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Abstract: Acute SSRIs increase conditioned fear expression
posted Friday, 25 May 2007
Biol Psychiatry. 2007;doi:10.1016/j.biopsych.2006.11.023
Acute Selective Serotonin Reuptake Inhibitors Increase Conditioned Fear Expression: Blockade With a 5-HT2C Receptor Antagonist
Burghardt NS, Bush DEA, McEwen BS, LeDoux JE.
W.M. Keck Foundation Laboratory of Neurobiology Center for Neural Science, New York University, New York, Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology Rockefeller University, New York, New York
Background: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear.
Methods: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory.
Results: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT3 receptor antagonist, but was blocked by SB 242084, a specific 5-HT2C receptor antagonist.
Conclusions: Enhanced activation of 5-HT2C receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.
(Text has been reformatted for clarity; ed.)
Comment:
There is a common conception that serotonin has some intrinsic 'feel good' quality. However, there is considerable evidence suggesting it has the opposite affect.
Serotonergic antidepressants increase serotonin levels both in synapses and the brain overall within an hour of the first dose, and levels may remain higher for some weeks. But they drop back to baseline or well below at about the time patients begin to feel an improvement in anxiety or depression.1 And, as the authors of this study found (some for the second time2), there is no initial increased anxiety with the French antidepressant tianeptine (Stablon®), a serotonin uptake enhancer. This suggests that tianeptine does directly what SSRIs do indirectly — reduce brain serotonin levels/synthesis — and that it is this reduction in serotonin that produces the therapeutic response. The fact that it begins working earlier than serotonin reuptake inhibiting antidepressants supports this hypothesis, though this is not the only possible explanation.
Additional support for the hypothesis comes from genetic rat models of depression. Rats with a high genetic predisposition for depression have up to 8 times more serotonin in their nucleus accumbens, prefrontal cortex, hippocampus, and hypothalamus than controls (there was no increase in other brain areas associated with anxiety & depression).3 Chronic antidepressant treatment reduces the high serotonin levels to values found in the controls.
References: (Note 5-HT = serotonin)
There is a common conception that serotonin has some intrinsic 'feel good' quality. However, there is considerable evidence suggesting it has the opposite affect.
Serotonergic antidepressants increase serotonin levels both in synapses and the brain overall within an hour of the first dose, and levels may remain higher for some weeks. But they drop back to baseline or well below at about the time patients begin to feel an improvement in anxiety or depression.1 And, as the authors of this study found (some for the second time2), there is no initial increased anxiety with the French antidepressant tianeptine (Stablon®), a serotonin uptake enhancer. This suggests that tianeptine does directly what SSRIs do indirectly — reduce brain serotonin levels/synthesis — and that it is this reduction in serotonin that produces the therapeutic response. The fact that it begins working earlier than serotonin reuptake inhibiting antidepressants supports this hypothesis, though this is not the only possible explanation.
Additional support for the hypothesis comes from genetic rat models of depression. Rats with a high genetic predisposition for depression have up to 8 times more serotonin in their nucleus accumbens, prefrontal cortex, hippocampus, and hypothalamus than controls (there was no increase in other brain areas associated with anxiety & depression).3 Chronic antidepressant treatment reduces the high serotonin levels to values found in the controls.
References: (Note 5-HT = serotonin)
- Bianchi M, Moser C, Lazzarini C, Vecchiato E, Crespi F. (2002)
Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes.
Exp Brain Res. 2002 Mar;143(2):191-7. [Abstract]
Stenfors C, Yu H, Ross SB. (2001)
Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram.
Naunyn Schmiedebergs Arch Pharmacol, vol 363(2):p 222-32 [Abstract]
Alvarez JC, Sanceaume M, Advenier C, et al. (1999)
Differential changes in brain and platelet 5-HT concentrations after steady-state achievement and repeated administration of antidepressant drugs in mice.
Eur Neuropsychopharmacol, vol 10(1):p 31-6 [Abstract]
Moret C, Briley M.
Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis.
J Neural Transm. 1997;104(2-3):147-60. [Abstract]
Trouvin JH, Gardier AM, Chanut E, et al. (1993)
Time course of brain serotonin metabolism after cessation of long-term fluoxetine treatment in the rat.
Life Sci, vol 52(18):p PL187-92 [Abstract]
Caccia S, Anelli M, Codegoni AM, Fracasso C, Garattini S. (1993)
The effects of single and repeated anorectic doses of 5-hydroxytryptamine uptake inhibitors on indole levels in rat brain.
Br J Pharmacol. 1993 Sep;110(1):355-9. [Abstract]
Caccia S, Fracasso C, Garattini S, Guiso G, Sarati S. (1992)
Effects of short- and long-term administration of fluoxetine on the monoamine content of rat brain.
Neuropharmacology. 1992 Apr;31(4):343-7. [Abstract]
Leonard BE. (1988)
Pharmacological effects of serotonin reuptake inhibitors.
J Clin Psychiatry. 1988 Aug;49 Suppl:12-7. [Abstract] - Burghardt NS, Sullivan GM, McEwen BS, et al. (2004)
The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine.
Biol Psychiatry. 2004 Jun 15;55(12):1171-8. [Abstract] - Zangen A, Overstreet DH, Yadid G. (1997)
High serotonin and 5-hydroxyindoleacetic acid levels in limbic brain regions in a rat model of depression: normalization by chronic antidepressant treatment.
J Neurochem, vol 69(6):p 2477-83 [Abstract]
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Action-potential
Wave of electrochemical activity generated by the flow of positively charged ions across the neuronal membrane which causes a neuron to 'fire'- Click page link for more information -
Affective disorders
Mental disorders characterized by dramatic changes or extremes of mood - depression, mania, or both - including depression, bipolar disorder (manic depression), and schizo affective disorders.- Click page link for more information -
Alleles
An alternative form of a gene (one member of a pair) that is located at a specific position on a specific chromosome.- Click page link for more information -
Amygdalae
Two almond-shaped groups of neurons - there is one amygdala (Greek for almond) in each brain hemisphere. They have the primary role in processing and storing memories of emotional reactions.Part of the Limbic System the amygdalae trigger an instant fear reaction to perceived threats, real or imagined.
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Anterior cingulate cortex
Involved in empathy, emotions, cognitive control (attention, conflict monitoring during information processing) and plays a role in stimulus reinforcement learning and reward-guided selection of actions.Also controls autonomic functions such as heart rate and blood pressure in the context of current behavior.
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Autonomic arousal
Arousal of the autonomic nervous system which regulates many bodily functions and produces the physical symptoms of stress including the 'fight-or-flight' response.Brain-derived neurotrophic factor
Protein required for the growth and survival of nerve cells during development, and for maintenance of adult nerve cells. Studies have shown that some neurotrophic factors can trigger regrowth of damaged nerve cells and stimulate growth and differentiation of new neurons in the hippocampus (neurogenesis).- Click page link for more information -
Client-centered therapy
An approach to counseling and psychotherapy that places much of the responsibility for the treatment process on the client, with the therapist taking a non-directive role. Also called non-directive, person-centered, or Rogerian therapy.- Click page link for more information -
Cognitive-behavior therapy (CBT)
Type of psychotherapy emphasizing the important role of thinking in how we feel and what we do.Based on the concept that our thoughts cause our feelings and behaviors, not external things like people, situations, and events. The benefit of this fact is that we can change the way we think to feel/act better even if the situation does not change.
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Clinical trial-Phase 1
The first test in humans of a new treatment to see if it is safe to use in people.- Click page link for more information -
Compassion meditation
Based on Tibetan Buddhism techniques. Trains the mind to optimize the way it perceives relationships with others. Experienced practitioners are able to alter brain functioning to boost positive emotions, and enhance their immune systems.Related to Mindfulness Meditation/Psychotherapy.
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Corticotropin-releasing factor
A polypeptide hormone and neuro- transmitter involved in the stress response.CRF hyper secretion is believed to contribute to hyperactivity of the hypothalamic-pituitary-adrenal axis in depressed patients. Hyper secretion has also been implicated in anxiety.
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Cortisol
The most potent of the stress hormones. Synthesized from cholesterol by the adrenal glands. Increases blood pressure, blood sugar levels and suppresses immune function.- Click page link for more information -
Cross sectional study
Epidemiological studies describing population characteristics which collect data at one point in time and then consider relationships between observed characteristics.. Because they don't look at time trends they cannot establish causes.
Cytochrome P450
Family of enzymes involved in the metabolic process. P450 liver enzymes metabolize most prescribed pharmaceutical and alternative medications.- Click page link for more information -
Cytokines
A diverse group of signaling (messenger) molecules that mediate both the innate and adaptive immune response by regulating immunity, inflammation, and hematopoiesis (blood cell development).Cytokines include the Interleukins, Interferons, Tumor Necrosis Factor Alpha and Transforming Growth Factor beta.
Cytokines are increasingly being used to treat cancers and viral infection, however, depression onset is a common side effect.
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Dentate gyrus
Part of the hippocampus. Thought to contribute to formation of new memories and is one of the few brain regions where neurogenesis occurs. Has a role in recognizing the differences that make each place unique. Processing errors may play a role in deja vu.- Click page link for more information -
Depression - Atypical
Defined by the ability to feel better temporarily in response to positive life events, plus any two of the following criteria: excessive sleep, overeating, a feeling of heaviness in the limbs and a sensitivity to rejection. Despite the name, it is actually the most common form of depression.- Click page link for more information -
Depression - Clinical/Major
Characterized by a pervasive, unremitting low mood and loss of interest or pleasure in usual activities. In addition there are other physical and mental symptoms that may include fatigue, difficulty with concentration and memory, feelings of hopelessness and helplessness, headaches, body aches, and thoughts of suicide.- Click page link for more information -
Dysthymia
Mood disorder within the depression spectrum. Considered a chronic depression, but less severe than major depression.- Click page link for more information -
Emotion focussed therapy
A short term (8-20 session) psychotherapy based on helping the patient express emotions more easily and thus release unprocessed feelings and thoughts so that they may be dealt with openly.- Click page link for more information -
Epigenetic inheritance
Process by which environmental factors like diet, stress, and ante/post-natal maternal factors can change gene function without altering the DNA sequence. These changes may remain through cell divisions and may also be passed down through multiple generations.- Click page link for more information -
Fear extinction
Suppression of the expression of previously learned fear by repeated exposure to the object of fear without negative consequences. Also called 'inhibitory learning'- Click page link for more information (
) -First-degree relative
A parent, sibling or child of an individual.Gamma-Aminobutyric Acid (GABA)
The major inhibitory neurotransmitter of the central nervous system. Dampens brain activity and promotes a state of calm.An amino acid produced in the brain as a by-product of the Krebs glucose metabolism cycle which powers brain cells.
Note 1: Benzodiazepines (Valium® etc) do not increase brain GABA levels, but increase the sensitivity of GABA receptors.
Note 2: GABA does not normally penetrate the Brain-Blood-Barrier (the BBB tends to pull GABA from the brain into the blood stream (Kakee A, 2001)) so GABA supplements are, at best, expensive placebos.
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Glial Cells
Support cells in the brain and spinal cord which provide physical and nutritional support for neurons, form the blood-brain barrier, clear dead cells and other debris, insulate neurons and, as part of the immune system, protect the brain from microorganisms.Long thought not to conduct electrical impulses as the neurons do, there is growing evidence that they do modulate neurotransmission.
The largest group of cells of the central nervous system being between 50-100 times more abundant than neurons.
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Haplotype
A group of alleles of different genes on a single chromosome that are so closely linked that they are usually inherited as a unit.- Click page link for more information -
Heterozygote, Homozygote
Heterozygote: Any organism which has two differing forms of a particular gene for a specific trait, one inherited from each parent.Homozygote: Any organism which has two identical forms of a particular gene for a specific trait, one inherited from each parent.
Because genes are either dominant or recessive, the genetic makeup (genotype) of an organism cannot always be determined by physical appearance alone.
Hippocampus
A seahorse shaped sheet of neurons laying next to the Amygdalae. Regulates emotions and short term memory.- Click page link for more information -
Homologous
Anatomical structures that perform the same function in different biological species having evolved from the same structure in a shared ancestor species.Hypothalamus
Regulates homeostasis, the maintenance of the body's status quo by producing hormones which control: Body temperature, Hunger, Moods, Sex drive, Sleep and Thirst.- Click page link for more information -
Hypothalamic-pituitary-adrenal axis
A major part of the neuroendocrine system, comprising of the hypothalamus, pituitary gland and the adrenal glands, which controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure.- Click page link for more information -
Interleukins - (IL-1 - IL-35)
Signaling molecules critical to the functioning of the immune system.A recombinant form of IL-2 has been approved as an anti cancer drug and and may have anti viral properties. Changes in mental states including irritability, confusion, or depression are a known side-effect.
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Interpersonal psychotherapy
Time-limited psychotherapy focusing on the interpersonal context and building interpersonal skills. Based on the belief that interpersonal factors may contribute heavily to psychological problems. Distinguished from other forms of therapy in its emphasis on the interpersonal rather than the intra psychic.- Click page link for more information -
in vitro - in vivo
in vitro (Latin: within the glass) Experiments conducted with parts of an organism (often only a few cells) in a test-tube, petri dish, etc.in vivo (Latin: within the living) Experiments conducted with more or less whole organisms.
Ion channel (ionopore)
Pore-forming proteins in cell walls which allow the movement of electrically charged ions across cell membranes that produce the electrical gradients responsible for nerve impulses.- Click page link for more information -
Learned helplessness
A psychological state in which people gradually come to feel that they have no control over repeated adverse events and that failure is inevitable so become less willing to attempt tasks. A coping mechanism for surviving difficult or abusive circumstances. It offers a model to explain human depression, in which apathy and submission prevail.- Click page link for more information -
Limbic system
Brain structure of the 'old' mammalian brain comprising the hippocampus, amygdalae, anterior thalamic nuclei, and the diencephalon in the forebrain. Regulates memory, and the emotions including fear, anger, and of sexual behavior.- Click page link for more information -
Ligand
A molecule that is able to bind to and form a complex with a biomolecule to serve a biological purpose. Neurotransmitters are one type of ligand.Longitudinal study
Research which studies a group of people over a period of time.Lyme disease
Caused by spirochaete bacteria of the genus Borrelia which are found worldwide. It is called 'Chronic lymphocytic meningitis', 'Neuroborreliosis', 'Garin-Bujadoux syndrome' and 'Bannwarth's syndrome' in Europe.In addition to symptoms typical of infectious disease - fever, chills, headache, rash etc, Lyme can also produce 'classic' anxiety symptoms including tingling or numbness of the extremities, disorientation, mental 'fog,' short term memory loss, fatigue, poor concentration and sleep disturbance, and may trigger depression. In some cases, these symptoms may not become apparent for many years after the initial infection.
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Meta-analysis
Mathematical technique to amalgamating, summarizing, and reviewing previous quantitative research to arrive at one overall measure of treatment effect.A weakness of the method is that sources of bias in the original research are not controlled by the method. A good meta-analysis of badly designed studies will still result in bad statistics.
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Mindfulness
"Mindfulness is not a quick fix. The mindful approach encourages the person suffering from anxiety to move in close to their uncomfortable feelings, to watch the feelings of panic and racing heart, trembling hands, etc., with curiosity, openness and acceptance because, in fact, they are already there. This is a practice. We begin to become more tolerant of so-called negative states of mind, and then comfortable with them, then aware that everything changes constantly, including these states of mind. We begin to see anxiety for what it is: our body's adaptation to stress or to a thought and its subsequent attempt at communicating it to us."Barbara Wilkinson,
certified trauma therapist
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Mindfulness meditation/ psychotherapy
Mindfulness is the practice of becoming more aware of the present moment, rather than dwelling in the past or projecting into the future. It generally involves a heightened awareness of sensory stimuli (really noticing your breathing, feeling the sensations of your body, etc); and being 'in the now'. Principles may be combined with the concepts of Cognitive-Behavior Therapy (CBT) as Mindfulness-based Psychotherapy.- Click page link for more information -
Narrative Exposure Therapy
Therapy developed to treat PTSD. Based on cognitive behavioral exposure therapy, it adapts classical exposure therapy to meet needs of traumatized survivors of war and torture.Survivors are asked to describe what happened to them in great detail, focusing on what they saw, heard, smelt, etc, and their feelings and thoughts at the time. Initially, sessions are distressing, but as they are long enough to allow habituation, distress levels diminish towards the end and more and more details are recalled.
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Neurogenesis
Process by which new neurons are generated after the postnatal stage of development. It appears to only occur in two areas of the brain, the hippocampus and the olfactory bulbs. Hippocampal neurogenesis is thought to counter anxiety and depression.- Click page link for more information -
Neuropeptide
One of about 100 peptides including endorphins, enkephalins, oxytocin and vasopressin which mediate brain function by regulating gene expression, local blood flow and synaptogenesis. The neuropeptides Cholecystokinin, Substance P and Neuropeptide Y have been linked to anxiety and depressive disorders.- Click page link for more information -
Neuroplastic
The brain's ability to reorganize itself by forming new neural connections.- Click page link for more information -
Nucleus accumbens
Twin brain structures (one in each hemisphere) involved in reward, laughter, pleasure, addiction, fear, and the placebo effect.- Click page link for more information -
Polymorphism
Natural variations in a gene, DNA sequence, protein, or chromosome.-Click page link for more information-
Prefrontal Cortex
Area of the brain's frontal lobes involved in planning complex cognitive behaviors, the expression of personality and social behavior.- Click page link for more information -
Prospective study
Tests a specific question, usually about how a specific exposure(s) affects a specific outcome(s) by recruiting appropriate participants and checks the outcomes over the following months or years.Psychodynamic psychotherapy
Talking therapy used to help a person find relief from emotional pain. It is based on the theories and techniques of Freudian/Jung style psychoanalysis. However, practitioners don't necessarily accept the 'classical' psychoanalysis theory that emotional conflicts are primarily sexual in nature.Receptor
Short-lived protein molecules embedded in the cell wall of neurons, especially of their synapses, to which neurotransmitters attach to initiate an action. Also called ´binding sites´- Click page link for more information -
Receptor agonist
A chemical which is able to bind to receptors of a neurotransmitter and trigger the same biological response as that neurotransmitter.Receptor antagonist
A drug that is so similar chemically to a neurotransmitter that it is capable of binding to a receptor for the neurotransmitter but which does not trigger the biological response of that neurotransmitter. By blocking its receptors the antagonist disrupts or inhibits the action of the neurotransmitter.Retrospective study
Research using data on exposures and/or outcomes that have already been collected through medical records or as part of another study. Such data may not be as reliable as data collected prospectively, as it relies on the accuracy of records made at the time, and on people’s recall of past events, which can be inaccurate (referred to as recall bias).Safety behavior
Behavior undertaken to reduce anxious thoughts, or to keep yourself 'safe' from imagined threats, or to hide your anxious state from others. Examples include constant monitoring of breathing or heart rate, shopping during quiet retail hours, taking precautionary tranquillizers "just in case," taking circuitous routes to avoid highways or bridges when driving, sitting close to exits, avoiding eye contact, playing with keys to hide trembling hands.Seasonal affective disorder
A type of depression triggered by the seasons. The most common type is winter-onset depression (aka Winter blues), but some also regularly become depressed at the start of spring-summer.- Click page link for more information -
Serotonin syndrome
A potentially life-threatening adverse reaction triggered by excess serotonergic activity in the central nervous system.- Click page link for more information -
Serotonin transporter
A protein that transports the neurotransmitter serotonin across cell membranes.- Click page link for more information -
Significant life events
Major stressors such as: death of relative (incl. miscarriage), friend, or pet; serious illness or injury, surviving a disaster; marriage, separation, divorce, relationship breakup; birth or adoption of a child; moving house or school; new job or promotion, unemployment or retirement;Somatization disorder
Manifests as chronic, persistent complaints of varied physical symptoms that have no identifiable organic origin or basis. Often co morbid with other psychological disorders, particularly anxiety or mood disorders, plus irritable bowel syndrome and chronic pain. Occurs in 0.2% to 2% of females and 0.2% of males. Also known as Briquet's disorder.Sympathetic nervous system
The part of the nervous system which controls the body’s internal, involuntary processes including breathing, digestion, blood vessel tone, heart rate, etc. It also mediates the fight-or-flight response.Subgenual cingulate
Brain region high in serotonin transporter-binding sites, with strong projections to the hypothalamus and brain stem. Modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. May be critical for modulating widespread behavioral changes mediated by the cortex. Volume is often decreased in mood disorders patients.Also known as Brodmann area 25.
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Synapses
Gaps between neurons through which "information" flows from one neuron (brain cell) to another.- Click page link for more information -
Thalamus
Regulates sleep and awake states, arousal and awareness. Processes and relays sensory information to the cerebral cortex where they are experienced as sensations of pain, touch, or temperature. Damage to the thalamus can produce permanent coma.- Click page link for more information -
Tumor necrosis factor-α
A cytokine which has wide range of pro inflammatory actions and induce necrosis (death) of tumor cells. Exacerbates chronic inflammatory autoimmune diseases such as rheumatoid arthritis.Blood plasma levels are raised in patients with depression. Research had shown that antidepressants reduce its expression.
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White matter
Regions of the brain and spinal cord largely composed of nerve fibers (axons) sheathed in insulating myelin composed of lipids (fats) which give them their color.White matter abnormalities (hyperintensities):
Damage to the myelin insulation. May be inherited, the result of disease (Multiple Sclerosis) or physical injury, stroke etc. Most brains accumulate some WM abnormalities with age.
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