psychiatry, Apr 1, 2008

Neuroscience Letters, Oct 1, 2019

Introduction: Pattern separation aids cognitive flexibility by reducing interference between clos... more Introduction: Pattern separation aids cognitive flexibility by reducing interference between closely related memories. Dentate gyrus (DG) neurogenesis may facilitate pattern separation by blocking memory retrieval via inhibition of non-neurogenic downstream CA3 neurons. We hypothesized that immature adult-born DG neurons would be associated with decreased CA3 activation and increased cognitive flexibility. Method: Two groups of adult male rats were tested either on the place avoidance task (PAT) (unflipped condition) or a subtly altered-PAT (flipped condition). Four weeks prior, the rats were injected with the mitotic marker BrdU. Immature new neurons were detected by the microtubule protein doublecortin (DCX). Cells that took up BrdU and expressed NeuN were identified as relatively more mature neurons. Synaptic activation was determined by c-Fos expression. Adaptation to the flipped versus unflipped condition reflected a measure of cognitive flexibility. Results: CA3 but not DG c-Fos was lower in the flipped versus unflipped condition [p = 0.002]. CA3 c-Fos correlated inversely with flipped task performance and immature (DCX) neurons with primary and secondary but not tertiary dendrites or more mature (BrdU + NeuN) new neurons. CA3 c-Fos was a significant predictor for the flipped versus unflipped condition specifically for DCX versus BrdU-NeuN neurons. Conclusion: Immature new neurons (DCX+) without tertiary dendrites may be preferentially implicated in cognitive flexibility relative to more mature new neurons (BrdU-NeuN). In combination with decreased CA3 activation in the flipped PAT, the functional contribution of these immature DG neurons may involve the inhibition of postsynaptic CA3 neurons containing traces of previously salient conditioned memories.

Journal of Psychiatric Practice, Nov 1, 2000

The recognition that the brain continues to generate new neurons well into adulthood has made a m... more The recognition that the brain continues to generate new neurons well into adulthood has made a marked impact on the field of neuroscience in general and specifically on neurobiological models of the pathogenesis of major depression. Stress, neuroendocrine activation, neurotransmitter systems, and other factors can down-regulate the process of neurogenesis and may contribute to certain morphological changes seen in depression. Evidence is emerging that antidepressant treatments may mitigate these effects by stimulating neurogenesis in particular regions of the brain. This review introduces the reader to recent literature on neurogenesis as it relates to the understanding and treatment of depression.

Psychiatric Annals, Jun 1, 2014

$Research paper thumbnail of Patterns of anterior versus posterior white matter fractional anistotropy concordance in adult nonhuman primates: Effects of early life stress$

Journal of Affective Disorders, Mar 1, 2016

Introduction-Functional neuroimaging studies report global prefrontal dysconnectivity in mood dis... more Introduction-Functional neuroimaging studies report global prefrontal dysconnectivity in mood disorders, supporting the notion of widespread disruptions in brain networks. Microscopic alterations in white matter (WM) tracts-which possess neuroplastic properties and play a central role in brain connectivity-are interrogated herein in the context of brain dysconnectivity. Early life stress (ELS), an antecedent to human mood disorders, induces WM alterations in volumetrics

Brain Stimulation, May 1, 2016

Background: Prefrontal Transcranial Magnetic Stimulation (TMS) therapy repeated daily over 4-6 we... more Background: Prefrontal Transcranial Magnetic Stimulation (TMS) therapy repeated daily over 4-6 weeks (20-30 sessions) is US Food and Drug Administration (FDA) approved for treating Major Depressive Disorder in adults who have not responded to prior antidepressant medications. In 2011, leading TMS clinical providers and researchers created the Clinical TMS Society (cTMSs) (www.clinicaltmssociety.org, Greenwich, CT, USA), incorporated in 2013. Methods: This consensus review was written by cTMSs leaders, informed by membership polls, and approved by the governing board. It summarizes current evidence for the safety and efficacy of the use of TMS therapy for treating depression in routine clinical practice. Authors systematically reviewed the published TMS antidepressant therapy clinical trials. Studies were then assessed and graded on their strength of evidence using the Levels of Evidence framework published by the University of Oxford Centre for Evidence Based Medicine. The authors then summarize essentials for using TMS therapy in routine clinical practice settings derived from discussions and polls of cTMSs members. Finally, each summary clinical recommendation is presented with the substantiating peer-reviewed, published evidence supporting that recommendation. When the current published clinical trial evidence was insufficient or incomplete, expert opinion was included when sufficient consensus was available from experienced clinician users among the membership of the cTMSs, who were polled at the Annual Meetings in 2014 and 2015. Conclusions: Daily left prefrontal TMS has substantial evidence of efficacy and safety for treating the acute phase of depression in patients who are treatment resistant or intolerant. Following the clinical recommendations in this document should result in continued safe and effective use of this exciting new treatment modality.

Scientific Reports, Mar 25, 2019

There is increasing focus on use of resting-state functional connectivity (RSFC) analyses to subt... more There is increasing focus on use of resting-state functional connectivity (RSFC) analyses to subtype depression and to predict treatment response. To date, identification of RSFC patterns associated with response to electroconvulsive therapy (ECT) remain limited, and focused on interactions between dorsal prefrontal and regions of the limbic or default-mode networks. Deficits in visual processing are reported in depression, however, RSFC with or within the visual network have not been explored in recent models of depression. Here, we support prior studies showing in a sample of 18 patients with depression that connectivity between dorsal prefrontal and regions of the limbic and default-mode networks serves as a significant predictor. In addition, however, we demonstrate that including visual connectivity measures greatly increases predictive power of the RSFC algorithm (>80% accuracy of remission). These exploratory results encourage further investigation into visual dysfunction in depression, and use of RSFC algorithms incorporating the visual network in prediction of response to both ECT and transcranial magnetic stimulation (TMS), offering a new framework for the development of RSFC-guided TMS interventions in depression. Major depressive disorder (MDD) is a severe mental disorder that affects up to 20% of the population worldwide. Approximately 50% of individuals with MDD fail to respond adequately to anti-depressant medications. For individuals with treatment resistant depression (TRD) electroconvulsive therapy (ECT) is the most effective treatment. However, ECT requires general anesthesia and may be accompanied by adverse cognitive effects, reducing its tolerability. The response and remission rates for patients with depression without psychotic symptoms are 70% and 50%, respectively 1. As a result, a significant number of individuals may be exposed to the significant risks of ECT without tangible benefit. At present, there are no measures available that are capable of differentiating responders from non-responders, and thus from preventing unneeded treatments. Also, despite considerable research, neural mechanisms underlying ECT effectiveness remain largely unknown, inhibiting the search for safer or more effective alternatives. Prominent theories of both TRD and ECT response emphasize disruptions of resting state functional connectivity (RSFC) between large-scale brain networks in TRD that may be reversed with ECT treatment. To date, such studies have focused most prominently on interactions between regions of the fronto-parietal network especially dorsolateral prefrontal cortex (DLPFC; BA46, BA9 and BA8) and limbic regions such as subgenual anterior

The International Journal of Neuropsychopharmacology, Sep 1, 2000

Introduced 15 years ago, transcranial magnetic stimulation (TMS) is a non-invasive means of stimu... more Introduced 15 years ago, transcranial magnetic stimulation (TMS) is a non-invasive means of stimulating the cortex that has proved to be a unique tool for probing brain-behaviour relationships. While a therapeutic role for TMS in neuropsychiatry is uncertain, the utility of TMS in studying brain function has been demonstrated in diverse neuroscience applications. We review studies in animals on the mechanisms of action of TMS, and present a summary of the applications of TMS in basic neuroscience. TMS is still a relatively young technique, and unanswered questions remain regarding its acute and chronic impact on neural excitability and various aspects of brain function. Nonetheless, recent work with TMS has demonstrated its unique role in complementing other tools for studying brain function. As a brain intervention tool, TMS holds the promise of moving beyond correlative studies to help define the functional role of cortical regions in selected cognitive and affective processes.

Journal of Affective Disorders, 2021

INTRODUCTION Attenuated adult hippocampal neurogenesis may manifest in affective symptomatology a... more INTRODUCTION Attenuated adult hippocampal neurogenesis may manifest in affective symptomatology and/or resistance to antidepressant treatment. While early-life adversity and the short variant ('s') of the serotonin transporter gene's long polymorphic region (5-HTTLPR) are suggested as interacting risk factors for affective disorders, no studies have examined whether their superposed risk effectuates neurogenic changes into adulthood. Similarly, it is not established whether reduced hippocampal volume in adolescence, variously identified as a marker and antecedent of affective disorders, anticipates diminished adult neurogenesis. We investigate these potential developmental precursors of neurogenic alterations using a bonnet macaque model. METHODS Twenty-five male infant bonnet macaques were randomized to stressed [variable foraging demand (VFD)] or normative [low foraging demand (LFD)] rearing protocols and genotyped for 5-HTTLPR polymorphisms. Adolescent MRI brain scans (mean age 4.2y) were available for 14 subjects. Adult-born neurons were detected post-mortem (mean age 8.6y) via immunohistochemistry targeting the microtubule protein doublecortin (DCX). Models were adjusted for age and weight. RESULTS A putative vulnerability group (VG) of VFD-reared 's'-carriers (all 's/l') exhibited reduced neurogenesis compared to non-VG subjects. Neurogenesis levels were positively predicted by ipsilateral hippocampal volume normalized for total brain volume, but not by contralateral or raw hippocampal volume. LIMITATIONS No 's'-carriers were identified in LFD-reared subjects, precluding a 2×2 factorial analysis. CONCLUSION The 's' allele (with adverse rearing) and low adolescent hippocampal volume portend a neurogenic deficit in adult macaques, suggesting persistent alterations in hippocampal plasticity may contribute to these developmental factors' affective risk in humans.

Frontiers in Human Neuroscience, 2021

Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an inc... more Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a “no-RSP” condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynure...

Translational Psychiatry, 2020

Transcranial magnetic stimulation (TMS) is an approved intervention for treatment-resistant depre... more Transcranial magnetic stimulation (TMS) is an approved intervention for treatment-resistant depression (TRD), but current targeting approaches are only partially successful. Our objectives were (1) to examine the feasibility of MRI-guided TMS in the clinical setting using a recently published surface-based, multimodal parcellation in patients with TRD who failed standard TMS (sdTMS); (2) to examine the neurobiological mechanisms and clinical outcomes underlying MRI-guided TMS compared to that of sdTMS. We used parcel-guided TMS (pgTMS) to target the left dorsolateral prefrontal cortex parcel 46. Resting-state functional connectivity (rsfc) was assessed between parcel 46 and predefined nodes within the default mode and visual networks, following both pgTMS and sdTMS. All patients (n = 10) who had previously failed sdTMS responded to pgTMS. Alterations in rsfc between frontal, default mode, and visual networks differed significantly over time between groups. Improvements in symptoms c...

European Psychiatry, 2011

BackgroundIn this study we examine potential mechanisms by which the stimulation of hippocampal n... more BackgroundIn this study we examine potential mechanisms by which the stimulation of hippocampal neurogenesis may generate an antidepressant effect.MethodsStudy-1: Adult male rats (N = 24) were trained to segregate relevant from irrelevant spatial cues (spatial segregation); tested on this task four and 8-weeks late; then exposed (on week 8) to a modified version of the task that conflicted with the memory of the initially learned experience (mnemonic segregation); and then euthanized to detect hippocampal neurogenesis. Study-2: Adult rats (N = 24) were trained in the spatial segregation task; three-days later, half were re-tested on the same task and half the tested on the modified task (mnemonic segregation); and euthanized immediately to detect neurons that were synaptically active during task performance.ResultsStudy-1: Good performers on the modified task (mnemonic segregation) had significantly greater rates of hippocampal neurogenesis, but the increase was only in immature neu...

The Neuroscientist, Aug 1, 2008

The discovery of newborn neurons in the adult brain has generated enormous interest over the past... more The discovery of newborn neurons in the adult brain has generated enormous interest over the past decade. Although this process is well documented in the hippocampus and olfactory bulb, the possibility of neuron formation in other brain regions is under vigorous debate. Neurogenesis within the adult hippocampus is suppressed by factors that predispose to major depression and stimulated by antidepressant interventions. This pattern has generated the hypothesis that impaired neurogenesis is pathoetiological in depression and stimulation of newborn neurons essential for effective antidepressant action. This review critically evaluates the evidence in support of and in conflict with this theory. The literature is divided into three areas: neuronal maturation, factors that influence neurogenesis rates, and function of newborn neurons. Unique elements in each of these areas allow for the refinement of the hypothesis. Newborn hippocampal neurons appear to be necessary for detecting subtle environmental changes and coupling emotions to external context. Thus speculatively, stress-induced suppression of neurogenesis would uncouple emotions from external context leading to a negative mood state. Persistence of negative mood beyond the duration of the initial stressor can be defined as major depression. Antidepressant-induced neurogenesis therefore would restore coupling of mood with environment, leading to the resolution of depression. This conceptual framework is provisional and merits evaluation in further experimentation. Critically, manipulation of newborn hippocampal neurons may offer a portal of entry for more effective antidepressant treatment strategies.NEUROSCIENTIST 14(4):326–338, 2008. DOI: 10.1177/1073858408317242

Biological Psychiatry Global Open Science, 2021

ABSTRACT Background Early life stress is associated with alterations in telomere length, a marker... more ABSTRACT Background Early life stress is associated with alterations in telomere length, a marker of accumulated stress and aging, and a risk factor for psychiatric disorders. Nonhuman primate maternal variable foraging demand (VFD) is a validated early life stress model resulting in anxiety- and depressive-like symptoms in offspring. Previous studies reported increased plasma glucagon-like peptide-1 (pGLP-1) along with insulin resistance in this model. We investigated whether VFD-rearing related to adult telomere length and to these neuroendocrine markers. Methods Adult leukocyte telomere length was measured in VFD- (12 males, 13 females) and non-VFD-reared (9 males, 26 females) bonnet macaques. Associations between adult telomere length and adolescent fasting pGLP-1 or insulin resistance in VFD-reared versus non-VFD-reared groups were examined using regression modeling; controlling for sex, weight and age. Results: VFD subjects had relatively longer telomeres than non-VFD subjects (p=0.017), and females relatively longer than males (p=0.0004). Telomere length was positively associated with pGLP-1 (p=0.0009) and with reduced insulin sensitivity [p Conclusions Unexpectedly, VFD was associated with longer adult telomere length. Insulin resistance may lead to higher pGLP-1 levels in adolescence, which could protect telomere length in VFD offspring as adults. Associations between adult telomere length and adolescent insulin resistance and high pGLP-1 may reflect an adaptive, compensatory response after ELS exposure.

Neurobiology of Stress, 2017

Background: Early life stress (ELS) in macaques in the form of insecure maternal attachment putat... more Background: Early life stress (ELS) in macaques in the form of insecure maternal attachment putatively induces epigenetic adaptations resulting in a "thrifty phenotype" throughout the life cycle. For instance, ELS induces persistent increases in insulin resistance, hippocampal and corpus callosum atrophy and reduced "behavioral plasticity", which, taken together, engenders an increased risk for mood and anxiety disorders in humans but also a putative sparing of calories. Herein, we test the hypothesis whether a thrifty phenotype induced by ELS is peripherally evident as hypotrophy of cardiac structure and function, raising the possibility that certain mood disorders may represent maladaptive physiological and central thrift adaptations. Methods: 14 adult bonnet macaques (6 males) exposed to the maternal variable foraging demand (VFD) model of ELS were compared to 20 non-VFD adult subjects (6 males). Left ventricle end-diastolic dimension (LVEDD), Left ventricle end-systolic dimension (LVESD) and stroke volume (SV) were calculated using echocardiography. Blood pressure and heart rate were measured only in females. Previously obtained neurobehavioral correlates available only in males were analyzed in the context of cardiac parameters. Results: Reduced LVESD (p < 0.05) was observed when controlled for age, sex, body weight and crownrump length whereas ejection fraction (EF) (p ¼ 0.037) was greater in VFD-reared versus non-VFD subjects. Pulse pressure was lower in VFD versus non-VFD females (p < 0.05). Male timidity in response to a human intruder was associated with reduced LVEDD (p < 0.05). Conclusions: ELS is associated with both structural and functional reductions of left ventricular measures, potentially implying a body-wide thrifty phenotype. Parallel "thrift" adaptations may occur in key brain areas following ELS and may play an unexplored role in mood and anxiety disorder susceptibility.

Molecular vision, 2014

To determine whether short-term pressure elevation affects complement gene expression in the reti... more To determine whether short-term pressure elevation affects complement gene expression in the retina in vitro and in vivo. Muller cell (TR-MUL5) cultures and organotypic retinal cultures from adult mice and monkeys were subjected to either 24-h or 72-h of pressure at 0, 15, 30, and 45 mmHg above ambient. C57BL/6 mice were subjected to microbead-induced intraocular pressure (IOP) elevation for 7 days. RNA and protein were extracted and used for analysis of expression levels of complement component genes and complement component 1, q subcomponent (C1q) and complement factor H (CFH) immunoblotting. mRNA levels of complement genes and C1q protein levels in Muller cell cultures remained the same for all pressure levels after exposure for either 24 or 72 h. In primate and murine organotypic cultures, pressure elevation did not produce changes in complement gene expression or C1q and CFH protein levels at either the 24-h or 72-h time points. Pressure-related glial fibrillary acidic protein ...

Neural Plasticity, 2014

Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We r... more Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge-high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2004

Since electroconvulsive therapy (ECT) can result in generalized seizures that lack efficacy, phys... more Since electroconvulsive therapy (ECT) can result in generalized seizures that lack efficacy, physiological markers of treatment adequacy are needed. Specific electroencephalographic (EEG) features differentiate seizures produced with barely suprathreshold right unilateral (RUL) ECT, an ineffective treatment, from effective forms of ECT. This study determined whether EEG features are sensitive to treatment condition using a broad dosing range for RUL ECT, as well as predictive of clinical and cognitive outcomes. Quantitative EEG measures and observer ratings were compared in predictive power. From a larger study, 54 in-patients with major depression were randomized to low (1.5 x seizure threshold (ST)), moderate (2.5 x ST), or high-dose (6 x ST) RUL ECT, or high-dose (2.5 x ST) bilateral (BL) ECT. High dosage RUL and BL ECT were comparable in efficacy, and superior to low and moderate dosage RUL ECT. In the slow frequency bands (delta), BL ECT resulted in greater ictal power, ictal c...

Background / Purpose: Antidepressant treatments (electroconvulsive shock and fluoxetine) increase... more Background / Purpose: Antidepressant treatments (electroconvulsive shock and fluoxetine) increase dentate gyrus neurogenesis in nonhuman primates. Conversely, irradiation of the temporal lobe ablates neurogenesis and abolishes efficacy of fluoxetine in a nonhuman primate model of depression. Following early life stress (maternal variable foraging demand (VFD)), macaque neurogenesis is reduced but not ablated. We examined susceptibility for distressed behavior following temporal lobe irradiation in VFD-reared subjects versus controls. Main conclusion: Following early life stress, ablation of suppressed neurogenesis may interact with a vulnerable biological substrate to induce affective distress. Ablating healthy neurogenesis in normally-reared subjects produces limited effects because compensatory mechanisms putatively maintain behavioral homeostasis.