Tarique D. Perera

Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates

New neurons are generated in the adult hippocampus of many species including rodents, monkeys, and humans. Conditions associated with major depression, such as social stress, suppress hippocampal neurogenesis in rodents and primates. In contrast, all classes of antidepressants stimulate neuronal generation, and the behavioral effects of these medications are abolished when neurogenesis is blocked. These findings generated the hypothesis that induction of neurogenesis is a necessary component in the mechanism of action of antidepressant treatments. To date, the effects of antidepressants on newborn neurons have been reported only in rodents and tree shrews. This study examines whether neurogenesis is increased in nonhuman primates after antidepressant treatment. Adult monkeys received repeated electroconvulsive shock (ECS), which is the animal analog of electroconvulsive therapy (ECT), the most effective short-term antidepressant. Compared with control conditions, ECS robustly increased precursor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus in the monkey hippocampus. A majority of these precursors differentiated into neurons or endothelial cells, while a few matured into glial cells. The ECS-mediated induction of cell proliferation and neurogenesis was accompanied by increased immunoreactivity for the neuroprotective gene product BCL2 (B cell chronic lymphocytic lymphoma 2) in the SGZ. The ECS interventions were not accompanied by increased hippocampal cell death or injury. This study demonstrates that ECS is capable of inducing neurogenesis in the nonhuman primate hippocampus and supports the possibility that antidepressant interventions produce similar alterations in the human brain.

Effects of Pulse Width and Electrode Placement on the Efficacy and Cognitive Effects of Electroconvulsive Therapy

BACKGROUND While electroconvulsive therapy (ECT) in major depression is effective, cognitive effects limit its use. Reducing the width of the electrical pulse and using the right unilateral electrode placement may decrease adverse cognitive effects, while preserving efficacy. METHODS In a double-masked study, we randomly assigned 90 depressed patients to right unilateral ECT at 6 times seizure threshold or bilateral ECT at 2.5 times seizure threshold, using either a traditional brief pulse (1.5 ms) or an ultrabrief pulse (0.3 ms). Depressive symptoms and cognition were assessed before, during, and immediately, two, and six months after therapy. Patients who responded were followed for a one-year period. RESULTS The final remission rate for ultrabrief bilateral ECT was 35 percent, compared with 73 percent for ultrabrief unilateral ECT, 65 percent for standard pulse width bilateral ECT, and 59 percent for standard pulse width unilateral ECT (all Ps<0.05 after covariate adjustment). The ultrabrief right unilateral group had less severe cognitive side effects than the other 3 groups in virtually all primary outcome measures assessed in the acute postictal period, and during and immediately following therapy. Both the ultrabrief stimulus and right unilateral electrode placement produced less short- and long-term retrograde amnesia. Patients rated their memory deficits as less severe following ultrabrief right unilateral ECT compared to each of the other three conditions (P<0.001). CONCLUSIONS The use of an ultrabrief stimulus markedly reduces adverse cognitive effects, and when coupled with markedly suprathreshold right unilateral ECT, also preserves efficacy. (ClinicalTrials.gov number, NCT00487500.).

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Background Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. Materials/Methodology Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels. Results Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation. Conclusion We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

Cognitive Role of Neurogenesis in Depression and Antidepressant Treatment

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

Seizure expression during electroconvulsive therapy: relationships with clinical outcome and cognitive side effects.

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 × seizure threshold (ST)), moderate (2.5 × ST), or high-dose (6 × ST) RUL ECT, or high-dose (2.5 × 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 (δ), BL ECT resulted in greater ictal power, ictal coherence, and postictal suppression than each RUL ECT condition, but the EEG measures failed to discriminate the RUL ECT groups. EEG measures were modestly associated with clinical outcome, with greater ictal power, δ coherence, and postictal suppression positive predictors. None of the EEG measures were associated with cognitive outcomes. Inability to distinguish forms of RUL ECT differing markedly in dosage and efficacy suggests that EEG measures have limited potential as markers of treatment adequacy. Rather than assaying treatment adequacy, the EEG features associated with efficacy may reflect individual differences in the strength of inhibitory processes that terminate the seizure, and can help isolate the biological variability that predisposes to positive or negative clinical response to ECT.

A magnetic resonance spectroscopic imaging study of adult nonhuman primates exposed to early-life stressors

BACKGROUND Long-term behavioral, immunologic, and neurochemical alterations have been found in primates exposed to adverse early rearing. METHODS Bonnet macaque (Macaca radiata) mother-infant dyads were exposed to uncertain requirements for food procurement (variable foraging demand, VFD) for a few months. Ten years later, these offspring and age- and gender-matched control subjects were studied using proton magnetic resonance spectroscopic imaging (MRSI). RESULTS In anterior cingulate, VFD-reared subjects displayed significantly decreased N-acetylaspartate (NAA) resonance and significantly increased glutamate-glutamine-gamma-aminobutyric acid (Glx) resonance relative to the stable neurometabolite creatine (Cr). Across all subjects, NAA/Cr and Glx/Cr ratios in the anterior cingulate were negatively correlated (r = -.638, p =.014). In the medial temporal lobe, the ratio of choline-containing compounds to Cr was significantly increased in VFD subjects. CONCLUSIONS These findings indicate that adverse early rearing in primates has an enduring impact on adult MRSI measures considered reflective of neuronal integrity and metabolism, membrane structure and glial function, and cerebral glutamate content, and that these alterations occur in the same brain regions implicated in trauma-related psychiatric disorders.

Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates

Male bonnet monkeys (Macaca radiata) were subjected to the variable foraging demand (VFD) early stress paradigm as infants, MRI scans were completed an average of 4 years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of interest (ROI) hippocampus and whole brain voxel-based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. The animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.

Transcranial magnetic stimulation: applications in basic neuroscience and neuropsychopharmacology

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.

Correlations between Hippocampal Neurogenesis and Metabolic Indices in Adult Nonhuman Primates

Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010), but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX), and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2), but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein). This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.

The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder

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.